FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Grady, CD Dehlendorf, C Cohen, ED Schwarz, EB Borrero, S AF Grady, Cynthia D. Dehlendorf, Christine Cohen, Elan D. Schwarz, E. Bimla Borrero, Sonya TI Racial and ethnic differences in contraceptive use among women who desire no future children, 2006-2010 National Survey of Family Growth SO CONTRACEPTION LA English DT Article DE Contraception; Disparities; Race/ethnicity; Unwanted pregnancy ID UNITED-STATES; UNINTENDED PREGNANCY; INTENTION; DISPARITIES; PATTERNS; BIRTHS; NONUSE; RISK AB Objective: To evaluate racial/ethnic differences in contraceptive use among women who do not desire future pregnancy. Study Design: We used the 2006-2010 National Survey of Family Growth to examine the associations between race/ethnicity and 1) use of any contraceptive method at last heterosexual intercourse and 2) effectiveness of contraceptive method used among women who stated that they did not desire any (more) children. We conducted multivariable logistic regression to assess the independent effect of race/ethnicity on these outcomes, adjusting for socio-demographic factors, reproductive characteristics, and indicators of healthcare access and utilization. Results: The study sample consisted of 2900 women, aged 15-44 years. The vast majority of women (91.2%) used contraception at last sex, although this varied significantly by race/ethnicity (p<.01). In the fully adjusted model controlling for demographic and reproductive characteristics as well as healthcare access, compared to whites, black women were significantly less likely to use any contraception at last sex (OR: 0.43; 95% CI: 0.27-0.73), while there was no significant difference for Hispanic women (OR: 0.95; 95% CI: 0.52-1.72). Among women who used a method at last sex, the type of contraceptive method varied significantly by race/ethnicity in bivariate analysis (p<.01), although most women (59%) used a highly effective method. In the fully adjusted model, racial/ethnic differences were no longer significant. Conclusions: In this nationally representative cohort of women who report that they do not desire (more) children, black women were significantly less likely than white women to use any contraception at last intercourse; this difference did not appear to be due to differential access to health care. Published by Elsevier Inc. C1 [Grady, Cynthia D.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Dehlendorf, Christine] Univ Calif San Francisco, Dept Family & Community Med, San Francisco, CA 94110 USA. [Dehlendorf, Christine] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94110 USA. [Dehlendorf, Christine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94110 USA. [Cohen, Elan D.] Univ Pittsburgh, Hlth Care Data Ctr, Res Ctr, Pittsburgh, PA 15213 USA. [Schwarz, E. Bimla] Univ Calif Davis, Sch Med, Div Gen Internal Med, Sacramento, CA 95817 USA. [Borrero, Sonya] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Borrero, Sonya] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. RP Borrero, S (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM borrerosp@upmc.edu FU Eunice Kennedy Shriver National Institute of Child Health & Human Development [1R21HD068736-01A1, K23HD067197]; University of Pittsburgh Clinical Scientist Training Program, (CSTP) [UL1 TL1TR000005] FX This work was supported by Grant Numbers 1R21HD068736-01A1 (S.B.) and K23HD067197 (C.D.) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development and from the University of Pittsburgh Clinical Scientist Training Program, (CSTP) UL1 TL1TR000005 (C.G.). NR 45 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD JUL PY 2015 VL 92 IS 1 BP 62 EP 70 DI 10.1016/j.contraception.2015.03.017 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CL5IG UT WOS:000356992400010 PM 25863228 ER PT J AU Boynton, GE Raoof, D Niziol, LM Hussain, M Mian, SI AF Boynton, Grace E. Raoof, Duna Niziol, Leslie M. Hussain, Munira Mian, Shahzad I. TI Prospective Randomized Trial Comparing Efficacy of Topical Loteprednol Etabonate 0.5% Versus Cyclosporine-A 0.05% for Treatment of Dry Eye Syndrome Following Hematopoietic Stem Cell Transplantation SO CORNEA LA English DT Article DE hematopoietic stem cell transplantation; graft versus host disease; cyclosporine; loteprednol; dry eye ID VERSUS-HOST-DISEASE; PLACEBO-CONTROLLED EVALUATION; BONE-MARROW-TRANSPLANTATION; KERATOCONJUNCTIVITIS SICCA; OCULAR MANIFESTATIONS; CONJUNCTIVITIS; GVHD AB Purpose:To evaluate the safety and efficacy of topical loteprednol etabonate (LE) 0.5% compared with cyclosporine A (CsA) 0.05% for the prophylaxis and treatment of dry eye syndrome (DES) after hematopoietic stem cell transplantation (HSCT).Methods:Seventy-five patients were randomized to LE (n = 76 eyes of 38 patients) or CsA (n = 74 eyes of 37 patients) pre-HSCT. Lissamine green and fluorescein staining, tear break-up time, tear osmolarity (Osm), Schirmer score (Sch), intraocular pressure, visual acuity, and Ocular Surface Disease Index were assessed pre-HSCT, 3, 6, 9, and 12 months post-HSCT.Results:There were no differences in DES incidence (P = 0.22; log-rank test) or progression (P = 0.41; log-rank test) between the 2 treatment arms during the course of the study. Among eyes with no DES at enrollment, the Kaplan-Meier analysis yielded a 90% rate of DES development in cyclosporine-treated eyes and a 79% rate of DES development in LE-treated eyes by 12 months post-HSCT. The Kaplan-Meier analysis of eyes with DES at enrollment demonstrated a 38% rate of disease progression among cyclosporine-treated eyes and a 26% rate of disease progression among loteprednol-treated eyes by 12 months. No patient in either group had an elevation of 10 mm Hg or greater from baseline at any study visit, and no patients had their treatment discontinued for elevation in intraocular pressure.Conclusions:Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT. C1 [Boynton, Grace E.; Raoof, Duna; Niziol, Leslie M.; Hussain, Munira; Mian, Shahzad I.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Raoof, Duna] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Mian, SI (reprint author), Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. EM smian@umich.edu NR 29 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2015 VL 34 IS 7 BP 725 EP 732 DI 10.1097/ICO.0000000000000436 PG 8 WC Ophthalmology SC Ophthalmology GA CL0AO UT WOS:000356601000001 PM 25850708 ER PT J AU Bagwell, CB Hunsberger, BC Herbert, DJ Munson, ME Hill, BL Bray, CM Preffer, FI AF Bagwell, C. Bruce Hunsberger, Benjamin C. Herbert, Donald J. Munson, Mark E. Hill, Beth L. Bray, Chris M. Preffer, Frederic I. TI Probability state modeling theory SO CYTOMETRY PART A LA English DT Article DE high-dimensional modeling; broadened quantile function modeling; cytometry; polychromatic; high-dimensional visualization ID DIMENSIONAL CYTOMETRY DATA; FLOW-CYTOMETRY; VISUALIZATION; CELLS AB As the technology of cytometry matures, there is mounting pressure to address two major issues with data analyses. The first issue is to develop new analysis methods for high-dimensional data that can directly reveal and quantify important characteristics associated with complex cellular biology. The other issue is to replace subjective and inaccurate gating with automated methods that objectively define subpopulations and account for population overlap due to measurement uncertainty. Probability state modeling (PSM) is a technique that addresses both of these issues. The theory and important algorithms associated with PSM are presented along with simple examples and general strategies for autonomous analyses. PSM is leveraged to better understand B-cell ontogeny in bone marrow in a companion Cytometry Part B manuscript. Three short relevant videos are available in the online supporting information for both of these papers. PSM avoids the dimensionality barrier normally associated with high-dimensionality modeling by using broadened quantile functions instead of frequency functions to represent the modulation of cellular epitopes as cells differentiate. Since modeling programs ultimately minimize or maximize one or more objective functions, they are particularly amenable to automation and, therefore, represent a viable alternative to subjective and inaccurate gating approaches. (c) 2015 International Society for Advancement of Cytometry C1 [Bagwell, C. Bruce; Hunsberger, Benjamin C.; Herbert, Donald J.; Munson, Mark E.; Hill, Beth L.; Bray, Chris M.] Ver Software House, Topsham, ME 04086 USA. [Preffer, Frederic I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Bagwell, CB (reprint author), Ver Software House, POB 247, Topsham, ME 04086 USA. EM cbb@vsh.com NR 30 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD JUL PY 2015 VL 87A IS 7 SI SI BP 646 EP 660 DI 10.1002/cyto.a.22687 PG 15 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL3ZK UT WOS:000356891200007 PM 26012929 ER PT J AU Preffer, F AF Preffer, Frederic TI Paired Cytometry Publications - from mathematical theory towards clinical applications SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. RP Preffer, F (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL-AUG PY 2015 VL 88 IS 4 BP 211 EP 211 DI 10.1002/cyto.b.21255 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA CL3SD UT WOS:000356869900001 PM 26068944 ER PT J AU Bagwell, CB Hill, BL Wood, BL Wallace, PK Alrazzak, M Kelliher, AS Preffer, FI AF Bagwell, C. Bruce Hill, Beth L. Wood, Brent L. Wallace, Paul K. Alrazzak, Muaz Kelliher, Abigail S. Preffer, Frederic I. TI Human B-cell and progenitor stages as determined by probability state modeling of multidimensional cytometry data SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE bone marrow ontogeny; flow cytometry; human B-cell differentiation; B-cell development; hematopoietic stem cells; bone marrow microenvironment; monoclonal antibodies; high-dimensional modeling; broadened quantile function modeling; flow cytometry; probability state modeling ID HUMAN-BONE-MARROW; FLOW-CYTOMETRY; DEVELOPMENT PATHWAYS; MULTIPLE-MYELOMA; PRECURSORS; DIFFERENTIATION; EXPRESSION; CD19 AB BackgroundHuman progenitor and B-cell development is a highly regulated process characterized by the ordered differential expression of numerous cell-surface and intracytoplasmic antigens. This study investigates the underlying coordination of these modulations by examining a series of normal bone marrow samples with the method of probability state modeling or PSM. ResultsThe study is divided into two sections. The first section examines B-cell stages subsequent to CD19 up-regulation. The second section assesses an earlier differentiation stage before and including CD19 up-regulation. Post-CD19 Antigenic Up-RegulationStatistical analyses of cytometry data derived from sixteen normal bone marrow specimens revealed that B cells have at least three distinct coordinated changes, forming four stages labeled as B1, B2, B3, and B4. At the end of B1; CD34 antigen expression down-regulates with TdT while CD45, CD81, and CD20 slightly up-regulate. At the end of B2, CD45 and CD20 up-regulate. At the end of B3 and beginning of B4; CD10, CD38, and CD81 down-regulate while CD22 and CD44 up-regulate. Pre-CD19 Antigenic Up-RegulationStatistical analysis of ten normal bone marrows revealed that there are at least two measurable coordinated changes with progenitors, forming three stages labeled as P1, P2, and P3. At the end of P1, CD38 up-regulates. At the end of P2; CD19, CD10, CD81, CD22, and CD9 up-regulate while CD44 down-regulates slightly. ConclusionsThese objective results yield a clearer immunophenotypic picture of the underlying cellular mechanisms that are operating in these important developmental processes. Also, unambiguously determined stages define what is meant by normal B-cell development and may serve as a preliminary step for the development of highly sensitive minimum residual disease detection systems. A companion article is simultaneously being published in Cytometry Part A that will explain in further detail the theory behind PSM. Three short relevant videos are available in the online supporting information for both of these papers. (c) 2015 International Clinical Cytometry Society C1 [Bagwell, C. Bruce; Hill, Beth L.] Ver Software House, Topsham, ME USA. [Wood, Brent L.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Wood, Brent L.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Wallace, Paul K.; Alrazzak, Muaz] Roswell Pk Canc Inst, Dept Flow & Image Cytometry, Buffalo, NY 14263 USA. [Kelliher, Abigail S.; Preffer, Frederic I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Bagwell, CB (reprint author), POB 247, Topsham, ME 04086 USA. EM cbb@vsh.com NR 39 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL-AUG PY 2015 VL 88 IS 4 BP 214 EP 226 DI 10.1002/cyto.b.21243 PG 13 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA CL3SD UT WOS:000356869900003 PM 25850810 ER PT J AU Vazquez, SE Inlay, MA Serwold, T AF Vazquez, Sara E. Inlay, Matthew A. Serwold, Thomas TI CD201 and CD27 identify hematopoietic stem and progenitor cells across multiple murine strains independently of Kit and Sca-1 SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID PROTEIN-C RECEPTOR; BONE-MARROW; NOD MICE; IN-VIVO; EXPRESSION; TRANSPLANTATION; IDENTIFICATION; INTERFERON; ACTIVATION; FREQUENCY AB Identification and isolation of hematopoietic stem cells (HSCs) in mice is most commonly based on the expression of surface molecules Kit and Sca-1 and the absence of markers of mature lineages. However, Sca-1 is absent or weakly expressed in hematopoietic progenitors in many strains, including nonobese diabetic (NOD), BALB/c, C3H, and CBA mice. In addition, both Kit and Sca-1 levels are modulated following bone marrow injury. In these cases, other markers and dye exclusion methods have been employed to identify HSCs, yet there is no antibody-based stain that enables identification of HSCs and early progenitors when Kit and Sca-1 are inadequate. CD201 is a marker that is highly restricted to HSCs and progenitors, and CD27 is expressed at moderate-to-high levels on HSCs. We show here that combining CD201 and CD27 enables highly efficient isolation of long-term HSCs in NOD mice as well as in other strains, including SJL, FVB, AKR, BALB/c, C3H, and CBA. We also find that HSCs appear to maintain expression of CD201 and CD27 after hematopoietic injury when Kit expression is downregulated. These results suggest a widely applicable yet simple alternative for HSC isolation in settings where Kit and Sea-1 expression are insufficient. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. C1 [Vazquez, Sara E.; Serwold, Thomas] Joslin Diabet Ctr, Dept Immunobiol, Boston, MA 02215 USA. [Vazquez, Sara E.; Serwold, Thomas] Harvard Univ, Sch Med, Boston, MA USA. [Inlay, Matthew A.] Univ Calif Irvine, Dept Mol Biol & Biochem, Sue & Bill Gross Stem Cell Res Ctr, Irvine, CA 92717 USA. RP Serwold, T (reprint author), Joslin Diabet Ctr, Dept Immunobiol, Room 468,1 Joslin Pl, Boston, MA 02215 USA. EM thomas.serwold@joslin.harvard.edu FU National Institutes of Health Diabetes Research Center grant [P30DK036836]; Harvard Stem Cell Institute; Peabody Foundation; AM Stewart Trust; Fleisher Family Foundation; Pittsburgh Foundation; Harvard Stem Cell Institute Internship Program FX We thank the Joslin Diabetes Center Flow Cytometry Core, supported by a National Institutes of Health Diabetes Research Center grant (no. P30DK036836) and the Harvard Stem Cell Institute. We thank Joslin Animal Facility for animal care. We also thank Leo Wang for helpful advice and MiJeong Kim and Martin Thelin for comments on the manuscript. This work was supported by grants from the Peabody Foundation, The A&M Stewart Trust, The Fleisher Family Foundation, and the Pittsburgh Foundation (to T Serwold). SE Vazquez received a fellowship from the Harvard Stem Cell Institute Internship Program. NR 34 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2015 VL 43 IS 7 BP 578 EP 585 DI 10.1016/j.exphem.2015.04.001 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA CL4ET UT WOS:000356906100009 PM 25892186 ER PT J AU Richardson, PG Laubach, JP Lonial, S Moreau, P Yoon, SS Hungria, VTM Dimopoulos, MA Beksac, M Alsina, M San-Miguel, JF AF Richardson, Paul G. Laubach, Jacob P. Lonial, Sagar Moreau, Philippe Yoon, Sung-Soo Hungria, Vania T. M. Dimopoulos, Meletios A. Beksac, Meral Alsina, Melissa San-Miguel, Jesus F. TI Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE bortezomib; deacetylase inhibitors; multiple myeloma; panobinostat; treatment of relapsed and refractory disease ID HISTONE DEACETYLASES; BORTEZOMIB; COMBINATION; DEXAMETHASONE; LBH589; MULTICENTER; CARFILZOMIB; PROGRESSION; MECHANISM; SURVIVAL AB Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM. C1 [Richardson, Paul G.; Laubach, Jacob P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Moreau, Philippe] Nantes Univ Hosp, Nantes, France. [Yoon, Sung-Soo] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Hungria, Vania T. M.] Santa Casa Misericordia Sao Paulo Hosp, Sao Paulo, Brazil. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Beksac, Meral] Ankara Univ, Sch Med, TR-06100 Ankara, Turkey. [Alsina, Melissa] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [San-Miguel, Jesus F.] Univ Navarra Clin, CIMA, Pamplona, Spain. RP Richardson, PG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu RI richard, chrystelle/K-8595-2015 FU Novartis; Celgene; Millennium; Onyx FX PG Richardson: advisory committees for Novartis, Takeda and Johnson & Johnson; JP Laubach: research funding from Novartis, Celgene, Millennium and Onyx; S Lonial: consultancy for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx and Sanofi; P Moreau: advisory committees for Novartis, Takeda, Janssen, Millennium and Onyx; MA Dimopoulos: honoraria from Novartis, Celgene, Onyx and Janssen; M Beksac: advisory committees for Celgene, Amgen, Novartis, Bristol-Myers Squibb and Millennium; M Alsina: advisory committee for Millennium; JFS-M: member of advisory committee for Janssen, Bristol-Myers Squibb, Merck Sharpe & Dohme, Millennium, Celgene, Novartis and Onyx. S Tanik and W Fazzone provided writing assistance funded by Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 34 TC 12 Z9 13 U1 2 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1473-7140 EI 1744-8328 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD JUL PY 2015 VL 15 IS 7 BP 737 EP 748 DI 10.1586/14737140.2015.1047770 PG 12 WC Oncology SC Oncology GA CL3UF UT WOS:000356875400002 PM 26051506 ER PT J AU Hasegawa, K Camargo, CA AF Hasegawa, Kohei Camargo, Carlos A., Jr. TI Airway microbiota and acute respiratory infection in children SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Editorial Material DE acute respiratory infection; bronchiolitis; Haemophilus; immune response; Lactobacillaceae; microbiome; microbiota; Moraxella; pneumonia; probiotics; virus ID PATHOGENIC BACTERIA; BRONCHIOLITIS; COMMUNITIES; PNEUMONIA AB Acute respiratory infections (ARIs), such as bronchiolitis and pneumonia, are the leading cause of hospitalization of infants in the US. While the incidence and severity of ARI can vary widely among children, the reasons for these differences are not fully explained by traditional risk factors (e. g., prematurity, viral pathogens). The recent advent of molecular diagnostic techniques has revealed the presence of highly functional communities of microbes inhabiting the human body (i.e., microbiota) that appear to influence development of local and systemic immune response. We propose a 'risk and resilience' model in which airway microbiota are associated with an increased (risk microbiota) or decreased (resilience microbiota) incidence and severity of ARI in children. We also propose that modulating airway microbiota (e. g., from risk to resilience microbiota) during early childhood will optimize airway immunity and, thereby, decrease ARI incidence and severity in children. C1 [Hasegawa, Kohei; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. RP Hasegawa, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02114 USA. EM khasegawa1@partners.org FU NHLBI NIH HHS [R21 HL129909]; NIAID NIH HHS [U01 AI-67693, U01 AI067693] NR 20 TC 7 Z9 8 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X EI 1744-8409 J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD JUL PY 2015 VL 11 IS 7 BP 789 EP 792 DI 10.1586/1744666X.2015.1045417 PG 4 WC Immunology SC Immunology GA CL3UM UT WOS:000356876100003 PM 25961472 ER PT J AU DuBrock, HM Channick, RN Krowka, MJ AF DuBrock, Hilary M. Channick, Richard N. Krowka, Michael J. TI What's new in the treatment of portopulmonary hypertension? SO EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Review DE macitentan; portopulmonary hypertension; pulmonary arterial hypertension; riociguat; treatment; treprostinil ID PULMONARY ARTERIAL-HYPERTENSION; ENDOTHELIN RECEPTOR ANTAGONIST; STAGE LIVER-DISEASE; INTRAVENOUS EPOPROSTENOL PROSTACYCLIN; RANDOMIZED CONTROLLED-TRIAL; 5 INHIBITOR THERAPY; OF-THE-LITERATURE; TERM-FOLLOW-UP; ORAL TREPROSTINIL; TRANSPLANTATION CANDIDATES AB Portopulmonary hypertension (POPH) is a complication of portal hypertension characterized by pulmonary vasoconstriction and vascular remodeling that can lead to right heart failure and death. Differentiation of POPH from other causes of pulmonary hypertension, such as volume overload or a hyperdynamic high flow state, is critical because a diagnosis of POPH has significant implications for liver transplant risk stratification, Model for End Stage Liver Disease exception points, and the use of pulmonary arterial hypertension-(PAH) specific therapy. Currently, there are 12 approved medications for the treatment of PAH in the US, and three of these were approved in 2013. This review will discuss the diagnosis, evaluation and management of POPH and the role of recently approved PAH therapies in the treatment of POPH. C1 [DuBrock, Hilary M.; Channick, Richard N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Krowka, Michael J.] Mayo Clin, Rochester, MN 55902 USA. RP DuBrock, HM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM hdubrock@mgh.harvard.edu FU Actelion FX MJ Krowka is a member of the steering committee for Portico, a multicenter study for the use of macitenan in portopulmonary hypertension, sponsored by Actelion. RN Channick is a consultant for Actelion pharmaceuticals, Bayer, United Therapeutics, Respira and ZappRx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 73 TC 4 Z9 4 U1 2 U2 13 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4124 EI 1747-4132 J9 EXPERT REV GASTROENT JI Expert Rev. Gastroenterol. Hepatol. PD JUL PY 2015 VL 9 IS 7 BP 983 EP 992 DI 10.1586/17474124.2015.1035647 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CL3OO UT WOS:000356859700010 PM 25882070 ER PT J AU Chung, DC AF Chung, Daniel C. TI The Enigma of Carcinoids SO GASTROENTEROLOGY LA English DT Editorial Material ID GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS; GENETICS; GENES C1 [Chung, Daniel C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. RP Chung, DC (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRJ 704, Boston, MA 02114 USA. EM dchung@partners.org NR 11 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2015 VL 149 IS 1 BP 14 EP 15 DI 10.1053/j.gastro.2015.05.029 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CL0DW UT WOS:000356610400009 PM 26021237 ER PT J AU McMeekin, S Dizon, D Barter, J Scambia, G Manzyuk, L Lisyanskaya, A Oaknin, A Ringuette, S Mukhopadhyay, P Rosenberg, J Vergote, I AF McMeekin, Scott Dizon, Don Barter, James Scambia, Giovanni Manzyuk, Lyudmila Lisyanskaya, Alla Oaknin, Ana Ringuette, Sarah Mukhopadhyay, Pralay Rosenberg, Julie Vergote, Ignace TI Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; Ixabepilone; Second-line; Advanced; Metastatic; Single-agent; Chemotherapy ID GYNECOLOGIC-ONCOLOGY-GROUP; BREAST-CANCER; CARCINOMA; CHEMOTHERAPY; RECURRENT; CISPLATIN; ANTHRACYCLINE; CAPECITABINE; RESISTANT; EFFICACY AB Objective. The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. Methods. Patients were randomized 1:1 to ixabepilone (40 mg/m(2)), or either paclitaxel (175 mg/m(2)) or doxorubicin (60 mg/m(2)), every 21 days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. Results. At the time of database lock, 496 patients were randomized to receive ixabepilone (n = 248) or control (n = 248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio = 1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P = 0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. Conclusions. The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control. (C) 2015 Elsevier Inc. All rights reserved. C1 [McMeekin, Scott] Univ Oklahoma, Stephenson Canc Ctr, Oklahoma City, OK USA. [Dizon, Don] Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Med Gynecol Oncol, Boston, MA 02114 USA. [Barter, James] Womens Hlth Specialists, Rockville, MD USA. [Scambia, Giovanni] Policlin Univ A Gemelli, Rome, Italy. [Manzyuk, Lyudmila] Russian Oncol Res Ctr, Moscow, Russia. [Lisyanskaya, Alla] City Clin Oncol Dispensary, St Petersburg, Russia. [Oaknin, Ana] Vall DHebron Univ Hosp, Barcelona, Spain. [Ringuette, Sarah; Mukhopadhyay, Pralay] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Rosenberg, Julie] Bayer HealthCare, Montville, NJ USA. [Vergote, Ignace] Katholieke Univ Leuven, Univ Hosp Leuven, Leuven Canc Inst, Dept Oncol, Leuven, Belgium. RP McMeekin, S (reprint author), Univ Oklahoma, Hlth Sci Ctr, 4502 East 41st St, Tulsa, OK 74135 USA. EM scott-mcmeekin@ouhsc.edu FU Bristol-Myers Squibb FX The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and scientific expertise. They wish to acknowledge Clair Thomas of StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. NR 18 TC 9 Z9 9 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 18 EP 23 DI 10.1016/j.ygyno.2015.04.026 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100003 PM 25925990 ER PT J AU Sun, SY Melamed, A Goldstein, DP Bernstein, MR Horowitz, NS Moron, AF Maesta, I Braga, A Berkowitz, RS AF Sun, Sue Yazaki Melamed, Alexander Goldstein, Donald P. Bernstein, Marilyn R. Horowitz, Neil S. Moron, Antonio Fernandes Maesta, Izildinha Braga, Antonio Berkowitz, Ross S. TI Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: Does early diagnosis alter risk for gestational trophoblastic neoplasia? SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Gestational trophoblastic disease; Gestational trophoblastic neoplasia ID PREGNANCY; FEATURES AB Objective. To compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among recent (1994-2013) and historical (1988-1993) cases of complete hydatidiform mole (CHM). Methods. This study included two non-concurrent cohorts (1988-1993 versus 1994-2013) of patients from the New England Trophoblastic Disease Center (NETDC). Clinical and pathologic reports of patients diagnosed with CHM between 1994 and 2013 were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin (hCG) levels, and the rate of progression to GTN were compared. Results. In the current cohort (1994 to 2013) the median gestational age at diagnosis continued to decline compared to our prior cohort (1988-1993) (9 weeks versus 12 weeks). Patients from the current cohort were significantly more likely to be diagnosed prior to the 11th week of gestation (56 versus 41%, p = 0.04). Patients in the current cohort were also significantly less likely to present with vaginal bleeding (46 versus 84%, p < 0.001). Earlier diagnosis of complete mole did not result in a decrease in the rate of postmolar GTN. The frequencies of postmolar GTN in the current (1994-2013) and prior (1988-1993) cohorts were 19 and 23%, respectively. In the current cohort, even diagnosis prior to ten weeks gestation did not decrease the risk of developing GTN. Conclusions. This study indicates that complete mole continues to be diagnosed progressively earlier resulting in a further decrease in some classical presenting symptoms. However, despite earlier detection, the risk of development of postmolar GTN has not been affected. (C) 2015 Elsevier Inc. All rights reserved. C1 [Sun, Sue Yazaki; Moron, Antonio Fernandes] UNIFESP Sao Paulo Fed Univ, Paulista Sch Med, Dept Obstet, Sao Paulo, SP, Brazil. [Melamed, Alexander; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02115 USA. [Maesta, Izildinha] UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Gynecol & Obstet, Botucatu, SP, Brazil. [Melamed, Alexander; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross S.] Donald P Goldstein MD Trophoblast Tumor Registry, New England Trophoblast Dis Ctr, Boston, MA USA. [Sun, Sue Yazaki; Moron, Antonio Fernandes] UNIFESP Sao Paulo Fed Univ, Paulista Sch Med, Trophoblast Dis Ctr, Sao Paulo Hosp, Sao Paulo, SP, Brazil. [Maesta, Izildinha] UNESP Sao Paulo State Univ, Botucatu Med Sch, Trophoblast Dis Ctr, Botucatu, SP, Brazil. [Braga, Antonio] Univ Fed Rio de Janeiro, Matern Sch, Trophoblast Dis Ctr, Rio De Janeiro, Brazil. [Braga, Antonio] Univ Fed Fluminense, Antonio Pedro Univ Hosp, Trophoblast Dis Ctr, Rio De Janeiro, Brazil. [Melamed, Alexander; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross S.] Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. [Melamed, Alexander; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross S.] Harvard Univ, Sch Med, Boston, MA USA. RP Berkowitz, RS (reprint author), Brigham & Womens Hosp, Dept OBGYN, Div Gynecol Oncol, ASBI, 75 Francis St, Boston, MA 02115 USA. EM rberkowitz@partners.org OI Melamed, Alexander/0000-0002-0654-0863 FU CNPq - Science Without Borders - Brazil [200756/2014-1]; Dyett Family Trophoblastic Disease Research and Registry Endowment FX This research was supported by a grant from the CNPq 200756/2014-1 - Science Without Borders - Brazil to support the work of Dr. Sue Yazaki Sun and the Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment and the Dyett Family Trophoblastic Disease Research and Registry Endowment. NR 17 TC 9 Z9 9 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 46 EP 49 DI 10.1016/j.ygyno.2015.05.002 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100008 PM 25969351 ER PT J AU Maesta, I Berkowitz, RS Goldstein, DP Bernstein, MR Ramirez, LAC Horowitz, NS AF Maesta, Izildinha Berkowitz, Ross S. Goldstein, Donald P. Bernstein, Marilyn R. Ramirez, Luz Angela C. Horowitz, Neil S. TI Relationship between race and clinical characteristics, extent of disease, and response to chemotherapy in patients with low-risk gestational trophoblastic neoplasia SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Low-risk gestational trophoblastic neoplasia; Racial disparities; Response to chemotherapy ID FOLINIC ACID; ETHNIC-DIFFERENCES; BREAST-CANCER; PROGNOSTIC-FACTORS; HYDATIDIFORM MOLE; PRIMARY THERAPY; METHOTREXATE; MANAGEMENT; WOMEN; STAGE AB Objective. To evaluate the potential effects of race on clinical characteristics, extent of disease, and response to chemotherapy in women with postmolar low-risk gestational trophoblastic neoplasia (GTN). Methods. This non-concurrent cohort study was undertaken including patients with FIGO-defined postmolar low-risk GTN treated with comparable doses and schedules of chemotherapy at the New England Trophoblastic Disease Center (NETDC) between 1973 and 2012. Racial groups investigated included whites, African American and Asians. Information on patient characteristics and response to chemotherapy (need for second line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles/regimens, need for combination chemotherapy, and time to hCG remission) was obtained. Results. Of 316 women, 274 (86.7%) were white, 19 (6%) African American, and 23 (7.3%) Asian. African Americans were significantly younger than white and Asian women (p = 0.008). Disease presentation, and extent of disease, including antecedent molar histology, median time to persistence, median hCG level at persistence, rate of D&C at persistence, presence of metastatic disease, and FIGO stage and risk score were similar among races. Need for second line chemotherapy (p = 0.023), and median number of regimens (p = 0.035) were greater in Asian women than in other races. Conclusions. Low-risk GTN was more aggressive in Asian women, who were significantly more likely to need second line chemotherapy and a higher number of chemotherapy regimens to achieve complete remission than women of African American and Asian descent. Further studies involving racial differences related to clinical, biological and environmental characteristics are needed. (C) 2015 Published by Elsevier Inc. C1 [Maesta, Izildinha; Ramirez, Luz Angela C.] UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Gynecol & Obstet, BR-18618970 Botucatu, SP, Brazil. [Berkowitz, Ross S.; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02115 USA. [Berkowitz, Ross S.; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.] Donald P Goldstein MD Tumor Registry, New England Trophoblast Dis Ctr, Boston, MA USA. [Maesta, Izildinha] UNESP Sao Paulo State Univ, Botucatu Med Sch, Trophoblast Dis Ctr, BR-18618970 Botucatu, SP, Brazil. [Ramirez, Luz Angela C.] Caldas Univ, Clin Dept, Manizales, Caldas, Colombia. [Berkowitz, Ross S.; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.] Harvard Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. [Berkowitz, Ross S.; Goldstein, Donald P.; Bernstein, Marilyn R.; Horowitz, Neil S.] Harvard Univ, Sch Med, Boston, MA USA. RP Maesta, I (reprint author), UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept GYNOB, Ave Prof Montenegro S-N, BR-18618970 Botucatu, SP, Brazil. EM imaesta@fmb.unesp.br FU Dyett Family Trophoblastie Disease Research and Registry Endowment FX The research in this manuscript was supported by the Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment and the Dyett Family Trophoblastie Disease Research and Registry Endowment. NR 41 TC 3 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 50 EP 54 DI 10.1016/j.ygyno.2015.04.030 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100009 PM 25933681 ER PT J AU Horowitz, NS Wright, AA AF Horowitz, Neil S. Wright, Alexi A. TI Impact of obesity on chemotherapy management and outcomes in women with gynecologic malignancies SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Obesity; Chemotherapy; Dosing; Pharmacokinetics; Ovarian cancer; Endometrial cancer ID BODY-SURFACE AREA; EPITHELIAL OVARIAN-CANCER; CELL LUNG-CANCER; MASS INDEX; BREAST-CANCER; ONCOLOGY-GROUP; ADJUVANT CHEMOTHERAPY; CREATININE CLEARANCE; PRIMARY PERITONEAL; COLORECTAL-CANCER AB Objective. To describe the effects of obesity on the pharmacokinetics and dosing of chemotherapies and provide recommendations for chemotherapy management in obese women with gynecologic malignancies. Methods. PubMEd and MEDLINE databases were searched for articles published before June 2014. Only English-language articles were considered. 84 manuscripts were reviewed and 66 were included. Search terms included: obesity, overweight, body mass index, body surface area, glomerular filtration rate, chemotherapy, ovarian cancer, endometrial cancer, inflammation, and pharmacokinetics. Results. Obese cancer patients have worse clinical outcomes, compared with non-obese patients. This may be because of differences in pharmacokinetics, metabolic dysregulation, or physicians' decisions to reduce chemotherapy dose-intensity during treatment to minimize toxicities. A 2012 American Society of Clinical Oncology Clinical Practice Guideline recommends using actual body weight for chemotherapy dosing in all patients treated with curative intent, irrespective of obesity, to avoid compromising clinical outcomes, including progression free survival (PFS) and overall survival (OS). In women with gynecologic cancers most studies demonstrate no difference in PFS or OS when obese patients receive the same chemotherapy dose intensity as non-obese patients, except perhaps with bevacizumab. Conclusions. Chemotherapy dose-intensity is a critical determinant of cancer outcomes and should be maintained in all patients, irrespective of obesity. Future studies should prospectively examine the impact of obesity on clinical outcomes (adverse events, survival) to improve the care of this growing population of patients who are at risk for inferior clinical outcomes. (C) 2015 Elsevier Inc. All rights reserved. C1 [Horowitz, Neil S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02115 USA. [Horowitz, Neil S.; Wright, Alexi A.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA USA. RP Horowitz, NS (reprint author), Brigham & Womens Hosp, Dept OB GYN, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. EM nhorowitz@partners.org FU NCI NIH HHS [K07 CA166210] NR 66 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 201 EP 206 DI 10.1016/j.ygyno.2015.04.002 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100031 PM 25870918 ER PT J AU Viswanathan, AN Erickson, BA AF Viswanathan, Akila N. Erickson, Beth A. TI Seeing is saving: The benefit of 3D imaging in gynecologic brachytherapy SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Brachytherapy; Cervical cancer; Image-guidance; MRI; CT ID ADVANCED CERVICAL-CANCER; DOSE-RATE BRACHYTHERAPY; GUIDED ADAPTIVE BRACHYTHERAPY; COMBINED INTRACAVITARY/INTERSTITIAL BRACHYTHERAPY; SOCIETY CONSENSUS GUIDELINES; EXTERNAL-BEAM RADIOTHERAPY; LOCALLY ADVANCED-CARCINOMA; MAGNETIC-RESONANCE; INTERSTITIAL BRACHYTHERAPY; COMPUTED-TOMOGRAPHY AB Despite a concerning decline in the use of brachytherapy over the past decade, no other therapy is able to deliver a very high dose of radiation into or near a tumor, with a rapid fall-off of dose to adjacent structures. Compared to traditional X-ray-based brachytherapy that relies on points, the use of CT and MR for 3D planning of gynecologic brachytherapy provides a much more accurate volume-based calculation of dose to an image-defined tumor and to the bladder, rectum, sigmoid, and other pelvic organs at risk (OAR) for radiation complications. The publication of standardized guidelines and an online contouring teaching atlas for performing 3D image-based brachytherapy has created a universal platform for communication and training. This has resulted in a uniform approach to using image-guided brachytherapy for treatment and an internationally accepted format for reporting clinical outcomes. Significant improvements in survival and reductions in toxicity have been reported with the addition of image guidance to increase dose to tumor and decrease dose to the critical OAR. Future improvements in individualizing patient treatments should include a more precise definition of the target. This will allow dose modulation based on the amount of residual disease visualized on images obtained at the time of brachytherapy. (C) 2015 Elsevier Inc. All rights reserved. C1 [Viswanathan, Akila N.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol,Med Sch, Boston, MA 02115 USA. [Erickson, Beth A.] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53266 USA. RP Viswanathan, AN (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol,Med Sch, 75 Francis St L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu; berickson@mcw.edu FU [NCI R21 167800] FX Dr Viswanathan receives support through NCI R21 167800. Thank you to Barbara Silver for reviewing this manuscript. NR 72 TC 2 Z9 2 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 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 207 EP 215 DI 10.1016/j.ygyno.2015.02.025 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100032 PM 25748646 ER PT J AU Bhatt, AD Goodwin, N Cash, E Bhatt, G Silverman, CL Spanos, WJ Bumpous, JM Potts, K Redman, R Allison, WA Dunlap, NE AF Bhatt, Aashish D. Goodwin, Nicole Cash, Elizabeth Bhatt, Geetika Silverman, Craig L. Spanos, William J. Bumpous, Jeffrey M. Potts, Kevin Redman, Rebecca Allison, Wes A. Dunlap, Neal E. TI Impact of transcutaneous neuromuscular electrical stimulation on dysphagia in patients with head and neck cancer treated with definitive chemoradiation SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE Vital Stim; laryngectomy; dysphagia; radiation; chemotherapy ID QUALITY-OF-LIFE; INTENSITY-MODULATED RADIOTHERAPY; RADIATION-THERAPY; SWALLOWING DYSFUNCTION; STROKE PATIENTS; CHEMOTHERAPY; CONCURRENT; ASPIRATION; METAANALYSIS; TOXICITY AB BackgroundThe purpose of this study was to investigate the role of transcutaneous neuromuscular electrical stimulation (TNMES) therapy in maintaining swallowing function during chemoradiation for locally advanced head and neck cancer. MethodsWe retrospectively compared 43 consecutive patients with locally advanced head and neck cancer treated with TNMES (treatment group) to 55 control patients. Validated swallowing scale scores were assigned. ResultsAll patients' swallowing scores declined post-chemoradiotherapy. A difference in mean decline in scores for the control group versus the treatment group using the Functional Oral Intake Scale (FOIS) was seen, favoring TNMES intervention (23% vs 7%; p = .015). Age, race, >10 pack-years smoking, diabetes, stage, nodal disease, accelerated fractionation, weight loss, dietary modification, no TNMES, and radiotherapy dose were all significant for poorer scores on the swallowing scales. ConclusionTNMES should be considered an adjunct to dysphagia reduction and possible prevention in patients with locally advanced head and neck cancer. Further studies should be conducted to define the benefit of TNMES intervention. (c) 2015 Wiley Periodicals, Inc. Head Neck 37: 1051-1056, 2015 C1 [Bhatt, Aashish D.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Goodwin, Nicole] Univ Louisville, Dept Speech Language Pathol, Louisville, KY 40202 USA. [Cash, Elizabeth; Bumpous, Jeffrey M.; Potts, Kevin] Univ Louisville, Sch Med, Div Otolaryngol HNS, Dept Surg, Louisville, KY 40202 USA. [Bhatt, Geetika] Univ Louisville, Dept Internal Med, Louisville, KY 40202 USA. [Silverman, Craig L.; Spanos, William J.; Dunlap, Neal E.] Univ Louisville, Dept Radiat Oncol, Louisville, KY 40202 USA. [Redman, Rebecca] Univ Louisville, Dept Internal Med, Div Hematol, Louisville, KY 40202 USA. [Allison, Wes A.] Adv ENT & Allergy, Louisville, KY USA. RP Dunlap, NE (reprint author), Univ Louisville, Dept Radiat Oncol, 401 E Chestnut St,580, Louisville, KY 40202 USA. EM nedunl01@louisville.edu NR 26 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD JUL PY 2015 VL 37 IS 7 BP 1051 EP 1056 DI 10.1002/hed.23708 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CL2WH UT WOS:000356807300019 PM 24710791 ER PT J AU Pillarisetti, J Reddy, YM Gunda, S Swarup, V Lee, R Rasekh, A Horton, R Massumi, A Cheng, J Bartus, K Badhwar, N Han, F Atkins, D Bommana, S Earnest, M Nath, J Ferrell, R Bormann, S Dawn, B Di Biase, L Mansour, M Natale, A Lakkireddy, D AF Pillarisetti, Jayasree Reddy, Yeruva Madhu Gunda, Sampath Swarup, Vijay Lee, Randall Rasekh, Abdi Horton, Rodney Massumi, Ali Cheng, Jie Bartus, Krzystzof Badhwar, Nitish Han, Frederick Atkins, Donita Bommana, Sudharani Earnest, Matthew Nath, Jayant Ferrell, Ryan Bormann, Steven Dawn, Buddhadeb Di Biase, Luigi Mansour, Moussa Natale, Andrea Lakkireddy, Dhanunjaya TI Endocardial (Watchman) vs epicardial (Lariat) left atrial appendage exclusion devices: Understanding the differences in the location and type of leaks and their clinical implications SO HEART RHYTHM LA English DT Article DE Watchman device; Lariat; Left atrial appendage; Exclusion; Efficacy; Safety ID STROKE RISK; INITIAL-EXPERIENCE; WARFARIN THERAPY; FIBRILLATION; CLOSURE; ANTICOAGULATION; LIGATION; THROMBUS; OBLITERATION; PREVENTION AB BACKGROUND Watchman and Lariat left atrial appendage (LAA) occlusion devices are associated with LAA leaks postdeployment. OBJECTIVE The purpose of this study was to compare the incidence, characteristics, and clinical significance of these leaks. METHODS We performed a multicenter prospective observational study of all patients who underwent LAA closure. Baseline, procedural, and imaging variables along with LAA occlusion rates at 30-90 days and 1-year postprocedure were compared. RESULTS A total of 478 patients (219 with the Watchman device and 259 with the Lariat device) with successful implants were included. Patients in the Lariat group had a higher CHADS(2) (congestive heart failure, hypertension, age >74 years, diabetes, stroke) score and a larger left atrium and LAA. A total of 79 patients (17%) had a detectable leak at 1 year. More patients in the Watchman group had a leak compared with those in the Lariat group (46 [21%] vs 33 [14%]; P = .019). All the leaks were eccentric (edge effect) in the Watchman group and concentric (gunny sack effect) in the Lariat group. The size of the leak was Larger in the Watchman group than in the Lariat group (3.10 +/- 1.5 mm vs 2.15 +/- 1.3 mm; P = .001). The Watchman group had 1 device embolization requiring surgery and 2 pericardial effusions requiring pericardiocentesis. In the Lariat group, 4 patients had cardiac tamponade requiring urgent surgical repair. Three patients in each group had a cerebrovascular accident and were not associated with device Leaks. CONCLUSION The Lariat device is associated with a lower rate of leaks at 1 year as compared with the Watchman device, with no difference in rates of cerebrovascular accident. There was no correlation between the presence of residual leak and the occurrence of cerebrovascular accident. C1 [Pillarisetti, Jayasree; Reddy, Yeruva Madhu; Atkins, Donita; Bommana, Sudharani; Earnest, Matthew; Nath, Jayant; Ferrell, Ryan; Bormann, Steven; Dawn, Buddhadeb; Lakkireddy, Dhanunjaya] Univ Kansas, Hosp & Med Ctr, Cardiovasc Res Inst, Div Cardiovasc Dis, Kansas City, KS 66196 USA. [Swarup, Vijay] Univ Kansas, Hosp & Med Ctr, Cardiovasc Res Inst, Div Cardiovasc Dis, Kansas City, KS 66196 USA. [Lee, Randall] Univ San Francisco, San Francisco, CA 94117 USA. [Rasekh, Abdi; Massumi, Ali; Cheng, Jie] St Lukes Hosp, Texas Heart Inst, Houston, TX USA. [Horton, Rodney] Texas Cardiac Arrhythmia Inst, Austin, TX USA. [Cheng, Jie] Univ Texas Houston, Houston, TX USA. [Bartus, Krzystzof] John Paul II, Krakow, Poland. [Han, Frederick] Univ Utah, Salt Lake City, UT USA. [Di Biase, Luigi; Natale, Andrea] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lakkireddy, D (reprint author), Univ Kansas, Med Ctr & Hosp, Ctr Excellencein Atrial Fibrillat & EP, Res Div Cardiovasc Dis, 3901 Rainbow Blvd,G-600, Kansas City, KS 66196 USA. EM dlakkireddy@gmail.com OI Di Biase, Luigi/0000-0001-6508-4047 FU SentreHEART FX Dr Lakkireddy has received unrestricted research grant and modest speaker's honorarium from SentreHEART; he has served as a consultant to Estech. Dr Lee is a stakeholder in SentreHEART. Dr Mansour has received modest speaker's honorarium from SentreREART. NR 35 TC 17 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2015 VL 12 IS 7 BP 1501 EP 1507 DI 10.1016/j.hrthm.2015.03.020 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL2II UT WOS:000356766500022 PM 25778430 ER PT J AU Varada, S Mahalingam, M AF Varada, Sowmya Mahalingam, Meera TI Mutation stability in primary and metastatic melanoma: what we know and what we don't SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE Melanoma; Mutations; Stability; BRAF; NRAS ID BRAF-MUTANT MELANOMA; DNA-REPAIR PATHWAYS; ACQUIRED-RESISTANCE; TARGETED THERAPY; DRUG-RESISTANCE; NRAS MUTATIONS; PRIMARY TUMORS; HETEROGENEITY; LANDSCAPE; MEDICINE AB Despite the efficacy and success of targeted therapies, a significant number of patients with melanoma exhibit either intrinsic or acquired resistance to these drugs. Numerous mechanisms for the development of resistance have been postulated, but the precise reason for this is not known. In this review, we examine the incidence of mutations in select genes (BRAF, NRAS, C-KIT, and GNAQ) known to occur in melanoma, specifically in primary tumors and their paired metastases, to understand the significance of intratumoral heterogeneity by assessing how changes in mutation status alters the process of metastatic spread. Our data revealed a small yet consistent degree of discordance of mutations in the MAPK pathway commonly occurring in melanoma indicating that failed targeted therapy may be a consequence of this. C1 [Varada, Sowmya] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Mahalingam, Meera] VA Boston Healthcare Syst, New England Dept Pathol & Lab Med 113, West Roxbury, MA USA. RP Mahalingam, M (reprint author), 609 Albany St,J-301, Boston, MA 02118 USA. EM me@meeramahalingam.com NR 43 TC 4 Z9 4 U1 0 U2 0 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 EI 1699-5848 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD JUL PY 2015 VL 30 IS 7 BP 763 EP 770 DI 10.14670/HH-11-584 PG 8 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CL2XN UT WOS:000356811200001 PM 25585249 ER PT J AU Ma, B Khazali, A Wells, A AF Ma, Bo Khazali, Ahmad Wells, Alan TI CXCR3 in carcinoma progression SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE Chemokines; Cancer; CXCR3; CXCR3-A; CXCR3-B ID CHEMOKINE RECEPTOR CXCR3; RENAL-CELL CARCINOMA; METASTATIC BREAST-CANCER; ACTIVATED T-LYMPHOCYTES; LUNG-CANCER; UP-REGULATION; OVARIAN CANCERS; LIGAND-BINDING; MURINE MODEL; LYMPH-NODES AB CXCR3 is a G-protein coupled receptor which binds to ELR-negative CXC chemokines that have been found to impact immune responses, vascular develop, and wound repair. More recently, CXCR3 has been examined in the context of cancer and increased expression in many human tumors has been correlated with poor prognosis in breast, melanoma, colon and renal cancer patients. Three variants of CXCR3 are identified so far (CXCR3-A, CXCR3-B and CXCR3-alt) with the two primary ones, CXCR3-A and CXCR3-B, considered to induce opposite physiological functions. Generally, CXCR3-A, the predominant form in hematopoietic cells, appears to mediate tumor "go" signaling via promoting cell proliferation, survival, chemotaxis, invasion and metastasis; while CXCR3-B, the main form on formed elements including epithelial cells, appears to mediate tumor "stop" signaling via promoting growth suppression, apoptosis and vascular involution. Thus, aberrant expression of the isoforms CXCR3-A and CXCR3-B could affect tumor progression. In this review, we have discussed the profiles of CXCR3 variants and related signaling, as well as the role of CXCR3 variants in cancer. C1 [Wells, Alan] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. RP Wells, A (reprint author), Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. EM wellsa@upmc.edu OI Wells, Alan/0000-0002-1637-8150 FU VA Merit Program; DoD CDMRP in Breast and Prostate Cancer; NIH [UH2 TR000496] FX This study was supported by grants from the VA Merit Program and the DoD CDMRP in Breast and Prostate Cancer, and the NIH UH2 TR000496. NR 72 TC 4 Z9 5 U1 1 U2 8 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 EI 1699-5848 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD JUL PY 2015 VL 30 IS 7 BP 781 EP 792 DI 10.14670/HH-11-594 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CL2XN UT WOS:000356811200003 PM 25663474 ER PT J AU Ellenson, LH Young, RH AF Ellenson, Lora Hedrick Young, Robert H. TI A New Historical Feature for the Journal: Eponyms and Entities SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Editorial Material C1 [Ellenson, Lora Hedrick] New York Presbyterian Hosp, Dept Pathol & Lab Med, Weill Cornell Med Coll, New York, NY 10065 USA. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Ellenson, LH (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, 1300 York Ave,F309D, New York, NY 10065 USA. EM lora.ellenson@med.cornell.edu; rhyoung@partners.org NR 0 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 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2015 VL 34 IS 4 BP 313 EP 313 DI 10.1097/PGP.0000000000000224 PG 1 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA CK9VU UT WOS:000356588400001 PM 26061069 ER PT J AU Rosai, J Young, RH AF Rosai, Juan Young, Robert H. TI Eponyms and Entities Javier Arias-Stella and His Famous Reaction SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Arias-Stella reaction; Javier Arias-Stella; M; D; History of Pathology ID HISTOLOGY; CELL C1 [Rosai, Juan] Ctr Diagnost Italiano, Milan, Italy. [Rosai, Juan] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Young, RH (reprint author), Massachusetts Gen Hosp, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM rhyoung@partners.org NR 24 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 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2015 VL 34 IS 4 BP 314 EP 322 DI 10.1097/PGP.0000000000000223 PG 9 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA CK9VU UT WOS:000356588400002 PM 26061070 ER PT J AU Bennett, JA Sanada, S Selig, MK Hariri, LP Nielsen, GP Oliva, E AF Bennett, Jennifer A. Sanada, Sakiko Selig, Martin K. Hariri, Lida P. Nielsen, Gunnlaugur P. Oliva, Esther TI Giant Cell Tumor of the Uterus: A Report of 3 Cases With a Spectrum of Morphologic Features SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Giant cell tumor; Osteoclast-like giant cells; Uterine carcinoma and; or sarcoma ID UNDIFFERENTIATED PLEOMORPHIC SARCOMA; INFLAMMATORY MYOFIBROBLASTIC TUMOR; MALIGNANT FIBROUS HISTIOCYTOMA; OF-THE-LITERATURE; SOFT-TISSUE; UTERINE LEIOMYOSARCOMA; SMOOTH-MUSCLE; BONE-TUMORS; H-CALDESMON; CYCLIN D1 AB Giant cell tumors, a well-recognized neoplasm of bone, can rarely be found in the uterus. Such tumors are characterized by a dual population of mononuclear and osteoclast-like giant cells that lack epithelial and specific mesenchymal differentiation. In this study, the clinicopathologic features of 3 giant cell tumors of the uterus were reviewed. Immunohistochemistry for CD68, CD163, h-caldesmon, desmin, SMA, AE1/AE3, CD10, ER, PR, cyclin D1, CD1a, CD34, CD30, S100, myogenin/myoglobin, and Ki-67 was performed in all tumors, along with ultrastructural analysis in one. The patients were 47, 57, and 59 yr and the tumors measured 2.5, 7.5, and 16.0 cm. One neoplasm was confined to the endometrium, whereas the other 2 were myometrial. All 3 tumors showed a nodular growth comprised of mononuclear and osteoclast-like giant cells. The endometrial-confined tumor consisted of histologically benign mononuclear cells, whereas the others exhibited marked atypia. Mitotic activity was up to 5/10 HPF in the benign tumor and up to 22/10 HPF in the malignant. No cytologic atypia or mitoses were observed in the giant cells. CD68 and CD10 were strongly and diffusely expressed in both components of 3 and 2 neoplasms, respectively. Cyclin D1 was focal in the mononuclear cells and focal to diffuse in the giant cells. CD163 was diffuse in the mononuclear cells, but absent to focal in the giant cells. Ultrastructural analysis lacked diagnostic features of epithelial or specific mesenchymal differentiation. Both malignant tumors demonstrated an aggressive behavior. In summary, although rare, giant cell tumor of the uterus should be included in the differential diagnosis of benign or malignant tumors containing osteoclast-like giant cells. C1 [Bennett, Jennifer A.; Selig, Martin K.; Hariri, Lida P.; Nielsen, Gunnlaugur P.; Oliva, Esther] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Bennett, Jennifer A.; Selig, Martin K.; Hariri, Lida P.; Nielsen, Gunnlaugur P.; Oliva, Esther] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sanada, Sakiko] Kurume Univ, Sch Med, Dept Pathol, Fukuoka, Japan. RP Bennett, JA (reprint author), Lahey Hosp & Med Ctr, Dept Pathol, 41 Mall Rd, Burlington, MA 01805 USA. EM Jennifer.A.Bennett@lahey.org NR 66 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2015 VL 34 IS 4 BP 340 EP 350 DI 10.1097/PGP.0000000000000164 PG 11 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA CK9VU UT WOS:000356588400005 PM 25851705 ER PT J AU Bennett, JA Oliva, E Young, RH AF Bennett, Jennifer A. Oliva, Esther Young, Robert H. TI Sclerosing Stromal Tumors With Prominent Luteinization During Pregnancy: A Report of 8 Cases Emphasizing Diagnostic Problems SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Sclerosing stromal tumor; Pregnancy; Lutein cells ID STEROID CELL TUMORS; OF-THE-LITERATURE; CLINICOPATHOLOGICAL ANALYSIS; LEYDIG-CELL; OVARY; INHIBIN; CALRETININ; NEOPLASMS; MARKER; WOMAN AB Ovarian tumors encountered during pregnancy can pose a diagnostic challenge due to an abundance of luteinized cells and other changes. We report 8 sclerosing stromal tumors with massive luteinization discovered in pregnant patients. The tumors ranged from 3.1 to 21 cm (mean=8.8 cm) in size and were typically solid and yellow; the neoplasm was bilateral in 1 case. On microscopic examination, the lutein cells, a feature of sclerosing stromal tumor, had more copious eosinophilic cytoplasm and were more numerous than is usually seen in nonpregnant patients and to varying degrees obscured the typical pseudolobular pattern. This resulted in particular diagnostic difficulty in 3 cases, especially when associated with other changes including irregular shapes of tumor cell nests, edema, and/or myxoid change. However, classic features of these tumors: ectatic vessels and admixed luteinized and nonluteinized cells were still focally evident, allowing for accurate classification. The tumors were cytologically bland and with 1 exception had rare mitoses. As sclerosing stromal tumors have been invariably benign, it is important that they not be confused with other tumors, such as steroid cell tumor, which can occasionally be malignant. C1 [Bennett, Jennifer A.; Oliva, Esther; Young, Robert H.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Bennett, Jennifer A.; Oliva, Esther; Young, Robert H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Bennett, JA (reprint author), Lahey Hosp & Med Ctr, Dept Pathol, 41 Mall Rd, Burlington, MA 01805 USA. EM jennifer.a.bennett@lahey.org NR 32 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2015 VL 34 IS 4 BP 357 EP 362 DI 10.1097/PGP.0000000000000163 PG 6 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA CK9VU UT WOS:000356588400007 PM 25851706 ER PT J AU Pabayo, R Kawachi, I Gilman, SE AF Pabayo, Roman Kawachi, Ichiro Gilman, Stephen E. TI US State-level income inequality and risks of heart attack and coronary risk behaviors: longitudinal findings SO INTERNATIONAL JOURNAL OF PUBLIC HEALTH LA English DT Article DE Income inequality; Coronary heart disease; Social determinants of health; Multilevel modeling; Longitudinal analysis; Population-based study ID STROKE STATISTICS-2013 UPDATE; UNITED-STATES; SOCIOECONOMIC POSITION; HEALTH INEQUALITIES; PHYSICAL-ACTIVITY; SOCIAL COHESION; DISEASE; ASSOCIATION; PREVALENCE; ALCOHOL AB To examine prospectively the association between US state income inequality and incidence of heart attack. We used data from the National Epidemiologic Survey on Alcohol and Related Conditions (n = 34,445). Respondents completed interviews at baseline (2001-2002) and follow-up (2004-2005). Weighted multilevel modeling was used to determine if US state-level income inequality (measured by the Gini coefficient) at baseline was a predictor of heart attack during follow-up, controlling for individual-level and state-level covariates. In comparison to residents of US states in the lowest quartile of income inequality, those living in the second [Adjusted Odds Ratio (AOR) = 1.71, 95 % CI 1.16-2.53)], third (AOR = 1.81, 95 % CI 1.28-2.57), and fourth (AOR = 2.04, 95 % CI 1.26-3.29) quartiles were more likely to have a heart attack. Similar findings were obtained when we excluded those who had a heart attack prior to baseline. This study is one of the first to empirically show the longitudinal relationship between income inequality and coronary heart disease. Living in a state with higher income inequality increases the risk for heart attack among US adults. C1 [Pabayo, Roman] Univ Nevada, Dept Community Hlth Sci, Reno, NV 89557 USA. [Pabayo, Roman; Kawachi, Ichiro; Gilman, Stephen E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Pabayo, R (reprint author), Univ Nevada, Dept Community Hlth Sci, Lombardi Bldg 203,MS 0274,1664 North Virginia St, Reno, NV 89557 USA. EM rpabayo@unr.edu RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU NIH [MH087544]; Canadian Institutes of Health Research [234617] FX This work was supported by NIH-grant number MH087544. RP was a Canadian Institutes of Health Research post-doctoral fellowship recipient #234617. NR 50 TC 4 Z9 4 U1 1 U2 9 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1661-8556 EI 1661-8564 J9 INT J PUBLIC HEALTH JI Int. J. Public Health PD JUL PY 2015 VL 60 IS 5 BP 573 EP 588 DI 10.1007/s00038-015-0678-7 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2WX UT WOS:000356809400007 PM 25981210 ER PT J AU Liggins, JTP Yoo, AJ Mishra, NK Wheeler, HM Straka, M Leslie-Mazwi, TM Chaudhry, ZA Kemp, S Mlynash, M Bammer, R Albers, GW Lansberg, MG AF Liggins, John T. P. Yoo, Albert J. Mishra, Nishant K. Wheeler, Hayley M. Straka, Matus Leslie-Mazwi, Thabele M. Chaudhry, Zeshan A. Kemp, Stephanie Mlynash, Michael Bammer, Roland Albers, Gregory W. Lansberg, Maarten G. CA DEFUSE 2 Investigators TI A score based on age and DWI volume predicts poor outcome following endovascular treatment for acute ischemic stroke SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE acute care; acute stroke; interventional neuroradiology; thrombolysis ID INFARCT VOLUME; THERAPY; RECANALIZATION; REPERFUSION; DIFFUSION; DEFUSE; TRIAL AB Background and AimsThe Houston Intra-Arterial Therapy score predicts poor functional outcome following endovascular treatment for acute ischemic stroke based on clinical variables. The present study sought to (a) create a predictive scoring system that included a neuroimaging variable and (b) determine if the scoring systems predict the clinical response to reperfusion. MethodsSeparate datasets were used to derive (n=110 from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 study) and validate (n=125 from Massachusetts General Hospital) scoring systems that predict poor functional outcome, defined as a modified Rankin Scale score of 4-6 at 90 days. ResultsAge (P<0001; =0087) and diffusion-weighted imaging volume (P=0023; =0025) were the independent predictors of poor functional outcome. The Stanford Age and Diffusion-Weighted Imaging score was created based on the patient's age (0-3 points) and diffusion-weighted imaging lesion volume (0-1 points). The percentage of patients with a poor functional outcome increased significantly with the number of points on the Stanford Age and Diffusion-Weighted Imaging score (P<001 for trend). The area under the receiver operating characteristic curve for the Stanford Age and Diffusion-Weighted Imaging score was 082 in the derivation dataset. In the validation cohort, the area under the receiver operating characteristic curve was 069 for the Stanford Age and Diffusion-Weighted Imaging score and 066 for the Houston Intra-Arterial Therapy score (P=045 for the difference). Reperfusion, but not the interactions between the prediction scores and reperfusion, were predictors of outcome (P>05). ConclusionsThe Stanford Age and Diffusion-Weighted Imaging and Houston Intra-Arterial Therapy scores can be used to predict poor functional outcome following endovascular therapy with good accuracy. However, these scores do not predict the clinical response to reperfusion. This limits their utility as tools to select patients for acute stroke interventions. C1 [Liggins, John T. P.; Mishra, Nishant K.; Wheeler, Hayley M.; Kemp, Stephanie; Mlynash, Michael; Albers, Gregory W.; Lansberg, Maarten G.] Stanford Univ, Med Ctr, Stanford Stroke Ctr, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Straka, Matus; Bammer, Roland] Stanford Univ, Med Ctr, Lucas Magnet Resonance Spect & Imaging Ctr, Dept Radiol, Stanford, CA 94305 USA. [Yoo, Albert J.; Leslie-Mazwi, Thabele M.; Chaudhry, Zeshan A.] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Neuroradiol, Boston, MA 02114 USA. RP Liggins, JTP (reprint author), Stanford Univ, Sch Med, Stanford Stroke Ctr, 1215 Welch Rd, Stanford, CA 94305 USA. EM jliggins@stanford.edu OI Mishra, Nishant/0000-0002-9327-3707 FU National Institute for Neurological Disorders and Stroke [R01 NS03932505, K23 NS051372]; Stanford Medical Scholars Fellowship Program FX The study was funded by grants from the National Institute for Neurological Disorders and Stroke (R01 NS03932505 to GWA and K23 NS051372 to MGL) and the Stanford Medical Scholars Fellowship Program. NR 11 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD JUL PY 2015 VL 10 IS 5 BP 705 EP 709 DI 10.1111/ijs.12207 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CL1QD UT WOS:000356718000022 PM 24207136 ER PT J AU Wintermark, M Luby, M Bornstein, NM Demchuk, A Fiehler, J Kudo, K Lees, KR Liebeskind, DS Michel, P Nogueira, RG Parsons, MW Sasaki, M Wardlaw, JM Wu, O Zhang, WW Zhu, GM Warach, SJ AF Wintermark, Max Luby, Marie Bornstein, Natan M. Demchuk, Andrew Fiehler, Jens Kudo, Kohsuke Lees, Kennedy R. Liebeskind, David S. Michel, Patrik Nogueira, Raul G. Parsons, Mark W. Sasaki, Makoto Wardlaw, Joanna M. Wu, Ona Zhang, Weiwei Zhu, Guangming Warach, Steven J. TI International survey of acute Stroke imaging used to make revascularization treatment decisions SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE CT; MRI; penumbra; perfusion imaging; stroke; vascular imaging ID ACUTE ISCHEMIC-STROKE; ENDOVASCULAR TREATMENT; TRIAL AB BackgroundTo assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. MethodsSTroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies. ResultsWe received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (IV) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) . ConclusionThere were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning. C1 [Wintermark, Max] Stanford Univ, Dept Radiol, Neuroradiol, Palo Alto, CA 94304 USA. [Luby, Marie] NINDS, NIH, Bethesda, MD 20892 USA. [Luby, Marie; Warach, Steven J.] UT Southwestern Med Ctr, Dept Neurol & Neurotherapeut, Seton UT Southwestern Clin Res Inst Austin, Austin, TX USA. [Bornstein, Natan M.] Tel Aviv Univ, Sackler Fac Med, Dept Neurol, Elias Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Demchuk, Andrew] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Demchuk, Andrew] Univ Calgary, Hotchkiss Brain Inst, Dept Radiol, Calgary, AB, Canada. [Fiehler, Jens] Univ Med Ctr Hamburg Eppendorf, Dept Neuroradiol, Hamburg, Germany. [Kudo, Kohsuke] Hokkaido Univ Hosp, Dept Diagnost Radiol, Sapporo, Hokkaido 060, Japan. [Lees, Kennedy R.] Univ Glasgow, Western Infirm, Univ Dept Med & Therapeut, Glasgow G11 6NT, Lanark, Scotland. [Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Stroke Ctr, Los Angeles, CA 90024 USA. [Michel, Patrik] Univ Lausanne, CHU Vaudois, Lausanne, Switzerland. [Nogueira, Raul G.] Emory Univ, Sch Med, Marcus Stroke & Neurosci Ctr, Atlanta, GA USA. [Parsons, Mark W.] Univ Newcastle, Dept Neurol, John Hunter Hosp, Med Res Inst, Newcastle, NSW 2300, Australia. [Sasaki, Makoto] Iwate Med Univ, Inst Biomed Sci, Yahaba, Iwate, Japan. [Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Brain Res Imaging Ctr, Div Neuroimaging Sci, Edinburgh, Midlothian, Scotland. [Wu, Ona] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Wu, Ona] Harvard Univ, Sch Med, Boston, MA USA. [Zhang, Weiwei; Zhu, Guangming] Beijing PLA, Mil Gen Hosp, Dept Neurol, Beijing, Peoples R China. RP Wintermark, M (reprint author), UVA Dept Radiol, Neuroradiol Div, Radiol Neurol Neurosurg & Biomed Engn, Box 800170, Charlottesville, VA 22908 USA. EM Max.Wintermark@gmail.com RI Michel, Patrik/Q-2275-2016; OI Michel, Patrik/0000-0003-4954-7579; Wintermark, Max/0000-0002-6726-3951 FU Intramural NIH HHS [Z99 NS999999] NR 7 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD JUL PY 2015 VL 10 IS 5 BP 759 EP 762 DI 10.1111/ijs.12491 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CL1QD UT WOS:000356718000030 PM 25833105 ER PT J AU Menendez, ME Neuhaus, V Ring, D AF Menendez, Mariano E. Neuhaus, Valentin Ring, David TI Inpatient mortality after orthopaedic surgery SO INTERNATIONAL ORTHOPAEDICS LA English DT Article DE Mortality; Charlson; Elixhauser; Orthopaedic surgery; Risk adjustment; Outcome; Prediction ID IN-HOSPITAL MORTALITY; CHARLSON COMORBIDITY INDEX; SIMPLE-RISK-SCORE; ADMINISTRATIVE DATA; PERIOPERATIVE MORTALITY; KNEE ARTHROPLASTY; HIP-FRACTURES; UNITED-STATES; ADJUSTMENT; VALIDATION AB Purpose Adequate comorbidity risk adjustment is central for reliable outcome prediction and provider performance evaluation. The two most commonly employed risk-adjustment methods in orthopaedic surgery were not originally validated in this patient population. We sought (1) to develop a single numeric comorbidity score for predicting inpatient mortality in patients undergoing orthopaedic surgery by combining and reweighting the conditions included in the Charlson and Elixhauser measures, and to compare its predictive performance to each of the separate component scores. We also (2) evaluated the new score separately for spine surgery, adult reconstruction, hip fracture, and musculoskeletal oncology admissions. Methods Data from the National Hospital Discharge Survey for the years 1990 through 2007 were obtained. A comorbidity score for predicting inpatient mortality was developed by combining conditions from the Charlson and Elixhauser measures. Weights were derived from a random sample of 80 % of the cohort (n = 26,454,972), and the predictive ability of the new score was internally validated on the remaining 20 % (n = 6,739,169). Performance of scores was assessed and compared using the area under the receiver operating characteristic curve (AUC) derived from multivariable logistic regression models. Results The new combined comorbidity score (AUC = 0.858, 95 % CI 0.856-0.859) performed 58 % better than the Charlson score (AUC = 0.794, 95 % CI 0.792-0.796) and 12 % better than the Elixhauser score (AUC = 0.845, 95 % CI 0.844-0.847). Of the seven conditions that received the highest weights in the new combined score, only three of them were included in both the Charlson and the Elixhauser indices. The new combined score achieved higher discriminatory power for all orthopaedic admission subgroups. Conclusion A single numeric comorbidity score combining conditions from the Charlson and Elixhauser models provided better discrimination of inpatient mortality than either of its constituent scores. Future research should test this score in other populations and data settings. C1 [Menendez, Mariano E.; Neuhaus, Valentin; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Boston, MA 02114 USA. RP Menendez, ME (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, 55 Fruit St,Suite 2100, Boston, MA 02114 USA. EM memenendez@partners.org OI Neuhaus, Valentin/0000-0003-4012-5628 NR 53 TC 1 Z9 1 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 EI 1432-5195 J9 INT ORTHOP JI Int. Orthop. PD JUL PY 2015 VL 39 IS 7 BP 1307 EP 1314 DI 10.1007/s00264-015-2702-1 PG 8 WC Orthopedics SC Orthopedics GA CL2XB UT WOS:000356809900009 PM 25711395 ER PT J AU O'Sullivan, NA Kobayashi, S Ranka, MP Zaleski, KL Yaremchuk, MJ Bonassar, LJ Randolph, MA AF O'Sullivan, Niamh A. Kobayashi, Shinji Ranka, Mitun P. Zaleski, Katherine L. Yaremchuk, Michael J. Bonassar, Lawrence J. Randolph, Mark A. TI Adhesion and integration of tissue engineered cartilage to porous polyethylene for composite ear reconstruction SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE cartilage tissue engineering; integrative repair; biomechanical analysis; adhesion; porous polyethylene; tissue engineered ear ID DIFFERENT CHONDROCYTES; BIOMECHANICAL ANALYSIS; SUBCUTANEOUS IMPLANTS; SHAPED CARTILAGE; NECK-SURGERY; IN-VITRO; MODEL; POLYMER; REPAIR; CONSTRUCT AB The objective of this study was to assess the ability of tissue engineered cartilage to adhere to and integrate with porous polyethylene (PPE) in vivo and to evaluate the biomechanical integrity of the bond formed at the interface. Porcine auricular, articular, and costal chondrocytes were suspended in fibrin gel polymer and placed between discs of PPE to form tri-layer constructs. Controls consisted of fibroblasts suspended in gel or gel alone between the discs. Constructs were implanted into nude mice for 6, 12, and 18 weeks. Upon harvest, specimens were evaluated for neocartilage formation and integration into the PPE, using histological, dimensional (mass, thickness, diameter), and biomechanical (adhesion strength, interfacial stiffness, failure energy and failure strain) analyses. Neotissue was formed in all experimental constructs, consisting mostly of neocartilage integrating with discs of PPE. Control samples contained only fibrous tissue. Biomechanical analyses demonstrated that adhesion strength, interfacial stiffness, and failure energy were all significantly higher in the chondrocyte-seeded samples than in fibroblast-seeded controls, with the exception of costal constructs at 12 weeks, which were not significantly greater than controls. In general, failure strains did not vary between groups. In conclusion, porous polyethylene supported the growth of neocartilage that formed mechanically functional bonds with the PPE. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 983-991, 2015. C1 [O'Sullivan, Niamh A.; Kobayashi, Shinji; Ranka, Mitun P.; Zaleski, Katherine L.; Yaremchuk, Michael J.; Randolph, Mark A.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Bonassar, Lawrence J.] Cornell Univ, Dept Biomed Engn, Ithaca, NY USA. [Bonassar, Lawrence J.] Cornell Univ, Sibley Sch Mech & Aerosp Engn, Ithaca, NY 14853 USA. [Randolph, Mark A.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Randolph, MA (reprint author), Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. EM marandolph@mgh.harvard.edu RI Bonassar, Lawrence/C-2103-2016; Randolph, Mark/A-4406-2009 OI Bonassar, Lawrence/0000-0003-1094-6433; NR 36 TC 2 Z9 2 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 EI 1552-4981 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD JUL PY 2015 VL 103 IS 5 BP 983 EP 991 DI 10.1002/jbm.b.33269 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CL0ZO UT WOS:000356671800004 PM 25196223 ER PT J AU Ominsky, MS Libanati, C Niu, QT Boyce, RW Kostenuik, PJ Wagman, RB Baron, R Dempster, DW AF Ominsky, Michael S. Libanati, Cesar Niu, Qing-Tian Boyce, Rogely W. Kostenuik, Paul J. Wagman, Rachel B. Baron, Roland Dempster, David W. TI Sustained Modeling-Based Bone Formation During Adulthood in Cynomolgus Monkeys May Contribute to Continuous BMD Gains With Denosumab SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE ANTIRESORPTIVES; BONE HISTOMORPHOMETRY; BONE MODELING AND REMODELING; OSTEOPOROSIS; PRECLINICAL STUDIES ID HUMAN RANKL ANTIBODY; POSTMENOPAUSAL WOMEN; STRUCTURAL ADAPTATIONS; COMPUTED-TOMOGRAPHY; TURNOVER MARKERS; ZOLEDRONIC ACID; TRABECULAR BONE; OSTEOPOROSIS; STRENGTH; ALENDRONATE AB Denosumab (DMAb) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (BMD) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. BMD increases were hypothesized to result from additional accrual of bone matrix via modeling-based bone formationa hypothesis that was tested by examining fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated monthly with vehicle for 16 months, whereas other OVX cynos received monthly 25 or 50mg/kg DMAb. DMAb groups exhibited very low serum bone resorption and formation biomarkers and near-absent fluorochrome labeling in proximal femur cancellous bone. Despite these reductions, femoral neck dual-energy X-ray absorptiometry (DXA) BMD continued to rise in DMAb-treated cynos, from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination of cortical bone in the proximal femur demonstrated consistent and prominent labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with continuous modeling-based bone formation. These findings were evident in all groups. Quantitative analysis at another modeling site, the ninth rib, demonstrated that DMAb did not alter the surface extent of modeling-based labels, or the cortical area bound by them, relative to OVX controls, while significantly reducing remodeling-based bone formation and eroded surface. This conservation of modeling-based formation occurred concomitantly with increased femoral neck strength and, when coupled with a reduction in remodeling-based bone loss, is likely to contribute to increases in bone mass with DMAb treatment. Thus, this study provides preclinical evidence for a potential mechanism that could contribute to the clinical observations of continued BMD increases and low fracture rates with long-term DMAb administration. (c) 2015 American Society for Bone and Mineral Research. C1 [Ominsky, Michael S.; Niu, Qing-Tian; Kostenuik, Paul J.] Amgen Inc, Metabol Disorders, Thousand Oaks, CA 91320 USA. [Libanati, Cesar; Wagman, Rachel B.] Amgen Inc, Clin Dev, Thousand Oaks, CA 91320 USA. [Boyce, Rogely W.] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA 91320 USA. [Baron, Roland] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA USA. [Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Dempster, David W.] Columbia Univ, Coll Physicians & Surg, Clin Pathol & Cell Biol, New York, NY USA. [Dempster, David W.] New York State Dept Hlth, Helen Hayes Hosp, Reg Bone Ctr, W Haverstraw, NY USA. RP Ominsky, MS (reprint author), One Amgen Ctr Dr,MS 29-M-B, Newbury Pk, CA 91320 USA. EM mominsky@amgen.com NR 38 TC 18 Z9 18 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2015 VL 30 IS 7 BP 1280 EP 1289 DI 10.1002/jbmr.2480 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CL1PL UT WOS:000356715900015 PM 25684625 ER PT J AU Ang, JWJ Khanna, A Walcott, BP Kahle, KT Eskandar, EN AF Ang, Jensen W. J. Khanna, Arjun Walcott, Brian P. Kahle, Kristopher T. Eskandar, Emad N. TI Central nervous system lymphoma presenting as trigeminal neuralgia: A diagnostic challenge SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Lymphoma; Skull base; Trigeminal neuralgia ID PRIMARY CNS LYMPHOMA; MIMICKING; BRAIN; BASE AB We describe an atypical man with diffuse large B cell lymphoma localized to the sphenoid wing and adjacent cavernous sinus, initially presenting with isolated ipsilateral facial pain mimicking trigeminal neuralgia due to invasion of Meckel's cave but subsequently progressing to intra-axial extension and having synchronous features of systemic lymphoma. Primary central nervous system lymphoma is uncommon, accounting for approximately 2% of all primary intracranial tumors, but its incidence has been steadily increasing in some groups [1]. It usually arises in the periventricular cerebral white matter, and reports of lymphoma in extra-axial regions are rare [2]. This man highlights the importance of maintaining lymphoma in the differential diagnosis of tumors of the skull base presenting with trigeminal neuralgia-like symptoms. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Khanna, Arjun; Walcott, Brian P.; Kahle, Kristopher T.; Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Ang, Jensen W. J.] Univ Edinburgh, Coll Med & Vet Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Khanna, Arjun; Walcott, Brian P.; Kahle, Kristopher T.; Eskandar, Emad N.] Harvard Univ, Sch Med, Boston, MA USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,WACC 745, Boston, MA 02115 USA. EM walcott.brian@mgh.harvard.edu FU NINDS NIH HHS [R25 NS065743] NR 16 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD JUL PY 2015 VL 22 IS 7 BP 1188 EP 1190 DI 10.1016/j.jocn.2015.01.018 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK9KE UT WOS:000356558200024 PM 25865026 ER PT J AU Walker, RJ Lynch, CP Williams, JS Voronca, D Egede, LE AF Walker, Rebekah J. Lynch, Cheryl P. Williams, Joni Strom Voronca, Delia Egede, Leonard E. TI Meaning of illness and quality of life in patients with type 2 diabetes SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Meaning of illness; Diabetes; Quality of life; Physical health; Mental health ID QUESTIONNAIRE; RELIABILITY; VALIDITY; SCALE AB Background: Investigations into personal factors influencing quality of life are important for those developing strategies to support patients with diabetes. This study aimed to investigate the influence of meaning of illness on quality of life in patients with type 2 diabetes. Methods: Veterans from primary care clinics in the southeastern United States completed a questionnaire including questions from the validated 5-scale Meaning of Illness Questionnaire (MIQ). Unadjusted and adjusted linear regression models investigated the physical and mental components of quality of life with the 5 MIQ factors. Results: The sample comprised 302 Black and White veterans. The physical component of quality of life (PCS) was positively associated with type of stress/attitude of harm (beta = 2.43, CI: 0.94 to 3.93) and challenge/motivation/hope (beta = 3.02, CI: 0.40 to 5.64) after adjustment, whereas the mental component of quality of life (MCS) was positively associated with the degree of stress/change in commitment (beta = 2.58, CI: 0.78 to 438), and negatively associated with challenge/motivation/hope (beta = -2.55, CI: -4.99 to -0.11). Conclusion: Attitudes of challenge, motivation and hope had opposite effects on mental and physical components of quality of life in this sample of veterans. Additionally, whereas, the type of stress and attitude towards harm or loss was associated with the physical component, the degree of stress and change in commitments was associated with the mental component This suggests addressing the meaning of an illness may be complex but is an important consideration in improving both physical and mental components of quality of life in patients with type 2 diabetes. Published by Elsevier Inc. C1 [Walker, Rebekah J.; Lynch, Cheryl P.; Egede, Leonard E.] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. [Walker, Rebekah J.; Lynch, Cheryl P.; Williams, Joni Strom; Voronca, Delia; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Lynch, Cheryl P.; Williams, Joni Strom; Voronca, Delia; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, Hlth Equ & Rural Outreach Innovat Ctr, 135 Rutledge Ave,Room 280G,POB 250593, Charleston, SC 29425 USA. EM egedel@musc.edu FU VHA Health Services Research and Development (HSRD) program [TRP 04-038] FX This study was supported by grant #TRP 04-038 (PI: Leonard Egede) funded by the VHA Health Services Research and Development (HSR&D) program. NR 19 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD JUL PY 2015 VL 29 IS 5 BP 665 EP 669 DI 10.1016/j.jdiacomp.2015.04.006 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CL4EW UT WOS:000356906400010 PM 25934437 ER PT J AU Lerner-Ellis, J Wang, M White, S Lebo, MS AF Lerner-Ellis, Jordan Wang, Marina White, Shana Lebo, Matthew S. TI Canadian Open Genetics Repository (COGR): a unified clinical genomics database as a community resource for standardising and sharing genetic interpretations SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID SEQUENCE AB Background The Canadian Open Genetics Repository is a collaborative effort for the collection, storage, sharing and robust analysis of variants reported by medical diagnostics laboratories across Canada. As clinical laboratories adopt modern genomics technologies, the need for this type of collaborative framework is increasingly important. Methods A survey to assess existing protocols for variant classification and reporting was delivered to clinical genetics laboratories across Canada. Based on feedback from this survey, a variant assessment tool was made available to all laboratories. Each participating laboratory was provided with an instance of GeneInsight, a software featuring versioning and approval processes for variant assessments and interpretations and allowing for variant data to be shared between instances. Guidelines were established for sharing data among clinical laboratories and in the final outreach phase, data will be made readily available to patient advocacy groups for general use. Results The survey demonstrated the need for improved standardisation and data sharing across the country. A variant assessment template was made available to the community to aid with standardisation. Instances of the GeneInsight tool were provided to clinical diagnostic laboratories across Canada for the purpose of uploading, transferring, accessing and sharing variant data. Conclusions As an ongoing endeavour and a permanent resource, the Canadian Open Genetics Repository aims to serve as a focal point for the collaboration of Canadian laboratories with other countries in the development of tools that take full advantage of laboratory data in diagnosing, managing and treating genetic diseases. C1 [Lerner-Ellis, Jordan] Univ Toronto, Lab Med & Pathobiol, Toronto, ON M5G 1X5, Canada. [Lerner-Ellis, Jordan] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Lerner-Ellis, Jordan] Ontario Inst Canc Res, Toronto, ON, Canada. [Wang, Marina] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada. [White, Shana; Lebo, Matthew S.] Partners HealthCare Personalized Med, Mol Med Lab, Cambridge, MA USA. [White, Shana] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lebo, Matthew S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lebo, Matthew S.] Harvard Univ, Sch Med, Boston, MA USA. RP Lerner-Ellis, J (reprint author), Univ Toronto, Lab Med & Pathobiol, 600 Univ Ave, Toronto, ON M5G 1X5, Canada. EM jlerner-ellis@mtsinai.on.ca RI Campeau, Philippe/J-8614-2015; Karsan, Aly/K-2067-2015; Hegele, Robert/G-3301-2011; Scherer, Stephen /B-3785-2013; Charames, George/J-2328-2016; Lerner-Ellis, Jordan/J-5559-2016; OI Lebo, Matthew/0000-0002-9733-5207; Campeau, Philippe/0000-0001-9713-7107; Scherer, Stephen /0000-0002-8326-1999; Charames, George/0000-0002-5937-9276; Wintle, Richard/0000-0003-1987-1095; Nelson, Tanya/0000-0001-5344-3516 FU Government of Canada through Genome Canada; Ontario Genomics Institute [OGI-070] FX This work was funded by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-070). NR 14 TC 4 Z9 4 U1 1 U2 10 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD JUL PY 2015 VL 52 IS 7 BP 438 EP 445 DI 10.1136/jmedgenet-2014-102933 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CL3PH UT WOS:000356861900002 PM 25904639 ER PT J AU Thoonen, R Ernande, L Cheng, J Nagasaka, Y Yao, V Miranda-Bezerra, A Chen, C Chao, W Panagia, M Sosnovik, DE Puppala, D Armoundas, AA Hindle, A Bloch, KD Buys, ES Scherrer-Crosbie, M AF Thoonen, Robrecht Ernande, Laura Cheng, Juan Nagasaka, Yasuko Yao, Vincent Miranda-Bezerra, Alexandre Chen, Chan Chao, Wei Panagia, Marcello Sosnovik, David E. Puppala, Dheeraj Armoundas, Antonis A. Hindle, Allyson Bloch, Kenneth D. Buys, Emmanuel S. Scherrer-Crosbie, Marielle TI Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Brown adipose tissue; Uncoupling protein 1; Isoproterenol; Cardioprotection; Heart failure ID STREPTOZOTOCIN-DIABETIC RATS; MYOCARDIAL-ISCHEMIA; PRESSURE-OVERLOAD; GLUCOSE-HOMEOSTASIS; INSULIN SENSITIVITY; UNCOUPLING PROTEIN; MICE; FAT; ISOPROTERENOL; REPERFUSION AB Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1(-/-)) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1(-/-) mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1(-/-) mice. UCP1(-/-) mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1(-/-) mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1(-/-) BAT transplanted to either UCP1(-/-) or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1(-/-) mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1(-/-) mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Thoonen, Robrecht; Ernande, Laura; Cheng, Juan; Nagasaka, Yasuko; Yao, Vincent; Miranda-Bezerra, Alexandre; Panagia, Marcello; Sosnovik, David E.; Puppala, Dheeraj; Armoundas, Antonis A.; Bloch, Kenneth D.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ernande, Laura] Hop Henri Mondor, AP HP, Fac Med Creteil, DHU Ageing Thorax Vessels Blood,Inserm Unit Team, F-94010 Creteil, France. [Cheng, Juan] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Ultrasound, Shanghai 200030, Peoples R China. [Nagasaka, Yasuko; Chen, Chan; Chao, Wei; Hindle, Allyson; Bloch, Kenneth D.; Buys, Emmanuel S.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Pain, Boston, MA 02114 USA. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St, Boston, MA 02114 USA. EM marielle@crosbie.com FU SPARK award from the Massachusetts General Hospital; French Federation of Cardiology; [R21-DK092909] FX This work was supported by grant R21-DK092909 and a SPARK award from the Massachusetts General Hospital (both to M.S-C.) and a training grant from the French Federation of Cardiology (to L.E.) NR 54 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUL PY 2015 VL 84 BP 202 EP 211 DI 10.1016/j.yjmcc.2015.05.002 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA CL3GU UT WOS:000356839200025 PM 25968336 ER PT J AU Ponte, PR Nicholas, PK AF Ponte, Patricia Reid Nicholas, Patrice K. TI Addressing the Confusion Related to DNS, DNSc, and DSN Degrees, With Lessons for the Nursing Profession SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Doctor of Nursing Practice (DNP); Doctor of Nursing Science (DNS; DNSc); Doctor of Philosophy (PhD); Doctor of Science in Nursing (DSN); doctoral education; nursing education; nursing research ID UNITED-STATES AB PurposeThis article examines the evolution of Doctor of Nursing Science (DNS or DNSc) and Doctor of Science in Nursing (DSN) degrees, including their emergence as research-intensive doctoral degrees in the 1960s, efforts to distinguish the degrees from the Doctor of Philosophy (PhD) and Doctor of Nursing Practice (DNP) degrees, the recent decline in program numbers, and implications for degree holders. ApproachThe article reviews the U.S. history of doctoral education in nursing, research examining similarities and differences between the PhD and DNS, DNSc, or DSN degrees, and how the DNS, DNSc, or DSN degree differs from DNP programs. The article also examines the confusion regarding the focus of the DNS, DNSc, or DSN degree among nurses, patients, and potential funders; and describes actions taken by universities to address the confusion, with examples provided by academic deans, nurse leaders, and nurse researchers. FindingsLongstanding confusion about the research merits of the DNS, DNSc, or DSN degree, and the growing prominence of the similarly-titled DNP degree, has created confusion about the focus of DNS, DNSc, or DSN programs and the capabilities of degree holders. Many universities have addressed this confusion by converting their DNS, DNSc, and DSN programs to a PhD or retroactively converting degrees to a PhD. Other universities have chosen not to pursue this route. ConclusionsThe DNS, DNSc, or DSN experience highlights the importance of clarifying and standardizing the purpose and goals of nursing education programs and the repercussions for degree holders when such clarity is lacking. The international academic nursing communities have consistently pursued one doctoral-level nursing degree and therefore have not shared this challenging landscape in nursing education. Clinical RelevanceFindings and recommendations presented in this article have implications for schools of nursing and professional groups that oversee the development of educational programs and pathways for nurses. C1 [Ponte, Patricia Reid] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02215 USA. [Ponte, Patricia Reid] Brigham & Womens Hosp, Dana Farber Canc Inst, Dana Farber Canc Ctr, Boston, MA 02215 USA. [Ponte, Patricia Reid] Brigham & Womens Hosp, Dana Farber Canc Inst, Oncol Nursing Serv, Boston, MA 02215 USA. [Ponte, Patricia Reid] Brigham & Womens Hosp, Dana Farber Canc Inst, Clin Serv, Boston, MA 02215 USA. [Nicholas, Patrice K.] Brigham & Womens Hosp, Global Hlth & Acad Partnerships, Boston, MA 02215 USA. [Nicholas, Patrice K.] MGH Inst Hlth Profess, Sch Nursing, Div Global Hlth Equ, Boston, MA USA. [Nicholas, Patrice K.] MGH Inst Hlth Profess, Sch Nursing, Ctr Nursing Excellence, Boston, MA USA. [Nicholas, Patrice K.] MGH Inst Hlth Profess, Sch Nursing, Boston, MA USA. RP Ponte, PR (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 450 Brookline Ave D1632A, Boston, MA 02215 USA. EM pat_reid_ponte@dfci.harvard.edu NR 18 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 EI 1547-5069 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD JUL PY 2015 VL 47 IS 4 BP 347 EP 353 DI 10.1111/jnu.12148 PG 7 WC Nursing SC Nursing GA CL5QV UT WOS:000357015800009 ER PT J AU Briggs, A Raja, AS Joyce, MF Yule, SJ Jiang, W Lipsitz, SR Havens, JM AF Briggs, Alexandra Raja, All S. Joyce, Maurice F. Yule, Steven J. Jiang, Wei Lipsitz, Stuart R. Havens, Joaquim M. TI The Role of Nontechnical Skills in Simulated Trauma Resuscitation SO JOURNAL OF SURGICAL EDUCATION LA English DT Article DE trauma team training; nontechnical skills; trauma simulation ID TEAMWORK TRAINING IMPROVES; CARE; PERFORMANCE; MULTIDISCIPLINARY; RELIABILITY; MANAGEMENT; SURGEONS AB OBJECTIVE: Trauma team training provides instruction on crisis management through debriefing and discussion of teamwork and leadership skills during simulated trauma scenarios. The effects of team leader's nontechnical skills (NTSs) on technical performance have not been thoroughly studied. We hypothesized that team's and team leader's NTSs correlate with technical performance of clinical tasks. DESIGN: Retrospective cohort study. SETTING: Brigham and Women's Hospital, STRATUS Center for Surgical Simulation PARTICIPANTS: A total of 20 teams composed of surgical residents, emergency medicine residents, emergency department nurses, and emergency services assistants underwent 2 separate, high-fidelity, simulated trauma scenarios. Each trauma scenario was recorded on video for analysis and divided into 4 consecutive sections. For each section, 2 raters used the Non-Technical Skills for Surgeons framework to assess NTSs of the team. To evaluate the entire team's NTS, 2 additional raters used the Modified Non-Technical Skills Scale for Trauma system. Clinical performance measures including adherence to guidelines and time to perform critical tasks were measured independently. RESULTS: NTSs performance by both teams and team leaders in all NTS categories decreased from the beginning to the end of the scenario (all p < 0.05). There was significant correlation between team's and team leader's cognitive skills and critical task performance, with correlation coefficients between 0.351 and 0.478 (p < 0.05). The NTS performance of the team leader highly correlated with that of the entire team, with correlation coefficients between 0.602 and 0.785 (p < 0.001). CONCLUSIONS: The NTSs of trauma teams and team leaders deteriorate as clinical scenarios progress, and the performance of team leaders and teams is highly correlated. Cognitive NTS scores correlate with critical task performance. Increased attention to NTSs during trauma team training may lead to sustained performance throughout trauma scenarios. Decision making and situation awareness skills are critical for both team leaders and teams and should be specifically addressed to improve performance. (J Surg 72:732-739. (C) 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.) C1 [Briggs, Alexandra; Yule, Steven J.; Havens, Joaquim M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Raja, All S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Joyce, Maurice F.; Yule, Steven J.] Brigham & Womens Hosp, STRATUS Ctr Med Simulat, Boston, MA 02115 USA. [Jiang, Wei; Lipsitz, Stuart R.; Havens, Joaquim M.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. RP Havens, JM (reprint author), Brigham & Womens Hosp, Div Trauma Burn & Surg Crit Care, 75 Francis St, Boston, MA 02115 USA. EM jhavens@partners.org RI JIANG, WEI /F-3930-2015 NR 12 TC 6 Z9 6 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-7204 EI 1878-7452 J9 J SURG EDUC JI J. Surg. Educ. PD JUL-AUG PY 2015 VL 72 IS 4 BP 732 EP 739 DI 10.1016/j.jsurg.2015.01.020 PG 8 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA CL3HT UT WOS:000356841700027 PM 25817012 ER PT J AU Tapias, LF Lanuti, M AF Tapias, Luis F. Lanuti, Michael TI Better Prognostic Models May Result in Improved Patient Selection for Adjuvant Therapies After Complete Resection of Solitary Fibrous Tumors of the Pleura SO JOURNAL OF THORACIC ONCOLOGY LA English DT Letter ID SCORING SYSTEM; RECURRENCE C1 [Tapias, Luis F.; Lanuti, Michael] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Lanuti, M (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM mlanuti@mgh.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2015 VL 10 IS 7 BP E61 EP E61 DI 10.1097/JTO.0000000000000556 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CL4SM UT WOS:000356944400003 PM 26134235 ER PT J AU Scali, S Patel, V Neal, D Bertges, D Ho, K Jorgensen, JE Cronenwett, J Beck, A AF Scali, Salvatore Patel, Virendra Neal, Daniel Bertges, Daniel Ho, Karen Jorgensen, Jens-Eldrup Cronenwett, Jack Beck, Adam TI Preoperative beta-blockers do not improve cardiac outcomes after major elective vascular surgery and may be harmful SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID PERIOPERATIVE CARDIOVASCULAR EVALUATION; RANDOMIZED-CONTROLLED-TRIAL; ASSOCIATION TASK-FORCE; ABDOMINAL AORTIC-ANEURYSM; NONCARDIAC SURGERY; PRACTICE GUIDELINES; AMERICAN-COLLEGE; MYOCARDIAL-INFARCTION; FOCUSED UPDATE; RISK PATIENTS AB Objective: Routine initiation beta-blocker medications before vascular surgery is controversial due to conflicting data. The purpose of this analysis was to determine whether prophylactic use of beta-blockers before major elective vascular surgery decreased postoperative cardiac events or mortality. Methods: The Society for Vascular Surgery Vascular Quality Initiative (SVS-VQI) data set was used to perform a retrospective cohort analysis of infrainguinal lower extremity bypass (LEB), aortofemoral bypass (AFB), and open abdominal aortic aneurysm(AAA) repair patients. Chronic (>30 days preoperatively) beta-blocker patients were excluded, and comparisons were made between preoperative (0-30 day) and no beta-blocker groups. Patients were risk stratified using a novel prediction tool derived specifically from the SVS-VQI data set. Propensity-matched pairs and interprocedural specific risk stratification comparisons were performed. End points included in-hospital major adverse cardiac events (MACEs), including myocardial infarction (MI; defined as new ST or T wave electrocardiographic changes, troponin elevation, or documentation by echocardiogram or other imaging modality), dysrhythmia, and congestive heart failure, and 30-day mortality. Results: The study analyzed 13,291 patients (LEB, 68% [n = 9047]; AFB, 11% [n = 1474]; and open AAA, 21% [n = 2770]); of these, 67.7% (n = 8999) were receiving beta-blockers at time of their index procedure. Specifically, 13.2% (n = 1753) were identified to have been started on a preoperative beta-blocker, 54.5% (n = 7426) were on chronic beta-blockers, and 32.3% (n = 4286) were on no preoperative beta-blockers. Among the three procedures, patients had significant demographic and comorbidity differences and thus were not combined. A 1: 1 propensity-matched pairs analysis (1459 pairs) revealed higher rates of postoperative MI with preoperative beta-blockers (preoperative beta-blocker relative risk, 1.65; 95% confidence interval, 1.02-2.68; P = .05 vs no beta-blocker), with no difference in dysrhythmia, congestive heart failure, or 30-day mortality. When stratified into low-risk, medium-risk, and high-risk groups within each procedure, all groups of preoperative beta-blocker patients had no difference or higher rates of MACEs and 30-day mortality, with the exception of high-risk open AAA patients, who had a lower rate of MI (odds ratio, 0.35; 95% confidence interval, 011-0.87; P = .04). Conclusions: Exclusive of high-risk open AAA patients, preoperative beta-blockers did not decrease rates of MACEs or mortality after LEB, AFB, or open AAA. Importantly, exposure to prophylactic preoperative beta-blockers increased the rates of some adverse events in several subgroups. Given these data, the SVS-VQI cannot support routine initiation of preoperative beta-blockers before major elective vascular surgery in most patients. C1 [Scali, Salvatore; Neal, Daniel; Beck, Adam] Univ Florida, Div Vasc Surg & Endovasc Therapy, Gainesville, FL 32610 USA. [Patel, Virendra] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA USA. [Bertges, Daniel] Univ Vermont, Div Vasc Surg, Burlington, VT USA. [Ho, Karen] Northwestern Univ, Div Vasc Surg, Chicago, IL 60611 USA. [Jorgensen, Jens-Eldrup] Maine Med Ctr, Vasc Ctr, Portland, ME 04102 USA. [Cronenwett, Jack] Darmouth Hitchcock Med Ctr, Heart & Vasc Ctr, Lebanon, NH USA. RP Scali, S (reprint author), Univ Florida, Sch Med, Div Vasc Surg & Endovasc Therapy, 1600 SW Archer Rd,Ste NG 45, Gainesville, FL 32610 USA. EM salvatore.scali@surgery.ufl.edu FU National Institutes of Health [NIH-NHLBI 5K23HL115673-02]; Society for Vascular Surgery Foundation Mentored Patient-Oriented Research Award FX This work was supported in part by funding from the National Institutes of Health (NIH-NHLBI 5K23HL115673-02) and the Society for Vascular Surgery Foundation Mentored Patient-Oriented Research Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Society for Vascular Surgery Foundation. NR 35 TC 7 Z9 7 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUL PY 2015 VL 62 IS 1 BP 166 EP U337 DI 10.1016/j.jvs.2015.01.053 PG 13 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CL3FR UT WOS:000356836300023 PM 26115922 ER PT J AU Drewry, J Sen, B Wingate, M Bronstein, J Foster, EM Kotelchuck, M AF Drewry, Jonathan Sen, Bisakha Wingate, Martha Bronstein, Janet Foster, E. Michael Kotelchuck, Milton TI The Impact of the State Children's Health Insurance Program's Unborn Child Ruling Expansions on Foreign-Born Latina Prenatal Care and Birth Outcomes, 2000-2007 SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Prenatal care; Foreign-born Latina; Differences-in-differences; Unborn child ruling; Immigrant health; Birth outcomes ID HISPANIC WOMEN; WELFARE-REFORM; WEIGHT; RISK; IMMIGRANTS; ADEQUACY; DELIVERY AB The 2002 "unborn child ruling" resulted in State Children's Health Insurance Program (SCHIP) expansion for states to cover prenatal care for low-income women without health insurance. Foreign-born Latinas who do not qualify for Medicaid coverage theoretically should have benefited most from the policy ruling given their documented low rates of prenatal care utilization. This study compares prenatal care utilization and subsequent birth outcomes among foreign-born Latinas in six states that used the unborn child ruling to expand coverage to those in ten states that did not implement the expansion. This policy analysis examines cross-sectional pooled US natality data from the pre-enactment years (2000-2003) versus post-enactment years (2004-2007) to estimate the effect of the UCR on prenatal care utilization and birth outcome measures for foreign-born Latinas. Then using a difference-in-difference estimator, we assessed these differences across time for states that did or did not enact the unborn child ruling. Analyses were then replicated on a high-risk subset of the population (single foreign-born Latinas with lower levels of education). The SCHIP unborn child ruling policy expansion increased PNCU over time in the six enacting states. Foreign-born Latinas in expansion enacting states experienced increases in prenatal care utilization though only the high-risk subset were statistically significant. Birth outcomes did not change. The SCHIP unborn child ruling policy was associated with enhanced PNC for a subset of high-risk foreign-born Latinas. C1 [Drewry, Jonathan] Pan Amer Hlth Org, Lima, Peru. [Sen, Bisakha; Wingate, Martha; Bronstein, Janet; Foster, E. Michael] UAB Sch Publ Hlth, Hlth Care Org & Policy, Birmingham, AL USA. [Kotelchuck, Milton] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Maternal Child Hlth Ctr,Ctr Child & Adolescent Hl, Boston, MA USA. RP Drewry, J (reprint author), Pan Amer Hlth Org, Lima, Peru. EM jdelpaso45@gmail.com; bsen@uab.edu; mslay@uab.edu; jbronste@uab.edu; MKOTELCHUCK@mgh.harvard.edu NR 51 TC 2 Z9 2 U1 2 U2 6 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 JUL PY 2015 VL 19 IS 7 BP 1464 EP 1471 DI 10.1007/s10995-014-1650-5 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL0DM UT WOS:000356609300005 PM 25476607 ER PT J AU Wallace, ML Iyengar, S Bramoweth, AD Frank, E Germain, A AF Wallace, Meredith L. Iyengar, Satish Bramoweth, Adam D. Frank, Ellen Germain, Anne TI Clarifying Heterogeneity of Daytime and Nighttime Symptoms of Posttraumatic Stress in Combat Veterans With Insomnia SO MILITARY PSYCHOLOGY LA English DT Article DE chronic insomnia; clustering; personalized medicine; PTSD; sleep ID SLEEP QUALITY INDEX; COGNITIVE-PROCESSING THERAPY; RANDOMIZED CONTROLLED-TRIAL; ADMINISTERED PTSD SCALE; MENTAL-HEALTH PROBLEMS; PSYCHOMETRIC PROPERTIES; BEHAVIORAL THERAPY; PROLONGED EXPOSURE; MILITARY VETERANS; DISORDER AB Daytime and nighttime symptoms of posttraumatic stress disorder (PTSD) are common among combat veterans and military service members. However, there is a great deal of heterogeneity in how symptoms are expressed. Clarifying the heterogeneity of daytime and nighttime PTSD symptoms through exploratory clustering may generate hypotheses regarding ways to optimally match evidence-based treatments to PTSD symptom profiles. We used mixture modeling to reveal clusters based on 6 daytime and nighttime symptoms of 154 combat veterans with insomnia and varying levels of PTSD symptoms. Three clusters with increasing symptom severity were identified (n1 = 50, n2 = 70, n3 = 34). These results suggest that, among veterans with insomnia, PTSD symptoms tend to exist on a continuum of severity, rather than as a categorical PTSD diagnosis. Hypotheses regarding possible targeted treatment strategies for veterans within each identified cluster, as well as ways to generalize these methods to other groups within the military, are discussed. C1 [Wallace, Meredith L.; Frank, Ellen; Germain, Anne] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Iyengar, Satish] Univ Pittsburgh, Dept Stat, Pittsburgh, PA 15260 USA. [Bramoweth, Adam D.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr MIRECC 4, Pittsburgh, PA USA. RP Wallace, ML (reprint author), 3811 OHara St, Pittsburgh, PA 15213 USA. EM lotzmj@upmc.edu FU VISN 4 Mental Illness Research, Education, and Clinical Center (MIRECC), VA Pittsburgh Healthcare System; [K01 MH096944]; [PR054093]; [PT073961]; [MH080696]; [MH083035]; [Log11293006] FX Drs. Wallace, Iyengar, Bramoweth, and Germain have no conflicts of interest. Dr. Frank has the following conflicts of interest: (a) American Psychiatric Press, Editorial Consultant; (b) Psychiatric Assessments Inc, Stockholder; (c) American Psychological Association Press and Guilford Press, Royalties; (d) Servier International, Advisory Board. The contents of this article do not represent the views of the Department of the Veterans Affairs of the United States Government. This research was supported by Grants K01 MH096944 (PI: Wallace) and PR054093, PT073961, MH080696, MH083035, and Log11293006 (PI: Germain). Dr. Bramoweth is supported by funds from the VISN 4 Mental Illness Research, Education, and Clinical Center (MIRECC, Director: D. Oslin; Pittsburgh Site Director: G. Haas), VA Pittsburgh Healthcare System. NR 60 TC 1 Z9 1 U1 3 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0899-5605 EI 1532-7876 J9 MIL PSYCHOL JI Milit. Psychol. PD JUL PY 2015 VL 27 IS 4 BP 212 EP 222 DI 10.1037/mil0000077 PG 11 WC Psychology, Multidisciplinary SC Psychology GA CL5BS UT WOS:000356975400002 PM 26457001 ER PT J AU Zhao, Y Olonisakin, TF Xiong, Z Hulver, M Sayeed, S Yu, MT Gregory, AD Kochman, EJ Chen, BB Mallampalli, RK Sun, M Silverstein, RL Stolz, DB Shapiro, SD Ray, A Ray, P Lee, JS AF Zhao, Y. Olonisakin, T. F. Xiong, Z. Hulver, M. Sayeed, S. Yu, M. T. Gregory, A. D. Kochman, E. J. Chen, B. B. Mallampalli, R. K. Sun, M. Silverstein, R. L. Stolz, D. B. Shapiro, S. D. Ray, A. Ray, P. Lee, J. S. TI Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection SO MUCOSAL IMMUNOLOGY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; BINDING COMPETITIVE INHIBITOR; IMPAIRED HOST-DEFENSE; ACUTE LUNG INJURY; CATHEPSIN-G; CYSTIC-FIBROSIS; PSEUDOMONAS-AERUGINOSA; ELASTASE; CELLS; ACTIVATION AB Neutrophil elastase (NE) and cathepsin G (CG) contribute to intracellular microbial killing but, if left unchecked and released extracellularly, promote tissue damage. Conversely, mechanisms that constrain neutrophil serine protease activity protect against tissue damage but may have the untoward effect of disabling the microbial killing arsenal. The host elaborates thrombospondin-1 (TSP-1), a matricellular protein released during inflammation, but its role during neutrophil activation following microbial pathogen challenge remains uncertain. Mice deficient in TSP-1 (thbs1(-/-)) showed enhanced lung bacterial clearance, reduced splenic dissemination, and increased survival compared with wildtype (WT) controls during intrapulmonary Klebsiella pneumoniae infection. More effective pathogen containment was associated with reduced burden of inflammation in thbs1(-/-) mouse lungs compared with WT controls. Lung NE activity was increased in thbs1(-/-) mice following K. pneumoniae challenge, and thbs1(-/-) neutrophils showed enhanced intracellular microbial killing that was abrogated with recombinant TSP-1 administration or WT serum. Thbs1(-/-) neutrophils exhibited enhanced NE and CG enzymatic activity, and a peptide corresponding to amino-acid residues 793-801 within the type-III repeat domain of TSP-1 bridled neutrophil proteolytic function and microbial killing in vitro. Thus, TSP-1 restrains proteolytic action during neutrophilic inflammation elicited by K. pneumoniae, providing a mechanism that may regulate the microbial killing arsenal. C1 [Zhao, Y.; Olonisakin, T. F.; Xiong, Z.; Hulver, M.; Sayeed, S.; Yu, M. T.; Gregory, A. D.; Kochman, E. J.; Chen, B. B.; Mallampalli, R. K.; Shapiro, S. D.; Ray, A.; Ray, P.; Lee, J. S.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. [Mallampalli, R. K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. [Sun, M.; Stolz, D. B.] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA USA. [Sun, M.; Stolz, D. B.] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA USA. [Silverstein, R. L.] Blood Ctr SE Wisconsin Inc, Dept Med, Med Coll Wisconsin, Milwaukee, WI 53233 USA. [Silverstein, R. L.] Blood Ctr SE Wisconsin Inc, Blood Res Inst, Milwaukee, WI 53233 USA. [Lee, J. S.] Univ Pittsburgh, Dept Med, Vasc Med Inst, Pittsburgh, PA USA. RP Lee, JS (reprint author), Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. EM leejs3@upmc.edu FU Flight Attendant Medical Research Institute; Pilot Project Program in Hemostasis and Vascular Biology (University of Pittsburgh CTSI) [UL1 RR024153, UL1 TR000005]; Vascular Medicine Institute; Hemophilia Center of Western Pennsylvania; Institute for Transfusion Medicine; Merit Review Award from the US Department of Veterans Affairs; [R01 HL086884]; [P01 HL114453] FX Funding sources include R01 HL086884 (J.S.L.), Flight Attendant Medical Research Institute (J.S.L.), Pilot Project Program in Hemostasis and Vascular Biology through UL1 RR024153 and UL1 TR000005 (University of Pittsburgh CTSI), the Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania, Institute for Transfusion Medicine (J.S.L.), P01 HL114453 (R.K.M., P.R.), and a Merit Review Award from the US Department of Veterans Affairs (R.K.M.). NR 51 TC 6 Z9 6 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2015 VL 8 IS 4 BP 896 EP 905 DI 10.1038/mi.2014.120 PG 10 WC Immunology SC Immunology GA CL3QP UT WOS:000356865700018 PM 25492474 ER PT J AU Kim, YH Choi, SH D'Avanzo, C Hebisch, M Sliwinski, C Bylykbashi, E Washicosky, KJ Klee, JB Brustle, O Tanzi, RE Kim, DY AF Kim, Young Hye Choi, Se Hoon D'Avanzo, Carla Hebisch, Matthias Sliwinski, Christopher Bylykbashi, Enjana Washicosky, Kevin J. Klee, Justin B. Bruestle, Oliver Tanzi, Rudolph E. Kim, Doo Yeon TI A 3D human neural cell culture system for modeling Alzheimer's disease SO NATURE PROTOCOLS LA English DT Article ID PLURIPOTENT STEM-CELLS; INTRACELLULAR A-BETA; IPSC-DERIVED NEURONS; LINE RENCELL VM; PROGENITOR CELLS; DIFFERENTIATION; BRAIN; RESPONSIVENESS; EXPRESSION; CHALLENGES AB Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of amyloid-beta (A beta) and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCNPCNPCs) with familial AD mutations, the differentiation of the hNPCNPCNPCs in a 3D matrix and the analysis of AD pathogenesis. The 3D culture generation takes 1-2 d. The aggregation of A beta is observed after 6 weeks of differentiation, followed by robust tau pathology after 10-14 weeks. C1 [Kim, Young Hye; Choi, Se Hoon; D'Avanzo, Carla; Hebisch, Matthias; Sliwinski, Christopher; Bylykbashi, Enjana; Washicosky, Kevin J.; Klee, Justin B.; Tanzi, Rudolph E.; Kim, Doo Yeon] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis,Genet & Aging, Charlestown, MA 02129 USA. [Kim, Young Hye] Korea Basic Sci Inst, Biomed Om Grp, Cheongju, Chungbuk, South Korea. [Hebisch, Matthias; Bruestle, Oliver] Univ Bonn, Life & Brain Ctr, Inst Reconstruct Neurobiol, Bonn, Germany. [Hebisch, Matthias; Bruestle, Oliver] Hertie Fdn, Bonn, Germany. RP Tanzi, RE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis,Genet & Aging, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu; dkim@helix.mgh.harvard.edu FU Cure Alzheimer's Fund; US National Institutes of Health (NIH) [1RF1AG048080-01, 5P01AG15379, 2R01AG014713, 5R37MH060009]; German Federal Ministry for Education and Research BioPharma-NeuroAllianz [0315608A]; EU SCRTox [HEALTH-F5-2010-266753]; Bio & Medical Technology Development Program of the National Research Foundation - Korean government; NIH/National Institute of Neurological Disorders and Stroke [P30NS04776] FX This work is supported by grants from the Cure Alzheimer's Fund to D.Y.K. and R.E.T., from the US National Institutes of Health (NIH) 1RF1AG048080-01 (D.Y.K. and R.E.T.), 5P01AG15379 (D.Y.K. and R.E.T.), 2R01AG014713 (D.Y.K.) and 5R37MH060009 (R.E.T.), from the German Federal Ministry for Education and Research BioPharma-NeuroAllianz 0315608A (O.B.), from EU SCR&Tox HEALTH-F5-2010-266753 (O.B.), and from Bio & Medical Technology Development Program of the National Research Foundation (funded by the Korean government) (Y.H.K.). We appreciate B.T. Hyman, O. Berezovska, D.M. Kovacs (MGH), J. Hardy (NIH) and P. Davies (Albert Einstein College of Medicine) for providing cDNAs and antibodies. We also acknowledge B.A. Tannos at MGH Viral Vector Core (supported by NIH/National Institute of Neurological Disorders and Stroke P30NS04776), M. Waring at Ragon Institute's Imaging Core facility (part of the Harvard Center for AIDS Research Immunology Core), and M.L. McKee and D. Capen at MGH Microscopy Core of the Center for Systems Biology for providing the detailed protocols and for revising the manuscript. NR 44 TC 16 Z9 17 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD JUL PY 2015 VL 10 IS 7 BP 985 EP 1006 DI 10.1038/nprot.2015.065 PG 22 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CL3QZ UT WOS:000356866700004 PM 26068894 ER PT J AU Scherzer, R Shlipak, MG AF Scherzer, Rebecca Shlipak, Michael G. TI Individual assessment of CKD risk in HIV-positive patients SO NATURE REVIEWS NEPHROLOGY LA English DT News Item ID KIDNEY-DISEASE RISK; TENOFOVIR; INFECTION AB Despite reductions in morbidity and mortality owing to widespread use of highly effective antiretroviral therapy (ART), HIV-positive patients remain at high risk of chronic kidney disease (CKD) and end-stage renal disease. A new report provides a HIV-specific CKD risk score to balance the potential benefits and harms of nephrotoxic ART. C1 [Scherzer, Rebecca; Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu FU NIAID NIH HHS [R01 AI098472] NR 10 TC 2 Z9 2 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD JUL PY 2015 VL 11 IS 7 BP 392 EP 393 DI 10.1038/nrneph.2015.75 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CL2UT UT WOS:000356801900003 PM 25963593 ER PT J AU Chen, PP Lin, SC Junk, AK Radhakrishnan, S Singh, K Chen, TC AF Chen, Philip P. Lin, Shan C. Junk, Anna K. Radhakrishnan, Sunita Singh, Kuldev Chen, Teresa C. TI The Effect of Phacoemulsification on Intraocular Pressure in Glaucoma Patients A Report by the American Academy of Ophthalmology SO OPHTHALMOLOGY LA English DT Article ID ANGLE-CLOSURE GLAUCOMA; CLEAR CORNEAL PHACOEMULSIFICATION; CATARACT-EXTRACTION; LENS IMPLANTATION; COMBINED PHACOTRABECULECTOMY; TRABECULAR ASPIRATION; PERIPHERAL-IRIDOTOMY; CLINICAL-OUTCOMES; RANDOMIZED-TRIAL; EYES AB Objective: To examine effects of phacoemulsification on longer-term intraocular pressure (IOP) in patients with medically treated primary open-angle glaucoma (POAG; including normal-tension glaucoma), pseudoexfoliation glaucoma (PXG), or primary angle-closure glaucoma (PACG), without prior or concurrent incisional glaucoma surgery. Methods: PubMed and Cochrane database searches, last conducted in December 2014, yielded 541 unique citations. Panel members reviewed titles and abstracts and selected 86 for further review. The panel reviewed these articles and identified 32 studies meeting the inclusion criteria, for which the panel methodologist assigned a level of evidence based on standardized grading adopted by the American Academy of Ophthalmology. One, 15, and 16 studies were rated as providing level I, II, and III evidence, respectively. Results: All follow-up, IOP, and medication data listed are weighted means. In general, the studies reported on patients using few glaucoma medications (1.5-1.9 before surgery among the different diagnoses). For POAG, 9 studies (total, 461 patients; follow-up, 17 months) showed that phacoemulsification reduced IOP by 13% and glaucoma medications by 12%. For PXG, 5 studies (total, 132 patients; follow-up, 34 months) showed phacoemulsification reduced IOP by 20% and glaucoma medications by 35%. For chronic PACG, 12 studies (total, 495 patients; follow-up, 16 months) showed phacoemulsification reduced IOP by 30% and glaucoma medications by 58%. Patients with acute PACG (4 studies; total, 119 patients; follow-up, 24 months) had a 71% reduction from presenting IOP and rarely required long-term glaucoma medications when phacoemulsification was performed soon after medical reduction of IOP. Trabeculectomy after phacoemulsification was uncommon; the median rate reported within 6 to 24 months of follow-up in patients with controlled POAG, PXG, or PACG was 0% and was 7% in patients with uncontrolled chronic PACG. Conclusions: Phacoemulsification typically results in small, moderate, and marked reductions of IOP and medications for patients with POAG, PXG, and PACG, respectively, and using 1 to 2 medications before surgery. Trabeculectomy within 6 to 24 months after phacoemulsification is rare in such patients. However, reports on its effects in eyes with advanced disease or poor IOP control before surgery are few, particularly for POAG and PXG. (C) 2015 by the American Academy of Ophthalmology. C1 [Chen, Philip P.] Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. [Lin, Shan C.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Junk, Anna K.] Univ Miami, Miami Vet Affairs Med Ctr, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL USA. [Radhakrishnan, Sunita] Glaucoma Res & Educ Grp, Glaucoma Ctr San Francisco, San Francisco, CA USA. [Singh, Kuldev] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Chen, Teresa C.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Chen, PP (reprint author), Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. FU American Academy of Ophthalmology FX Funded without commercial support by the American Academy of Ophthalmology. NR 38 TC 15 Z9 15 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2015 VL 122 IS 7 BP 1294 EP 1307 DI 10.1016/j.ophtha.2015.03.021 PG 14 WC Ophthalmology SC Ophthalmology GA CL0HI UT WOS:000356621700012 PM 25943711 ER PT J AU Witkin, AJ Shah, AR Engstrom, RE Kron-Gray, MM Baumal, CR Johnson, MW Witkin, DI Leung, J Albini, TA Moshfeghi, AA Batlle, IR Sobrin, L Eliott, D AF Witkin, Andre J. Shah, Anjali R. Engstrom, Robert E. Kron-Gray, Michelle M. Baumal, Caroline R. Johnson, Mark W. Witkin, Deborah I. Leung, John Albini, Thomas A. Moshfeghi, Andrew A. Batlle, Ivan R. Sobrin, Lucia Eliott, Dean TI Postoperative Hemorrhagic Occlusive Retinal Vasculitis Expanding the Clinical Spectrum and Possible Association with Vancomycin SO OPHTHALMOLOGY LA English DT Article ID CATARACT EXTRACTION ENDOPHTHALMITIS; INTRACAMERAL ANTIBIOTICS; SURGERY; PROPHYLAXIS; TOXICITY; GENTAMICIN; DIAGNOSIS; PURPURA; CHOICE AB Purpose: To describe a syndrome of hemorrhagic occlusive retinal vasculitis (HORV) that developed after seemingly uncomplicated cataract surgery. Design: Retrospective case series. Subjects: Eleven eyes of 6 patients from 6 different institutions. Methods: Cases were identified after discussion among retina specialists. The findings on presentation, clinical course, and outcome of a series of 7 eyes of 4 patients were compared with a previous report of 4 eyes of 2 patients, and data from both series were combined for a comprehensive analysis. Main Outcome Measures: Historical data, examination findings, imaging results, systemic evaluation findings, treatment regimens, and visual outcomes. Results: Eleven eyes of 6 patients underwent otherwise uncomplicated cataract surgery, receiving viscoelastic and prophylactic intracameral vancomycin during the procedure. Despite good initial vision on postoperative day 1, between 1 to 14 days after surgery, all eyes demonstrated painless vision loss resulting from HORV. Extensive ocular and systemic evaluations were unrevealing in all patients. All patients were treated with aggressive systemic and topical corticosteroids. Additional treatments included systemic antiviral medication in 4 patients, intravitreal antibiotics in 4 eyes, and pars plana vitrectomy in 4 eyes. Skin testing for vancomycin sensitivity showed negative results in 3 patients and was not performed in the others. Neovascular glaucoma developed in 7 eyes, and all eyes received intravitreal anti-vascular endothelial growth factor (VEGF) injection, panretinal photocoagulation, or both for retinal ischemia. Final visual acuity was less than 20/100 in 8 of 11 eyes. Conclusions: Postoperative HORV is an exceedingly rare and potentially devastating condition that can occur after otherwise uncomplicated cataract surgery. Although the precise cause remains unknown, this disease may represent a delayed immune reaction similar to vancomycin-induced leukocytoclastic vasculitis. Despite treatment with high-dose corticosteroids, antiviral medication, and early vitrectomy in many patients, visual outcomes typically were poor in this series. Early intervention with intravitreal anti-VEGF medication and panretinal photocoagulation may help to prevent additional vision loss resulting from neovascular glaucoma. (C) 2015 by the American Academy of Ophthalmology. C1 [Witkin, Andre J.; Baumal, Caroline R.; Witkin, Deborah I.] Tufts Med Ctr, Dept Ophthalmol, New England Eye Ctr, Boston, MA 02111 USA. [Shah, Anjali R.; Kron-Gray, Michelle M.; Johnson, Mark W.] Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Engstrom, Robert E.] Valley Retina Associates, Encino, CA USA. [Leung, John] Tufts Med Ctr, Div Allergy, Boston, MA 02111 USA. [Albini, Thomas A.; Moshfeghi, Andrew A.] Univ Miami, Bascom Palmer Eye Inst, Miami, FL USA. [Batlle, Ivan R.] Retina Associates PA, Shawnee Mission, KS USA. [Sobrin, Lucia; Eliott, Dean] Harvard Univ, Sch Med, Retina Serv, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Witkin, AJ (reprint author), Tufts Med Ctr, Dept Ophthalmol, 800 Washington St,Box 450, Boston, MA 02111 USA. EM ajwitkin@gmail.com OI Albini, Thomas/0000-0003-2199-9047 FU Research to Prevent Blindness, Inc, New York, New York FX Supported by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York, to the New England Eye Center. The sponsor had no role in the design or conduct of this research. NR 28 TC 25 Z9 25 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2015 VL 122 IS 7 BP 1438 EP 1451 DI 10.1016/j.ophtha.2015.03.016 PG 14 WC Ophthalmology SC Ophthalmology GA CL0HI UT WOS:000356621700025 PM 25886796 ER PT J AU Amparo, F Schaumberg, DA Dana, R AF Amparo, Francisco Schaumberg, Debra A. Dana, Reza TI Comparison of Two Questionnaires for Dry Eye Symptom Assessment The Ocular Surface Disease Index and the Symptom Assessment in Dry Eye SO OPHTHALMOLOGY LA English DT Article ID EPIDEMIOLOGY; VALIDATION; DIAGNOSIS AB Purpose: The aim of this study was to compare patient-reported symptoms of dry eye disease (DED) as assessed by the Ocular Surface Disease Index (OSDI), a 12-item symptom frequency-based questionnaire, and the Symptom Assessment iN Dry Eye (SANDE), a 2-item frequency-and severity-based visual analog scale. Design: Clinic-based evaluation of a diagnostic test. Participants: A total of 114 patients with DED. Methods: Patients were administered the OSDI and SANDE questionnaires at baseline and follow-up visits to evaluate DED-related symptoms. The correlations between both questionnaires' scores were evaluated using the Spearman coefficient, and their clinical differences were assessed using Bland-Altman analysis. Main Outcome Measures: Baseline and follow-up visit OSDI and SANDE dry eye symptom scores. Results: At the baseline visit, the OSDI and SANDE questionnaire scores were significantly correlated (R = 0.64; P < 0.001). Moreover, a significant correlation was found between changes in the OSDI and SANDE scores from baseline to follow-up visits (R = 0.47; P < 0.001). A Bland-Altman analysis, after score normalization, revealed a difference (bias) of less than 2 centesimal units between the scores of the 2 questionnaires. Conclusions: Data collected from the SANDE questionnaire showed a significant correlation and negligible score differences with those from the OSDI, suggesting that the SANDE visual analog scale-based questionnaire has the potential to provide clinicians with a short, quick, and reliable measure for DED symptoms. (C) 2015 by the American Academy of Ophthalmology. C1 [Amparo, Francisco; Dana, Reza] Harvard Univ, Sch Med, Dept Ophthalmol, Cornea Serv,Massachusetts Eye & Ear Infirm, Boston, MA USA. [Schaumberg, Debra A.] Univ Utah, Sch Med, John A Moran Eye Ctr, Moran Ctr Translat Med, Salt Lake City, UT USA. [Schaumberg, Debra A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Dana, R (reprint author), Massachusetts Eye & Ear Infirm, Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM reza_dana@meei.harvard.edu FU National Eye Institute, National Institutes of Health [K24-EY019098]; Research to Prevent Blindness FX Supported by the National Eye Institute, National Institutes of Health (grant no: K24-EY019098) and Research to Prevent Blindness. The funding organizations had no role in the design or conduct of this research. NR 16 TC 6 Z9 6 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2015 VL 122 IS 7 BP 1498 EP 1503 DI 10.1016/j.ophtha.2015.02.037 PG 6 WC Ophthalmology SC Ophthalmology GA CL0HI UT WOS:000356621700031 PM 25863420 ER PT J AU Pace-Schott, EF Germain, A Milad, MR AF Pace-Schott, Edward F. Germain, Anne Milad, Mohammed R. TI Effects of Sleep on Memory for Conditioned Fear and Fear Extinction SO PSYCHOLOGICAL BULLETIN LA English DT Article DE sleep; fear conditioning; extinction; memory; habituation; anxiety ID POSTTRAUMATIC-STRESS-DISORDER; EYE-MOVEMENT SLEEP; MEDIAL PREFRONTAL CORTEX; SLOW-WAVE SLEEP; CORTICOTROPIN-RELEASING-FACTOR; OBSESSIVE-COMPULSIVE DISORDER; SOCIAL ANXIETY DISORDER; ANTERIOR CINGULATE CORTEX; REM-SLEEP; EXPOSURE THERAPY AB Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. C1 [Pace-Schott, Edward F.; Milad, Mohammed R.] Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. [Pace-Schott, Edward F.; Milad, Mohammed R.] Massachusetts Gen Hosp, Charlestown, MA USA. [Germain, Anne] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. RP Pace-Schott, EF (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp E, CNY 149 13th St Room 2624, Charlestown, MA 02129 USA. EM epace-schott@mgh.harvard.edu FU [MH090357]; [USAMRAA Log11293006]; [MH097965] FX Research supported by MH090357, USAMRAA Log11293006, MH097965. We thank Marie-France Marin, Lisa Maeng, and Kara Cover for helpful comments. NR 268 TC 13 Z9 13 U1 10 U2 50 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0033-2909 EI 1939-1455 J9 PSYCHOL BULL JI Psychol. Bull. PD JUL PY 2015 VL 141 IS 4 BP 835 EP 857 DI 10.1037/bul0000014 PG 23 WC Psychology; Psychology, Multidisciplinary SC Psychology GA CL5BG UT WOS:000356974100006 PM 25894546 ER PT J AU Vachha, BA Schaefer, PW AF Vachha, Behroze A. Schaefer, Pamela W. TI Imaging Patterns and Management Algorithms in Acute Stroke An Update for the Emergency Radiologist SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Stroke; Infarct; MR imaging; MRA; Perfusion; Diffusion; CT angiography; CT perfusion ID ACUTE ISCHEMIC-STROKE; CEREBRAL-BLOOD-FLOW; DIGITAL-SUBTRACTION-ANGIOGRAPHY; CAROTID-ARTERY STENOSIS; SPIRAL CT ANGIOGRAPHY; COMPUTED-TOMOGRAPHY; MR-ANGIOGRAPHY; INTRAVENOUS THROMBOLYSIS; SYMPTOM ONSET; INFARCT CORE AB Neuroimaging plays a key role in the initial work-up of patients with symptoms of acute stroke. Understanding the advantages and limitations of available CT and MR imaging techniques and how to use them optimally in the emergency setting is crucial for accurately making the diagnosis of acute stroke and for rapidly determining appropriate treatment. C1 [Vachha, Behroze A.; Schaefer, Pamela W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroradiol, Boston, MA 02114 USA. RP Schaefer, PW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroradiol, 55 Fruit St, Boston, MA 02114 USA. EM pschaefer@mgh.harvard.edu NR 122 TC 4 Z9 4 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD JUL PY 2015 VL 53 IS 4 BP 801 EP + DI 10.1016/j.rcl.2015.02.012 PG 27 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL5GF UT WOS:000356987100012 PM 26046512 ER PT J AU Fink, KR Benjert, JL AF Fink, Kathleen R. Benjert, Jayson L. TI Imaging of Nontraumatic Neuroradiology Emergencies SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Subarachnoid hemorrhage; Vasogenic edema; Hydrocephalus; Neurologic abnormalities ID RADIOLOGIC-PATHOLOGICAL CORRELATION; CEREBRAL VASOCONSTRICTION SYNDROME; ENCEPHALOPATHY SYNDROME PRES; OF-THE-LITERATURE; SUBARACHNOID HEMORRHAGE; PERIMESENCEPHALIC HEMORRHAGE; INTRACEREBRAL HEMORRHAGE; CT ANGIOGRAPHY; BRAIN-ABSCESS; AMYLOID ANGIOPATHY AB Imaging of acute neurologic disease in the emergency department can be challenging because of the wide range of possible causes and the overlapping imaging appearance of many of these entities on nonenhanced computed tomography (CT). The key to formulating a succinct, pertinent differential diagnosis includes characterizing the pattern of abnormalities on CT and identifying key features that suggest a particular diagnosis. This article divides neurologic emergencies into 5 scenarios based on the CT findings, including subarachnoid hemorrhage, intraparenchymal hemorrhage, vasogenic edema without and with underlying mass lesion, and acute hydrocephalus. Specific common or important diagnoses in each category are discussed. C1 [Fink, Kathleen R.] Univ Washington, Dept Radiol, Seattle, WA 98104 USA. [Benjert, Jayson L.] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA 98108 USA. RP Fink, KR (reprint author), Univ Washington, Dept Radiol, Box 359728,325 9th Ave, Seattle, WA 98104 USA. EM ktozer@u.washington.edu NR 59 TC 1 Z9 1 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD JUL PY 2015 VL 53 IS 4 BP 871 EP + DI 10.1016/j.rcl.2015.02.004 PG 21 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL5GF UT WOS:000356987100015 PM 26046515 ER PT J AU Xian, Y O'Brien, EC Fonarow, GC Olson, DM Schwamm, LH Lindholm, B Maisch, L Lytle, BL Greiner, MA Wu, JJ Peterson, ED Pencina, MJ Hernandez, AF AF Xian, Ying O'Brien, Emily C. Fonarow, Gregg C. Olson, DaiWai M. Schwamm, Lee H. Lindholm, Brianna Maisch, Lesley Lytle, Barbara L. Greiner, Melissa A. Wu, Jingjing Peterson, Eric D. Pencina, Michael J. Hernandez, Adrian F. TI Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research: Implementing the patient-driven research paradigm to aid decision making in stroke care SO AMERICAN HEART JOURNAL LA English DT Article ID TRANSIENT ISCHEMIC ATTACK; NONRHEUMATIC ATRIAL-FIBRILLATION; AMERICAN-HEART-ASSOCIATION; GUIDELINES-STROKE; POSTSTROKE DEPRESSION; PATIENTS PERSPECTIVE; UNCERTAINTY LIFE; PREVENTION; WARFARIN; PROFESSIONALS AB Background Stroke is common and costly, annually depriving the lives and well-being of 800,000 Americans. Despite demonstrated efficacy in clinical trials, questions remain about the safety and clinical effectiveness of various treatment options given patient characteristics, conditions, preferences, and their desired outcomes. Methods and results The Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute-sponsored project designed to help patients, physicians, and other stakeholders make informed decisions regarding stroke care and improve outcomes through patient-centered comparative effectiveness research. The primary outcomes identified and prioritized by stroke patients are "home time" (time spent alive and outside a hospital) and major adverse cardiovascular events. With inputs from stroke patients themselves, a series of comparative safety and effectiveness analyses will be performed across 3 prioritized therapeutic areas identified as important by stroke survivors: oral anticoagulants, statin therapy, and antidepressants. We obtained data from Get With the Guidelines-Stroke linked with Medicare claims and follow-up telephone interviews. Our combined retrospective and prospective research strategy allows the evaluation of the safety and effectiveness of various treatment options and patient-centered longitudinal outcomes. To ensure the rapid translation of findings into clinical practice, results will be disseminated to stroke survivors, caregivers, and health care providers through traditional and social media, including an online decision aid tool. Conclusions PROSPER is a patient-centered outcome research study guided by patients, caregivers, and the broader health care community. By addressing knowledge gaps in treatment uncertainties through comparative effectiveness research, PROSPER has the potential to improve decision making in stroke care and patient outcomes reflecting individual patient preferences, needs, and values. C1 [Xian, Ying; O'Brien, Emily C.; Lytle, Barbara L.; Greiner, Melissa A.; Wu, Jingjing; Peterson, Eric D.; Pencina, Michael J.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC 27705 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Olson, DaiWai M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. RP Xian, Y (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM ying.xian@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] FX This work was supported by an award (CE-1304) from the Patient-Centered Outcomes Research Institute. NR 47 TC 7 Z9 7 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUL PY 2015 VL 170 IS 1 BP 36 EP U66 DI 10.1016/j.ahj.2015.04.008 PG 21 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK7YJ UT WOS:000356452700005 PM 26093862 ER PT J AU Pokorney, SD Simon, DN Thomas, L Fonarow, GC Kowey, PR Chang, P Singer, DE Ansell, J Blanco, RG Gersh, B Mahaffey, KW Hylek, EM Go, AS Piccini, JP Peterson, ED AF Pokorney, Sean D. Simon, DaJuanicia N. Thomas, Laine Fonarow, Gregg C. Kowey, Peter R. Chang, Paul Singer, Daniel E. Ansell, Jack Blanco, Rosalia G. Gersh, Bernard Mahaffey, Kenneth W. Hylek, Elaine M. Go, Alan S. Piccini, Jonathan P. Peterson, Eric D. CA ORBIT-AF Investigators TI Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry SO AMERICAN HEART JOURNAL LA English DT Article ID NORMALIZED RATIO CONTROL; ORAL ANTICOAGULATION; STROKE PREVENTION; UNITED-STATES; QUALITY; OUTCOMES; EFFICACY; RISK; INTENSITY; ALGORITHM AB Background Time in therapeutic range (TTR) of international normalized ratio (INR) of 2.0 to 3.0 is important for the safety and effectiveness of warfarin anticoagulation. There are few data on TTR among patients with atrial fibrillation (AF) in community-based clinical practice. Methods Using the US Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we examined TTR (using a modified Rosendaal method) among 5,210 patients with AF on warfarin and treated at 155 sites. Patients were grouped into quartiles based on TTR data. Multivariable logistic regression modeling with generalized estimating equations was used to determine patient and provider factors associated with the lowest (worst) TTR. Results Overall, 59% of the measured INR values were between 2.0 and 3.0, with an overall mean and median TTR of 65%+/- 20% and 68% (interquartile range [IQR] 53%-79%). The median times below and above the therapeutic range were 17% (IQR 8%-29%) and 10% (IQR 3%-19%), respectively. Patients with renal dysfunction, advanced heart failure, frailty, prior valve surgery, and higher risk for bleeding (ATRIA score) or stroke (CHA2DS2-VASc score) had significantly lower TTR (P < .0001 for all). Patients treated at anticoagulation clinics had only slightly higher median TTR (69%) than those not (66%) (P < .0001). Conclusions Among patients with AF in US clinical practices, TTR on warfarin is suboptimal, and those at highest predicted risks for stroke and bleeding were least likely to be in therapeutic range. C1 [Pokorney, Sean D.; Piccini, Jonathan P.; Peterson, Eric D.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Pokorney, Sean D.; Simon, DaJuanicia N.; Thomas, Laine; Blanco, Rosalia G.; Piccini, Jonathan P.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Kowey, Peter R.] Lankenau Inst Med Res, Wynnewood, PA USA. [Chang, Paul] Janssen Sci Affairs, Raritan, NJ USA. [Singer, Daniel E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Ansell, Jack] Lenox Hill Hosp, New York, NY USA. [Gersh, Bernard] Mayo Clin, Rochester, MN USA. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Hylek, Elaine M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Go, Alan S.] Kaiser Permanente, Oakland, CA USA. RP Peterson, ED (reprint author), Duke Univ, Med Ctr, Div Cardiol, DUMC 3236, Durham, NC 27710 USA. EM eric.peterson@duke.edu FU Astra Zeneca; Janssen Pharmaceuticals; Boehringer Ingelheim; Bristol-Myers Squibb; Johnson Johnson; Portola; Merck; Sanofi; Daiichi Sankyo; Bayer Healthcare; Pfizer; CSL Behring; Medtronic; Baxter Healthcare Corporation; InspireMD; Johnson & Johnson/Janssen Pharmaceuticals; Bayer HealthCare Pharmaceuticals Inc; Boston Scientific Corporation; Johnson & Johnson Pharmaceutical Research Development; Forest Laboratories, Inc; Medtronic, Inc; Eli Lilly Company; Janssen Pharmaceuticals, Inc; American Heart Association; Genentech Inc FX D.N.H., L.T., R.G.B., and A.S.G. report no disclosures. S.D.P. reports modest educational grant support from Astra Zeneca and modest advisory board to Janssen Pharmaceuticals. G.C.F. reports modest consultant/advisory board support from Janssen Pharmaceuticals. P.R.K. reports modest consultant/advisory board support from Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Portola, Merck, Sanofi, and Daiichi Sankyo. P.C. reports significant employment with Johnson & Johnson. D.E.S. reports significant consulting fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer, and CSL Behring; significant research grant from Johnson & Johnson. J.A. reports modest consultant/advisory board: Boehringer Ingelheim, Alere, Bristol-Myers Squibb, Pfizer, Janssen, and Daiichi. B.G. reports modest Data and Safety Monitoring Board/advisory board support from Medtronic, Baxter Healthcare Corporation, InspireMD, Cardiovascular Research Foundation, PPD Development, LP, Boston Scientific, and St. Jude. K.W.M. financial disclosures before August 1, 2013, can be viewed at https://www.dcri.org/aboutus/conflict-of-interest/Mahaffey-COI_2011-2013 . pdf; disclosures after August 1, 2013, can be viewed at http://med.stanford.edu/profiles/kenneth_mahaffey. E.M.H. reports modest honoraria from Boehringer Ingelheim and Bayer and modest consultant/advisory board from Daiichi Sankyo, Ortho-McNeil-Janssen, Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, and Pfizer. J.P.P. reports significant research grant support from Johnson & Johnson/Janssen Pharmaceuticals; significant other research support from Bayer HealthCare Pharmaceuticals Inc (formerly Berlex Labs), Boston Scientific Corporation, Johnson & Johnson Pharmaceutical Research & Development; modest Consultant/Advisory Board support from Forest Laboratories, Inc and Medtronic, Inc; and significant Consultant/Advisory Board support from Johnson & Johnson/Janssen Pharmaceuticals. E.D.P. reports significant research grant support from Eli Lilly & Company, Janssen Pharmaceuticals, Inc, and the American Heart Association; modest consultant/advisory board support from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc, Pfizer, and Genentech Inc. NR 28 TC 22 Z9 23 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUL PY 2015 VL 170 IS 1 BP 141 EP U194 DI 10.1016/j.ahj.2015.03.017 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK7YJ UT WOS:000356452700018 PM 26093875 ER PT J AU Wang, SA Hasserjian, RP AF Wang, Sa A. Hasserjian, Robert P. TI Acute Erythroleukemias, Acute Megakaryoblastic Leukemias, and Reactive Mimics SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Review DE Acute erythroid leukemia; Pure erythroid leukemia; Megaloblastic anemia; Acute megakaryoblastic leukemia; Transient abnormal myelopoiesis; Down syndrome ID ACUTE MYELOID-LEUKEMIA; TRANSIENT MYELOPROLIFERATIVE DISORDER; WORLD-HEALTH-ORGANIZATION; ACUTE ERYTHROID LEUKEMIA; ACUTE MEGAKARYOCYTIC LEUKEMIA; DOWN-SYNDROME; MYELODYSPLASTIC SYNDROMES; BONE-MARROW; NATURAL-HISTORY; CLASSIFICATION AB Objectives: At the 2013 Society for Hematopathology/European Association for Hematopathology Workshop, 36 cases were submitted to the session that covered acute erythroid leukemia (AEL), acute megakaryoblastic leukemia (AMKL), and reactive mimics. Methods: Cases were reviewed by the session chairs and workshop panel to reach a consensus diagnosis. Results: For acute erythroleukemia, erythroid/myeloid type, discussion acknowledged overlapping features between AEL and myelodysplastic syndromes. Cases submitted as pure erythroid leukemia had distinctive morphology and immunophenotype, complex karyotypes, and aggressive clinical behavior, illustrating certain diagnostic features not currently captured by the current World Health Organization (WHO) definition. In Down syndrome, there were striking similarities between transient abnormal myelopoiesis and AMKL. Most cases of AMKL in adults would be classified as acute myeloid leukemia with myelodysplasia-related changes according to the WHO classification, but this approach deemphasizes their unique clinical, morphologic, and immunophenotypic features. Conclusions: The broad spectrum of cases illustrated the difficulties and complex issues involved in establishing a diagnosis of these entities and the need for better disease definitions. C1 [Wang, Sa A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wang, SA (reprint author), Dept Hematopathol, 1515 Holcombe Blvd,Unit 72, Houston, TX 77030 USA. EM Swang5@mdanderson.org; RHasserjian@mgh.harvard.edu NR 55 TC 6 Z9 7 U1 1 U2 5 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUL PY 2015 VL 144 IS 1 BP 44 EP 60 DI 10.1309/AJCPRKYAT6EZQHC7 PG 17 WC Pathology SC Pathology GA CL2DH UT WOS:000356753300005 PM 26071461 ER PT J AU Wormser, GP Villafuerte, P Nolan, SM Wang, GQ Lerner, RG Saetre, KL Maria, MH Branda, JA AF Wormser, Gary P. Villafuerte, Patrick Nolan, Sheila M. Wang, Guiqing Lerner, Robert G. Saetre, Kirsten L. Maria, Mazen H. Branda, John A. TI Neutropenia in Congenital and Adult Babesiosis SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Babesia; Babesiosis; Diagnosis; Neutropenia ID PLASMODIUM-FALCIPARUM MALARIA; CLINICAL-MANIFESTATIONS; UNITED-STATES; TRANSMISSION; COUNTS AB Objectives: Anemia and thrombocytopenia are expected hematologic abnormalities in patients with acute babesiosis, whereas neutropenia (defined as an absolute neutrophil count of <= 1,800 neutrophils/mu L for adults and <1,200 neutrophils/mu L for infants) is not usually considered a feature of this infection. We studied the frequency with which neutropenia occurs in congenital and adult cases of babesiosis. Methods: The frequency of neutropenia in cases of congenital babesiosis was determined based on a literature review and on the findings in an unreported case. The frequency of neutropenia in adult patients was assessed based on a review of the medical records of 51 patients who were diagnosed with babesiosis between 2010 and 2013 at two medical centers in the Northeastern United States. Results: Four (80%; 95% confidence interval [CI], 36%-98%) of five infants with congenital babesiosis whose neutrophil count was reported were neutropenic. Among 51 adult cases with babesiosis, 11 (22%; 95% CI, 12%-35%) were neutropenic on clinical presentation, and seven others developed neutropenia over the next 1 to 21 days. Thus, a total of 18 (35%; 95% CI, 24%-49%) of the adult patients with babesiosis had neutropenia. Conclusions: Neutropenia appears to be a common finding in infants with congenital babesiosis and is also observed not infrequently in adults with this infection. C1 [Wormser, Gary P.; Villafuerte, Patrick] New York Med Coll, Div Adult Infect Dis, Valhalla, NY 10595 USA. [Nolan, Sheila M.] New York Med Coll, Div Pediat Infect Dis, Valhalla, NY 10595 USA. [Lerner, Robert G.] New York Med Coll, Div Hematol, Valhalla, NY 10595 USA. [Saetre, Kirsten L.; Maria, Mazen H.] New York Med Coll, Div Gen Pediat, Valhalla, NY 10595 USA. [Wang, Guiqing] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Branda, John A.] Harvard Univ, Sch Med, Boston, MA USA. RP Wormser, GP (reprint author), New York Med Coll, Div Infect Dis, 40 Sunshine Cottage Rd, Valhalla, NY 10595 USA. EM gwormser@nymc.edu FU Immunetics; Rarecyte; bioMerieux SA; Institute for Systems Biology; Alere; DiaSorin FX Dr Wormser reports receiving research grants from Immunetics, Rarecyte, bioMerieux SA, and the Institute for Systems Biology. He owns equity in Abbott, has been an expert witness in a malpractice case involving babesiosis, is an unpaid board member of the American Lyme Disease Foundation, has been an expert witness regarding Lyme disease in a disciplinary action for the Missouri Board of Registration for the Healing Arts, and was a consultant to Baxter for Lyme disease vaccine development. Dr Branda reports receiving research grants from Immunetics, bioMerieux SA, Alere, and DiaSorin and was a consultant to AdvanDx. NR 13 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUL PY 2015 VL 144 IS 1 BP 94 EP 96 DI 10.1309/AJCP2PHH4HBVHZFS PG 3 WC Pathology SC Pathology GA CL2DH UT WOS:000356753300010 PM 26071466 ER PT J AU Cohen, AR Caruso, P Duhaime, AC Klig, JE AF Cohen, Ari R. Caruso, Paul Duhaime, Ann-Christine Klig, Jean E. TI Feasibility of "rapid" magnetic resonance imaging in pediatric acute head injury SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT; COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; HYDROCEPHALUS; CT AB Objective: The objective was to determine the feasibility of "rapid" magnetic resonance imaging (rMRI) versus noncontrast computed tomography (NCCT) for pediatric patients with possible traumatic brain injury and to compare the populations receiving imaging in an urban tertiary care emergency department ED. Methods: We retrospectively reviewed the electronic medical records of ED patients younger than 19 years with possible traumatic brain injury over 4 years who received an rMRI and then age-matched with NCCT patients. Data collection and analysis included demographic and clinical variables, ED length of stay (LOS), and follow-up outcomes. Results: The final cohort had 45 rMRIs and 45 NCCTs. The mean age was 2.7 years, 63% were male, and 65% sustained a fall. Age, sex, and injury mechanism were similar. Time parameters were longer for rMRI patients: ED arrival to completion of imaging (172 vs 93 minutes, P < .001) and ED LOS (266 vs 225 minutes, P = .008). The NCCT group had higher-acuity patients with higher pediatric intensive care unit admission rates (33% vs 7%, P = .002). No patients returned to the ED within 72 hours. Follow-up was available on 78% patients. No clinically significant intracranial injuries were missed. Conclusions: Rapid MRI may be a viable imaging modality for moderate-risk pediatric head injury. Although rMRI took longer to obtain during this pilot study, scan time was only 3 to 4 minutes; and LOS was only 41 minutes longer. Further integration of rMRI in patient care should decrease time variation. Future study of rMRI reliability and satisfaction is needed. (C) 2015 Elsevier Inc. All rights reserved. C1 [Cohen, Ari R.; Klig, Jean E.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Caruso, Paul] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Cohen, AR (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM Acohen7@partners.org NR 13 TC 7 Z9 7 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JUL PY 2015 VL 33 IS 7 BP 887 EP 890 DI 10.1016/j.ajem.2015.03.052 PG 4 WC Emergency Medicine SC Emergency Medicine GA CL0BG UT WOS:000356602900005 PM 25912791 ER PT J AU Edla, S Reisner, AT Liu, JB Convertino, VA Carter, R Reifman, J AF Edla, Shwetha Reisner, Andrew T. Liu, Jianbo Convertino, Victor A. Carter, Robert, III Reifman, Jaques TI In reply to "Utility of shock index calculation in hemorrhagic trauma" SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Letter ID VITAL SIGNS C1 [Edla, Shwetha; Liu, Jianbo; Reifman, Jaques] US Army Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Biotechnol High Performance Comp Software Applica, Dept Def, Ft Detrick, MD 21702 USA. [Reisner, Andrew T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Convertino, Victor A.; Carter, Robert, III] US Army Inst Surg Res, Ft Sam Houston, TX 78234 USA. RP Reifman, J (reprint author), US Army Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Biotechnol High Performance Comp Software Applica, Dept Def,ATTN MCMR TT, 504 Scott St, Ft Detrick, MD 21702 USA. EM jaques.reifman.civ@mail.mil NR 5 TC 1 Z9 1 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JUL PY 2015 VL 33 IS 7 BP 978 EP 979 DI 10.1016/j.ajem.2015.04.002 PG 4 WC Emergency Medicine SC Emergency Medicine GA CL0BG UT WOS:000356602900031 PM 25913084 ER PT J AU Hoenig, MP AF Hoenig, Melanie P. TI Share Your Passion for Nephrology: Ten Tips to Invigorate Attending Rounds and Precepting Sessions SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Nephrology education; mentoring; precepting; nephrology workforce; teaching strategies; medical student; resident; attending rounds; inpatient ward ID METABOLIC-ACIDOSIS; RENAL-FAILURE; URINE; DIAGNOSIS; SODIUM; WATER AB Although there have been mounting concerns over the decline in applicants to nephrology training programs, strategies to entice students and trainees to pursue a career in nephrology are lacking. Furthermore, the complex factors that contribute to career decisions and the lag between a positive interaction and a decision to pursue nephrology make such strategies difficult to assess. Nevertheless, it is still important to continue efforts to mentor and inspire. This article offers 10 strategies to help nephrologists share passion for nephrology in the clinical arena. These include the excitement of the dialysis unit, ethical dilemmas, pearls for the bedside, and questions "on the fly." (C) 2015 by the National Kidney Foundation, Inc. C1 [Hoenig, Melanie P.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Hoenig, Melanie P.] Harvard Univ, Sch Med, Boston, MA USA. RP Hoenig, MP (reprint author), Beth Israel Deaconess Med Ctr Clin, Dept Med, Div Renal, Fa 8-185 Pilgrim Rd, Boston, MA 02215 USA. EM mhoenig@bidmc.harvard.edu NR 35 TC 2 Z9 2 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2015 VL 66 IS 1 BP 28 EP 32 DI 10.1053/j.ajkd.2015.03.027 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA CL1UO UT WOS:000356730600009 PM 26003473 ER PT J AU Nigwekar, SU Kroshinsky, D Nazarian, RM Goverman, J Malhotra, R Jackson, VA Kamdar, MM Steele, DJR Thadhani, RI AF Nigwekar, Sagar U. Kroshinsky, Daniela Nazarian, Rosalynn M. Goverman, Jeremy Malhotra, Rajeev Jackson, Vicki Ann Kamdar, Mihir M. Steele, David J. R. Thadhani, Ravi I. TI Calciphylaxis: Risk Factors, Diagnosis, and Treatment SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Calcific uremic arteriolopathy; calciphylaxis; risk factors; sodium thiosulfate; warfarin; review ID CALCIFIC UREMIC ARTERIOLOPATHY; STAGE RENAL-DISEASE; INTRAPERITONEAL SODIUM THIOSULFATE; TISSUE-PLASMINOGEN ACTIVATOR; HYPERBARIC-OXYGEN THERAPY; OF-THE-LITERATURE; VASCULAR CALCIFICATION; PROXIMAL CALCIPHYLAXIS; HEMODIALYSIS-PATIENT; SKIN NECROSIS AB Calciphylaxis is a rare but devastating condition that has continued to challenge the medical community since its early descriptions in the scientific literature many decades ago. It is predominantly seen in patients with chronic kidney failure treated with dialysis (uremic calciphylaxis) but is also described in patients with earlier stages of chronic kidney disease and with normal kidney function. In this review, we discuss the available medical literature regarding risk factors, diagnosis, and treatment of both uremic and nonuremic calciphylaxis. High-quality evidence for the evaluation and management of calciphylaxis is lacking at this time due to its rare incidence and poorly understood pathogenesis and the relative paucity of collaborative research efforts. We hereby provide a summary of recommendations developed by a multidisciplinary team for patients with calciphylaxis. (C) 2015 by the National Kidney Foundation, Inc. C1 [Nigwekar, Sagar U.; Steele, David J. R.; Thadhani, Ravi I.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dermatopathol Unit, Pathol Serv, Boston, MA 02114 USA. [Goverman, Jeremy] Massachusetts Gen Hosp, Dept Surg, Burn Serv, Boston, MA 02114 USA. [Malhotra, Rajeev] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jackson, Vicki Ann; Kamdar, Mihir M.] Massachusetts Gen Hosp, Palliat Care Div, Boston, MA 02114 USA. RP Nigwekar, SU (reprint author), 165 Cambridge St,Ste 302, Boston, MA 02114 USA. EM snigwekar@mgh.harvard.edu OI Malhotra, Rajeev/0000-0003-0120-4630 FU Sanofi-Aventis; Abbott Laboratories FX Dr Nigwekar reports receiving lecture honoraria from Sanofi-Aventis and is a prior recipient of Nephrology Fellowship Award from Sanofi-Aventis. Dr Thadhani is a consultant to Fresenius Medical Care, North America and has received a research grant from Abbott Laboratories. The remaining authors declare that they have no relevant financial interests. NR 135 TC 41 Z9 41 U1 6 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2015 VL 66 IS 1 BP 133 EP 146 DI 10.1053/j.ajkd.2015.01.034 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA CL1UO UT WOS:000356730600023 PM 25960299 ER PT J AU Hoo, GWS Lin, HK Junaid, I Klaustermeyer, WB AF Hoo, Guy W. Soo Lin, Henry K. Junaid, Imran Klaustermeyer, William B. TI Angiotensin-converting Enzyme Inhibitor Angioedema Requiring Admission to an Intensive Care Unit SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Angioedema; Angiotensin-converting enzyme inhibitor; Respiratory failure ID EMERGENCY-DEPARTMENT; CLINICAL-EXPERIENCE; RISK; HOSPITALIZATIONS; STATES; DRUGS AB OBJECTIVE: The purpose of this study was to review consecutive cases of angiotensin-converting enzyme (ACE) inhibitor angioedema admitted to an intensive care unit. METHODS: Fifty subjects with ACE-inhibitor angioedema admitted from 1998-2011 were reviewed. RESULTS: All 50 subjects were men, 62.8 +/- 8.4 years of age, 76% African Americans. Fifteen (30%) required ventilatory support and 2 (4%) required tracheostomy. Over half (56%) had taken ACE inhibitors for over a year. Logistic regression identified dyspnea and tongue involvement with the need for ventilatory support (P < .01). Hypercapnia (PaCO2 +/- 45.2 +/- 6.7; P < 0.046) also identified patients needing ventilatory support. CONCLUSIONS: Ventilatory support was provided for about one-third of those with ACE inhibitorassociated angioedema. Angioedema can occur even after extended use. Dyspnea and tongue involvement identified patients requiring ventilatory support. Published by Elsevier Inc. C1 [Hoo, Guy W. Soo] Univ Calif Los Angeles, Pulm & Crit Care Sect, Los Angeles, CA USA. [Lin, Henry K.; Junaid, Imran; Klaustermeyer, William B.] Univ Calif Los Angeles, Allergy & Immunol Sect, Dept Med, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lin, Henry K.; Junaid, Imran; Klaustermeyer, William B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Hoo, GWS (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Pulm & Crit Care Sect, 11301 Wilshire Blvd W111Q, Los Angeles, CA 90073 USA. EM guy.soohoo@va.gov NR 19 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUL PY 2015 VL 128 IS 7 BP 785 EP 789 DI 10.1016/j.amjmed.2015.02.006 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA CK6WS UT WOS:000356370000036 ER PT J AU Kelly, JF Wakeman, SE Saitz, R AF Kelly, John F. Wakeman, Sarah E. Saitz, Richard TI Neither Abusiveness with Patients nor Naivety with Drugs Reply SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Kelly, John F.; Wakeman, Sarah E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kelly, John F.] Harvard Univ, Sch Med, Boston, MA USA. [Saitz, Richard] Boston Univ, Med Ctr, Boston, MA USA. RP Kelly, JF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 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 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUL PY 2015 VL 128 IS 7 BP E29 EP E29 DI 10.1016/j.amjmed.2015.03.003 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CK6WS UT WOS:000356370000015 ER PT J AU Hernandez, RA Hevelone, ND Lopez, L Finlayson, SRG Chittenden, E Cooper, Z AF Hernandez, Roland A. Hevelone, Nathanael D. Lopez, Lenny Finlayson, Samuel R. G. Chittenden, Eva Cooper, Zara TI Racial variation in the use of life-sustaining treatments among patients who die after major elective surgery SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE End-of-life care; Life-sustaining treatment; Quality of death; Racial disparities ID INTENSIVE-CARE-UNIT; QUALITY-OF-LIFE; MEDICARE BENEFICIARIES; ETHNIC-DIFFERENCES; MENTAL-HEALTH; END; DEATH; PREFERENCES; ATTITUDES; CANCER AB BACKGROUND: Although various studies have documented increased life-sustaining treatments among racial minorities in medical patients, whether similar disparities exist in surgical patients is unknown. METHODS: A retrospective cohort study using the Nationwide Inpatient Sample (2006 to 2011) examining patients older than 39 years who died after elective colectomy was performed. Primary predictor variable was race, and main outcome was the use of life-sustaining treatment. RESULTS: In univariate analysis, significant differences existed in use of cardiopulmonary resuscitation (CPR; black, 35.9%; Hispanic, 29.0%; other, 24.5%; white, 11.7%; P = .002) and reintubation (Hispanic, 75.0%; other, 69.0%; black, 52.3%; white, 45.2%; P = .01). In multivariate analysis, black (odds ratio [OR], 3.67; P = .01) and Hispanic (OR, 4.21; P = .03) patients were more likely to have undergone CPR, and Hispanic patients (OR, 4.24; P = .01) were more likely to have been reintubated (reference: white). CONCLUSIONS: Blacks and Hispanics had increased odds of experiencing CPR, and Hispanics were more likely to have been reintubated before death after a major elective operation. These variations may imply worse quality of death and increased associated costs. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hernandez, Roland A.; Hevelone, Nathanael D.; Cooper, Zara] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Hernandez, Roland A.] Dartmouth Hitchcock Med Ctr, Dept Surg, Lebanon, NH 03766 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02115 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Dept Gen Med, Boston, MA 02114 USA. [Lopez, Lenny] Brigham & Womens Hosp, Boston, MA 02115 USA. [Finlayson, Samuel R. G.] Univ Utah, Sch Med, Dept Surg, Salt Lake City, UT USA. [Chittenden, Eva] Massachusetts Gen Hosp, Div Pain & Palliat Med, Boston, MA 02114 USA. [Cooper, Zara] Brigham & Womens Hosp, Div Trauma Burns & Surg Crit Care, Boston, MA 02115 USA. RP Cooper, Z (reprint author), Brigham & Womens Hosp, Ctr Surg & Publ Hlth, 75 Francis St, Boston, MA 02115 USA. EM zcooper@partners.org OI Hernandez, Roland/0000-0002-8258-3339 FU Loan Repayment Grant National Institute on Minority Health and Health Disparities,; Klarman Family Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [1K23DK098280-01] FX Zara Cooper was supported by a Loan Repayment Grant National Institute on Minority Health and Health Disparities, and a grant from the Klarman Family Foundation. Dr. Lopez thanks the RWJ Foundation Harold Amos Faculty Development Program and National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK098280-01). Dr. Cooper had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 29 TC 6 Z9 6 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2015 VL 210 IS 1 BP 52 EP 58 DI 10.1016/j.amjsurg.2014.08.025 PG 7 WC Surgery SC Surgery GA CK4YR UT WOS:000356229800009 PM 25465749 ER PT J AU Tang, R Coopey, SB Specht, MC Lei, L Gadd, MA Hughes, KS Brachtel, EF Smith, BL AF Tang, Rong Coopey, Suzanne B. Specht, Michelle C. Lei, Lan Gadd, Michele A. Hughes, Kevin S. Brachtel, Elena F. Smith, Barbara L. TI Lumpectomy specimen margins are not reliable in predicting residual disease in breast conserving surgery SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Breast cancer; Lumpectomy margins; Shaved cavity margins; Residual disease ID CARCINOMA IN-SITU; RE-EXCISION RATES; 20-YEAR FOLLOW-UP; TUMOR BURDEN; SURGICAL MARGINS; LOCAL RECURRENCE; CANCER PATIENTS; MASTECTOMY; CONSERVATION; IRRADIATION AB BACKGROUND: In breast conserving surgery, the concordance between lumpectomy margin (LM) status and the status of the corresponding lumpectomy cavity remains uncertain. METHODS: We analyzed pathology reports of lumpectomies from 2004 to 2006. We included those which contained both ink-directed LM and complete (>= 4) separate corresponding shaved cavity margins (SCMs). SCM pathology was used as a surrogate for lumpectomy cavity status, to determine the predictive value of LM for residual disease. RESULTS: Pathology from 1,201 pairs of LM and SCM from 242 patients was compared. LM status predicted corresponding lumpectomy cavity status with 50.9% sensitivity, 69.5% specificity, 35% positive predictive value, and 81.4% negative predictive value, giving an overall accuracy of 64.9%. CONCLUSIONS: Oriented LMs are not reliable for predicting lumpectomy cavity status, and therefore not reliable for directing re-excision. Taking complete, oriented SCMs at the time of lumpectomy may improve accuracy compared with traditional LM assessment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Tang, Rong; Coopey, Suzanne B.; Specht, Michelle C.; Lei, Lan; Gadd, Michele A.; Hughes, Kevin S.; Smith, Barbara L.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Tang, Rong] Cent S Univ, Affiliated Tumor Hosp, Hunan Prov Tumor Hosp, Xiangya Med Sch,Div Breast Surg, Changsha 410013, Hunan, Peoples R China. [Brachtel, Elena F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Smith, BL (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, 55 Fruit St, Boston, MA 02114 USA. EM blsmith1@partners.org OI Hughes, Kevin/0000-0003-4084-6484 NR 36 TC 2 Z9 2 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2015 VL 210 IS 1 BP 93 EP 98 DI 10.1016/j.amjsurg.2014.09.029 PG 6 WC Surgery SC Surgery GA CK4YR UT WOS:000356229800015 PM 25613784 ER PT J AU Fishman, JA Thomson, AW AF Fishman, J. A. Thomson, A. W. TI Clinical Implications of Basic Science Discoveries: Immune Homeostasis and the Microbiome-Dietary and Therapeutic Modulation and Implications for Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Review ID SEGMENTED FILAMENTOUS BACTERIA; STEM-CELL TRANSPLANTATION; VERSUS-HOST-DISEASE; ALLOGRAFT ACCEPTANCE; INFECTION PREVENTS; COMMENSAL BACTERIA; RETINOIC ACID; GUT MICROBES; TOLERANCE; ECOLOGY AB Links between the human microbiome and the innate and adaptive immune systems and their impact on autoimmune and inflammatory diseases are only beginning to be recognized. Characterization of the complex human microbial community is facilitated by culture-independent nucleic acid sequencing tools and bioinformatics systems. Specific organisms and microbial antigens are linked with initiation of innate immune responses that, depending on the context, may be associated with tolerogenic or effector immune responses. Further complexity is introduced by preclinical data that demonstrate the impacts of dietary manipulation on the prevention of genetically determined, systemic autoimmune disorders and on gastrointestinal microbiota. Investigation of interactions of complex microbial populations with the human immune system may provide new targets for clinical management in allotransplantation. C1 [Fishman, J. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fishman, J. A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Thomson, A. W.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jfishman@mgh.harvard.edu NR 49 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2015 VL 15 IS 7 BP 1755 EP 1758 DI 10.1111/ajt.13236 PG 4 WC Surgery; Transplantation SC Surgery; Transplantation GA CK8NF UT WOS:000356494300011 PM 25810247 ER PT J AU Streblow, DN Hwee, YK Kreklywich, CN Andoh, T Denton, M Smith, P Hart, E Broekel, R Pallett, C Rogers, K Streblow, AD Chuop, M Perry, A Slifka, M Messaoudi, I Orloff, SL AF Streblow, D. N. Hwee, Y. K. Kreklywich, C. N. Andoh, T. Denton, M. Smith, P. Hart, E. Broekel, R. Pallett, C. Rogers, K. Streblow, A. D. Chuop, M. Perry, A. Slifka, M. Messaoudi, I. Orloff, S. L. TI Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naive Recipients of Infected Donor Allograft Hearts SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID GANCICLOVIR-RESISTANT CYTOMEGALOVIRUS; TRANSPLANT VASCULAR SCLEROSIS; CELL IMMUNE RECONSTITUTION; GLYCOPROTEIN-B VACCINE; CD8(+) T-CELLS; SMALL-BOWEL; PREEMPTIVE THERAPY; CARDIAC ALLOGRAFTS; VIRUS-VACCINE; RESPONSES AB Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naive recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naive or H2O2-inactivated RCMV-vaccinated Lewis recipients. Recipients of RCMV-infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection-POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naive recipients demonstrate that both T-cell and B-cell arms of the adaptive immune response provide protection against CMV-accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti-viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. C1 [Streblow, D. N.; Perry, A.; Slifka, M.; Orloff, S. L.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Streblow, D. N.; Kreklywich, C. N.; Denton, M.; Smith, P.; Hart, E.; Broekel, R.; Pallett, C.; Rogers, K.; Streblow, A. D.; Chuop, M.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Hwee, Y. K.; Kreklywich, C. N.; Andoh, T.; Orloff, S. L.] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR USA. [Andoh, T.; Orloff, S. L.] Portland VA Med Ctr, Portland, OR USA. [Slifka, M.] Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR USA. [Messaoudi, I.] Univ Calif Riverside, Sch Med, Div Biomed Sci, Riverside, CA 92521 USA. RP Streblow, DN (reprint author), Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. EM streblow@ohsu.edu FU National Institutes of Health [HL083194, HL 66238-01] FX This work was supported by research grants from the National Institutes of Health to D.N.S. (HL083194) and S.L.O. (HL 66238-01). NR 44 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2015 VL 15 IS 7 BP 1805 EP 1816 DI 10.1111/ajt.13188 PG 12 WC Surgery; Transplantation SC Surgery; Transplantation GA CK8NF UT WOS:000356494300016 PM 25766876 ER PT J AU Adler, JT Dong, N Markmann, JF Schoenfeld, D Yeh, H AF Adler, J. T. Dong, N. Markmann, J. F. Schoenfeld, D. Yeh, H. TI Role of Patient Factors and Practice Patterns in Determining Access to Liver Waitlist SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID DEATH CERTIFICATES; UNITED-STATES; TRANSPLANTATION; RISK; MORTALITY; SURVIVAL; FAILURE; CANCER AB Geographic variability in access to care is a persistent challenge in transplantation. Little is known about how patients with end-stage liver disease are chosen for referral, evaluation and listing. Utilizing death certificate data from the Centers for Disease Control and Prevention from 2002 to 2009, estimated liver demand (ELD) was measured by aggregating annual deaths from liver disease and liver transplants performed in each donor service area (DSA). In DSAs with higher ELD, more patients per capita were listed for transplantation (p<0.001). In addition, listing rates per ELD varied fivefold across DSAs, with more patients per ELD being transplanted in DSAs with higher listing rates (p<0.001). After adjusting for liver donor risk index and MELD at transplant, there was no association between listing rate and posttransplant survival (HR 1.002, p=0.77). In addition, DSAs with lower listing rates were more likely to export organs (p<0.001) of lower liver donor risk index (p<0.001). Listing sicker patients was associated with increased access to the waitlist and transplantation and more efficient organ utilization, but had minimal effect on posttransplant outcomes after adjusting for the resulting organ shortage. C1 [Adler, J. T.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Adler, J. T.; Dong, N.; Markmann, J. F.; Yeh, H.] Massachusetts Gen Hosp, Dept Surg, Div Transplant Surg, Boston, MA 02114 USA. [Markmann, J. F.; Yeh, H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Schoenfeld, D.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Yeh, H (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Transplant Surg, Boston, MA 02114 USA. EM hyeh@partners.org OI Adler, Joel/0000-0001-8190-3444 FU Harvard Catalyst (National Center for Research Resources); Harvard Catalyst (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR00170-05]; Harvard University; NIH [K08-DK094965]; Center for Surgery and Public Health at Brigham and Women's Hospital FX J.T.A. is funded by the Arthur Tracy Cabot fellowship from the Center for Surgery and Public Health at Brigham and Women's Hospital. This work was conducted with support from Harvard Catalyst (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR00170-05, and financial contributions from Harvard University and its affiliated academic healthcare centers) (DAS) and NIH K08-DK094965 (HY). NR 18 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2015 VL 15 IS 7 BP 1836 EP 1842 DI 10.1111/ajt.13301 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA CK8NF UT WOS:000356494300019 PM 25931200 ER PT J AU Bao, Y Curhan, G Merriman, T Plenge, R Kraft, P Choi, HK AF Bao, Ying Curhan, Gary Merriman, Tony Plenge, Robert Kraft, Peter Choi, Hyon K. TI Lack of gene-diuretic interactions on the risk of incident gout: the Nurses' Health Study and Health Professionals Follow-up Study SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID GENOME-WIDE ASSOCIATION; COFFEE CONSUMPTION; MEN; HYPERTENSION; VARIANTS; DISEASE; COHORT AB Background Diuretic-induced gout might occur only among those with a genetic predisposition to hyperuricaemia, as suggested by a recent study with 108 self-reported gout cases. Methods We examined the role of urate genes on the risk of diuretic-induced incident gout in 6850 women from the Nurses' Health Study (NHS) and in 4223 men from the Health Professionals Follow-up Study (HPFS). Two published genetic risk scores (GRSs) were calculated using urate-associated single-nucleotide polymorphisms for 8 (GRS8) and 29 genes (GRS29). Results Our analyses included 727 and 354 confirmed incident gout cases in HPFS and NHS, respectively. The multivariate relative risk (RR) for diuretic use was 2.20 and 1.69 among those with GRS8 < and >= the median (p for interaction=0.27). The corresponding RRs using GRS29 were 2.19 and 1.88 (p for interaction=0.40). The lack of interaction persisted in NHS (all p values >0.20) and in our analyses limited to those with hypertension in both cohorts. SLC22A11 (OAT4) showed a significant interaction only among women but in the opposite direction to the recent study. Conclusions In these large prospective studies, individuals with a genetic predisposition for hyperuricaemia are not at a higher risk of developing diuretic-induced gout than those without. C1 [Bao, Ying; Curhan, Gary; Choi, Hyon K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02114 USA. [Curhan, Gary; Plenge, Robert] Harvard Univ, Sch Med, Brigham & Womens Hosp, Renal Div,Dept Med, Boston, MA 02114 USA. [Merriman, Tony] Univ Otago, Dunedin, New Zealand. [Kraft, Peter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Sch Publ Hlth, Boston, MA 02114 USA. [Choi, Hyon K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA 02114 USA. RP Choi, HK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St,Bulfinch 165, Boston, MA 02114 USA. EM hchoi@partners.org OI Merriman, Tony/0000-0003-0844-8726 FU National Institutes of Health [R01AR056291, R01AR065944, UM1CA167552, P01CA87969] FX This research was supported by grants R01AR056291, R01AR065944, UM1CA167552 and P01CA87969 from the National Institutes of Health. NR 20 TC 7 Z9 7 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2015 VL 74 IS 7 BP 1394 EP 1398 DI 10.1136/annrheumdis-2014-206534 PG 5 WC Rheumatology SC Rheumatology GA CK2EZ UT WOS:000356024700011 PM 25667207 ER PT J AU Zhang, Y Vasheghani, F Li, YH Blati, M Simeone, K Fahmi, H Lussier, B Roughley, P Lagares, D Pelletier, JP Martel-Pelletier, J Kapoor, M AF Zhang, Yue Vasheghani, Faezeh Li, Ying-hua Blati, Meryem Simeone, Kayla Fahmi, Hassan Lussier, Bertrand Roughley, Peter Lagares, David Pelletier, Jean-Pierre Martel-Pelletier, Johanne Kapoor, Mohit TI Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; LIFE-SPAN; MOUSE; RAPAMYCIN; MODEL; AMPK; KINASE; GROWTH; ULK1 AB Objectives Mammalian target of rapamycin (mTOR) (a serine/threonine protein kinase) is a major repressor of autophagy, a cell survival mechanism. The specific in vivo mechanism of mTOR signalling in OA pathophysiology is not fully characterised. We determined the expression of mTOR and known autophagy genes in human OA cartilage as well as mouse and dog models of experimental OA. We created cartilage-specific mTOR knockout (KO) mice to determine the specific role of mTOR in OA pathophysiology and autophagy signalling in vivo. Methods Inducible cartilage-specific mTOR KO mice were generated and subjected to mouse model of OA. Human OA chondrocytes were treated with rapamycin and transfected with Unc-51-like kinase 1 (ULK1) siRNA to determine mTOR signalling. Results mTOR is overexpressed in human OA cartilage as well as mouse and dog experimental OA. Upregulation of mTOR expression co-relates with increased chondrocyte apoptosis and reduced expression of key autophagy genes during OA. Subsequently, we show for the first time that cartilage-specific ablation of mTOR results in increased autophagy signalling and a significant protection from destabilisation of medial meniscus (DMM)-induced OA associated with a significant reduction in the articular cartilage degradation, apoptosis and synovial fibrosis. Furthermore, we show that regulation of ULK1/adenosine monophosphate-activated protein kinase (AMPK) signalling pathway by mTOR may in part be responsible for regulating autophagy signalling and the balance between catabolic and anabolic factors in the articular cartilage. Conclusions This study provides a direct evidence of the role of mTOR and its downstream modulation of autophagy in articular cartilage homeostasis. C1 [Zhang, Yue; Vasheghani, Faezeh; Li, Ying-hua; Blati, Meryem; Simeone, Kayla; Fahmi, Hassan; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne; Kapoor, Mohit] Univ Montreal Res Ctr CRCHUM, Osteoarthrit Res Unit, Montreal, PQ, Canada. [Lussier, Bertrand] Univ Montreal, Dept Clin Sci, Fac Vet Med, Montreal, PQ, Canada. [Roughley, Peter] McGill Univ, Shriners Hosp, Genet Unit, Montreal, PQ, Canada. [Lagares, David] Harvard Univ, Pulm & Crit Care Unit, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. [Lagares, David] Harvard Univ, Ctr Immunol & Inflammatory Dis, Massachusetts Gen Hosp, Dept Med,Med Sch, Cambridge, MA 02138 USA. [Kapoor, Mohit] Toronto Western Hosp, Div Genet & Dev, Toronto Western Res Inst, UHN, Toronto, ON M5T 2S8, Canada. RP Kapoor, M (reprint author), Toronto Western Hosp, Div Genet & Dev, Toronto Western Res Inst, UHN, 60 Leonard Ave, Toronto, ON M5T 2S8, Canada. EM mkapoor@uhnresearch.ca FU Dr Mohit Kapoor's Canadian Institutes of Health Research [MOP126016]; European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO); Amgen FX This work was supported by Dr Mohit Kapoor's Canadian Institutes of Health Research Operating Grant MOP126016. Y Z is a recipient of Young Investigator Fellowship from The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and Amgen. NR 30 TC 36 Z9 37 U1 6 U2 17 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2015 VL 74 IS 7 BP 1432 EP 1440 DI 10.1136/annrheumdis-2013-204599 PG 9 WC Rheumatology SC Rheumatology GA CK2EZ UT WOS:000356024700016 PM 24651621 ER PT J AU McGuire, JF Piacentini, J Scahill, L Woods, DW Villarreal, R Wilhelm, S Walkup, JT Peterson, AL AF McGuire, Joseph F. Piacentini, John Scahill, Lawrence Woods, Douglas W. Villarreal, Robert Wilhelm, Sabine Walkup, John T. Peterson, Alan L. TI Bothersome tics in patients with chronic tic disorders: Characteristics and individualized treatment response to behavior therapy SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Tourette's disorder; Behavior therapy; Habit reversal training; Comprehensive behavioral intervention for tics; Treatment outcome; Individualized treatment response ID OBSESSIVE-COMPULSIVE DISORDER; RANDOMIZED CONTROLLED-TRIAL; SYNDROME IMPACT SURVEY; TOURETTE SYNDROME; PREMONITORY URGES; ANXIETY DISORDERS; HABIT-REVERSAL; SUPPORTIVE PSYCHOTHERAPY; NEGATIVE REINFORCEMENT; SEVERITY-SCALE AB This report examined the most frequently reported bothersome tics among individuals with chronic tic disorders and evaluated the improvement and remission of tics and their associated characteristics. Youths and adults (N = 240) were randomly assigned to receive the comprehensive behavioral intervention for tics (CBIT) or psychoeducation and supportive therapy (PST). At baseline, motor tics and tics with an urge were rated as more bothersome relative to vocal tics and tics without premonitory urges. The five most common bothersome tics included eye blinking, head jerks, sniffing, throat clearing, and other complex motor tics. While CBIT outperformed PST across tic type and urge presence, tics preceded by premonitory urges at baseline had higher severity at posttreatment across treatment condition. Six individual tic types had lower severity at posttreatment following CBIT relative to PST. Baseline urge presence was associated with tic remission for CBIT but not PST. Specific bothersome tics were more likely to remit with CBIT relative to PST. Findings suggest that individual tics respond and remit differently to CBIT relative to PST, with implications highlighting the negative reinforcement hypothesis in tic symptom maintenance. Clinicaltrials.gov identifiers: NCT00218777; NCT00231985. Published by Elsevier Ltd. C1 [McGuire, Joseph F.; Piacentini, John] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Scahill, Lawrence] Emory Univ, Marcus Ctr, Sch Med, Atlanta, GA 30329 USA. [Woods, Douglas W.] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Villarreal, Robert; Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Wilhelm, Sabine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wilhelm, Sabine] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Walkup, John T.] Cornell Univ, Weil Cornell Med Coll, New York, NY 10065 USA. [Peterson, Alan L.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Peterson, Alan L.] Univ Texas San Antonio, San Antonio, TX 78249 USA. RP Peterson, AL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7550 IH 10 West,Suite 1325, San Antonio, TX 78229 USA. EM jfmcguire@mednet.ucla.edu; jpiacentini@mednet.ucla.edu; lawrence.scahill@emory.edu; dowoods@tamu.edu; villarrear10@uthscsa.edu; swilhelm@mgh.harvard.edu; jtw9001@med.cornell.edu; petersona3@uthscsa.edu FU National Institute of Mental Health [R01MH070802, 5R01MH069877, R01MH069874, RO1MH069875] FX This research was supported by the following National Institute of Mental Health grants: R01MH070802 (Dr. Piacentini) with subcontracts to Drs. Woods, Scahill, Wilhelm, Peterson, and Walkup; 5R01MH069877 (Dr. Wilhelm), R01MH069874 (Dr. Scahill), and RO1MH069875 (Dr. Peterson), with subcontracts to Drs. Piacentini and Woods. Dr. Walkup served as a consult on these three grants. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health. NR 51 TC 4 Z9 4 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 EI 1873-622X J9 BEHAV RES THER JI Behav. Res. Ther. PD JUL PY 2015 VL 70 BP 56 EP 63 DI 10.1016/j.brat.2015.05.006 PG 8 WC Psychology, Clinical SC Psychology GA CK9HW UT WOS:000356552200007 PM 25988365 ER PT J AU Safdar, N Perencevich, E AF Safdar, Nasia Perencevich, Eli TI Crossing the quality chasm for Clostridium difficile infection prevention SO BMJ QUALITY & SAFETY LA English DT Editorial Material ID CARE; HOSPITALS C1 [Safdar, Nasia] Univ Wisconsin, Dept Med, Sch Med, Infect Dis Sect,William S Middleton Mem Vet Hosp, Madison, WI USA. [Perencevich, Eli] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Perencevich, Eli] Iowa City VA Healthcare Syst, Iowa City, IA USA. RP Safdar, N (reprint author), Univ Wisconsin Hosp & Clin, 1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu FU AHRQ HHS [R03 HS023791, R03HS023791, R18 HS024039] NR 17 TC 1 Z9 1 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD JUL PY 2015 VL 24 IS 7 BP 409 EP 411 DI 10.1136/bmjqs-2015-004344 PG 3 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CK9EI UT WOS:000356543000001 PM 25979001 ER PT J AU Sacks, GD Shannon, EM Dawes, AJ Rollo, JC Nguyen, DK Russell, MM Ko, CY Maggard-Gibbons, MA AF Sacks, Greg D. Shannon, Evan M. Dawes, Aaron J. Rollo, Johnathon C. Nguyen, David K. Russell, Marcia M. Ko, Clifford Y. Maggard-Gibbons, Melinda A. TI Teamwork, communication and safety climate: a systematic review of interventions to improve surgical culture SO BMJ QUALITY & SAFETY LA English DT Review ID RANDOMIZED-CONTROLLED-TRIAL; OPERATING-ROOM BRIEFINGS; INTERRUPTED TIME-SERIES; PATIENT SAFETY; TRAINING-PROGRAM; CHECKLIST; THEATER; PERFORMANCE; SURGERY; CARE AB Objectives To define the target domains of culture-improvement interventions, to assess the impact of these interventions on surgical culture and to determine whether culture improvements lead to better patient outcomes and improved healthcare efficiency. Background Healthcare systems are investing considerable resources in improving workplace culture. It remains unclear whether these interventions, when aimed at surgical care, are successful and whether they are associated with changes in patient outcomes. Methods PubMed, Cochrane, Web of Science and Scopus databases were searched from January 1980 to January 2015. We included studies on interventions that aimed to improve surgical culture, defined as the interpersonal, social and organisational factors that affect the healthcare environment and patient care. The quality of studies was assessed using an adapted tool to focus the review on higher-quality studies. Due to study heterogeneity, findings were narratively reviewed. Findings The 47 studies meeting inclusion criteria (4 randomised trials and 10 moderate-quality observational studies) reported on interventions that targeted three domains of culture: teamwork (n=28), communication (n=26) and safety climate (n=19); several targeted more than one domain. All moderate-quality studies showed improvements in at least one of these domains. Two studies also demonstrated improvements in patient outcomes, such as reduced postoperative complications and even reduced postoperative mortality (absolute risk reduction 1.7%). Two studies reported improvements in healthcare efficiency, including fewer operating room delays. These findings were supported by similar results from low-quality studies. Conclusions The literature provides promising evidence for various strategies to improve surgical culture, although these approaches differ in terms of the interventions employed as well as the techniques used to measure culture. Nevertheless, culture improvement appears to be associated with other positive effects, including better patient outcomes and enhanced healthcare efficiency. C1 [Sacks, Greg D.; Dawes, Aaron J.; Rollo, Johnathon C.; Nguyen, David K.; Russell, Marcia M.; Ko, Clifford Y.; Maggard-Gibbons, Melinda A.] Univ Calif Los Angeles, David Geffen Sch Med, Surg, Los Angeles, CA 90095 USA. [Shannon, Evan M.] UCSF Sch Med, San Francisco, CA USA. [Russell, Marcia M.; Ko, Clifford Y.; Maggard-Gibbons, Melinda A.] VA Greater Los Angeles Healthcare Syst, Gen Surg, Los Angeles, CA USA. RP Sacks, GD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Surg, Los Angeles, CA 90095 USA. EM gsacks@mednet.ucla.edu OI Dawes, Aaron/0000-0003-4574-6765 NR 73 TC 10 Z9 10 U1 3 U2 29 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD JUL PY 2015 VL 24 IS 7 BP 458 EP 467 DI 10.1136/bmjqs-2014-003764 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CK9EI UT WOS:000356543000012 PM 26002946 ER PT J AU Brown, LC Petersen, IA Haddock, MG Bakkum-Gamez, JN Lee, LJ Cimbak, NC Berkowitz, RS Viswanathan, AN AF Brown, Lindsay C. Petersen, Ivy A. Haddock, Michael G. Bakkum-Gamez, Jamie N. Lee, Larissa J. Cimbak, Nicole C. Berkowitz, Ross S. Viswanathan, Akila N. TI Vaginal brachytherapy for early-stage carcinosarcoma of the uterus SO BRACHYTHERAPY LA English DT Article DE Carcinosarcoma; Radiation therapy; Uterine cancer ID GYNECOLOGIC-ONCOLOGY-GROUP; MIXED MULLERIAN TUMORS; PHASE-III TRIAL; CELL ENDOMETRIAL CANCER; UTERINE CARCINOSARCOMA; METAPLASTIC CARCINOMAS; RADIOTHERAPY; IFOSFAMIDE; SARCOMAS; THERAPY AB OBJECTIVE: Uterine caicinosarcoma (CS) is an aggressive malignancy and the optimal adjuvant treatment is not well-established. We report outcomes with vaginal brachytherapy (VB) for women with early-stage CS. METHODS AND MATERIALS: A multi-institutional retrospective study of Stage CS treated with hysterectomy, surgical staging, and adjuvant high-dose-rate VB without external-beam pelvic radiotherapy was performed. Rates of vaginal control, pelvic control, locoregional control, disease-free survival, and overall survival were determined using the Kaplan-Meier method. RESULTS: 33 patients were identified. Prescribed VB dose was 21 Gy in three fractions (n = 15 [45%]) or 24 Gy in six fractions (n = 18 [55%]). Eighteen patients (55%) received chemotherapy. Median followup was 2.0 years. Twenty-seven patients (82%) underwent pelvic lymphadenectomy, 5 (15%) had nodal sampling, and 1 (3%) had no lymph node assessment. Relapse occurred in 11 patients (33%), all of whom had lymph node evaluation. Locoregional relapse was a component of failure in 6 patients (18%), of whom 3 (9%) failed in the pelvis alone. Three patients (9%) had simultaneous distant and locoregional relapse (two vaginal, one pelvic). Five additional patients (15%) had distant relapse. Six of the 11 patients (55%) with disease recurrence received chemotherapy. Two-year vaginal control and pelvic control were 94% and 87%. Two-year locoregional control, disease-free survival, and overall survival were 81%, 66%, and 79%. CONCLUSIONS: Despite having early-stage disease and treatment with VB, patients in this series had relatively high rates of local and distant relapse. Patients who undergo lymphadenectomy and VB remain at risk for relapse. Novel treatment strategies are needed. (C) 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. C1 [Brown, Lindsay C.; Petersen, Ivy A.; Haddock, Michael G.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Bakkum-Gamez, Jamie N.] Mayo Clin, Dept Gynecol Oncol, Rochester, MN USA. [Lee, Larissa J.; Cimbak, Nicole C.; Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Berkowitz, Ross S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Dana Farber Canc Inst, Div Gynecol Oncol, Boston, MA 02115 USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu NR 28 TC 3 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 EI 1873-1449 J9 BRACHYTHERAPY JI Brachytherapy PD JUL-AUG PY 2015 VL 14 IS 4 BP 433 EP 439 DI 10.1016/j.brachy.2015.02.194 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK9JH UT WOS:000356555900002 PM 25890795 ER PT J AU Damato, AL Lee, LJ Bhagwat, MS Buzurovic, I Cormack, RA Finucane, S Hansen, JL O'Farrell, DA Offiong, A Randall, U Friesen, S Viswanathan, AN AF Damato, Antonio L. Lee, Larissa J. Bhagwat, Mandar S. Buzurovic, Ivan Cormack, Robert A. Finucane, Susan Hansen, Jorgen L. O'Farrell, Desmond A. Offiong, Alecia Randall, Una Friesen, Scott Viswanathan, Akila N. TI Redesign of process map to increase efficiency: Reducing procedure time in cervical cancer brachytherapy SO BRACHYTHERAPY LA English DT Article DE Brachytherapy; Efficiency; Process maps; Workflow ID DOSE-RATE BRACHYTHERAPY; SOCIETY CONSENSUS GUIDELINES; QUALITY MANAGEMENT PROGRAM; LOCALLY ADVANCED-CARCINOMA; GYNECOLOGIC BRACHYTHERAPY; AMERICAN BRACHYTHERAPY; ADAPTIVE BRACHYTHERAPY; COMPUTED-TOMOGRAPHY; VOLUME PARAMETERS; CLINICAL-OUTCOMES AB PURPOSE: To increase intraprocedural efficiency in the use of clinical resources and to decrease planning time for cervical cancer brachytherapy treatments through redesign of the procedure's process map. METHODS AND MATERIALS: A multidisciplinary team identified all tasks and associated resources involved in cervical cancer brachytherapy in our institution and arranged them in a process map. A redesign of the treatment planning component of the process map was conducted with the goal of minimizing planning time. Planning time was measured on 20 consecutive insertions, of which 10 were performed with standard procedures and 10 with the redesigned process map, and results were compared. Statistical significance (p < 0.05) was measured with a two-tailed t test. RESULTS: Twelve tasks involved in cervical cancer brachytherapy treatments were identified. The process map showed that in standard procedures, the treatment planning tasks were performed sequentially. The process map was redesigned to specify that contouring and some planning tasks are performed concomitantly. Some quality assurance tasks were reorganized to minimize adverse effects of a possible error on procedure time. Test dry runs followed by live implementation confirmed the applicability of the new process map to clinical conditions. A 29% reduction in planning time (p < 0.01) was observed with the introduction of the redesigned process map. CONCLUSIONS: A process map for cervical cancer brachytherapy was generated. The treatment planning component of the process map was redesigned, resulting in a 29% decrease in planning time and a streamlining of the quality assurance process. (C) 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. C1 [Damato, Antonio L.; Lee, Larissa J.; Bhagwat, Mandar S.; Buzurovic, Ivan; Cormack, Robert A.; Finucane, Susan; Hansen, Jorgen L.; O'Farrell, Desmond A.; Offiong, Alecia; Randall, Una; Friesen, Scott; Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Damato, AL (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM adamato@lroc.harvard.edu RI Buzurovic, Ivan/C-8036-2011 OI Buzurovic, Ivan/0000-0001-9632-3434 FU National Institutes of Health [R21 CA167800] FX This work was partially funded by the National Institutes of Health R21 CA167800 (Principal Investigator: ANV). NR 38 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 EI 1873-1449 J9 BRACHYTHERAPY JI Brachytherapy PD JUL-AUG PY 2015 VL 14 IS 4 BP 471 EP 480 DI 10.1016/j.brachy.2014.11.016 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK9JH UT WOS:000356555900007 PM 25572438 ER PT J AU Muralidhar, V Mahal, BA Ziehr, DR Chen, YW Nezolosky, MD Viswanathan, VB Beard, CJ Devlin, PM Martin, NE Orio, PF Nguyen, PL AF Muralidhar, Vinayak Mahal, Brandon A. Ziehr, David R. Chen, Yu-Wei Nezolosky, Michelle D. Viswanathan, Vidya B. Beard, Clair J. Devlin, Phillip M. Martin, Neil E. Orio, Peter F., III Nguyen, Paul L. TI Shifting brachytherapy monotherapy case mix toward intermediate-risk prostate cancer SO BRACHYTHERAPY LA English DT Article DE Prostate cancer; Intermediate-risk prostate cancer; Prostate brachytherapy ID BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; CARCINOMA; OUTCOMES; SURGERY; TRENDS AB PURPOSE: The relative use of brachytherapy (BT) for prostate cancer has declined in recent years. In this setting, we sought to determine whether the case mix of BT monotherapy treated men has changed over time in terms of risk group composition. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was used to identify 30,939 patients diagnosed with prostate adenocarcinoma between 2004 and 2011 who received BT monotherapy. The case mix of BT monotherapy patients was calculated by patient risk group and year of diagnosis. RESULTS: Between 2004 and 2011, the use of BT monotherapy declined overall. The relative percentage of men undergoing BT with low-risk disease declined by 4.5%, whereas the relative percentage of patients with intermediate-risk disease increased by 4.7%. Non-white patients and those from poorer counties did not show shifts in the risk group makeup of BT monotherapy patients, whereas white patients and those from wealthier counties did. CONCLUSIONS: Although fewer patients with prostate cancer are undergoing BT monotherapy, men with intermediate-risk disease comprised a significantly larger portion of the BT case mix in 2011 compared with 2004. Future research efforts by brachytherapists should be directed toward improving BT technique, optimizing radiation doses, and obtaining long-term followup data for patients with intermediate-risk prostate cancer. (C) 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. C1 [Muralidhar, Vinayak] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Mahal, Brandon A.; Ziehr, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Yu-Wei] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA USA. [Nezolosky, Michelle D.; Viswanathan, Vidya B.; Beard, Clair J.; Devlin, Phillip M.; Martin, Neil E.; Orio, Peter F., III; Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Nezolosky, Michelle D.; Viswanathan, Vidya B.; Beard, Clair J.; Devlin, Phillip M.; Martin, Neil E.; Orio, Peter F., III; Nguyen, Paul L.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Health Sciences and Technology IDEA2 Program - Peter C. Farrell (1967) Fund; Prostate Cancer Foundation; Fitz's Cancer Warriors; Scott Forbes and Gina Ventre Fund FX This work was supported by grants from the Health Sciences and Technology IDEA2 Program supported by the Peter C. Farrell (1967) Fund, The Prostate Cancer Foundation, Fitz's Cancer Warriors, David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, and The Scott Forbes and Gina Ventre Fund. NR 22 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 EI 1873-1449 J9 BRACHYTHERAPY JI Brachytherapy PD JUL-AUG PY 2015 VL 14 IS 4 BP 511 EP 516 DI 10.1016/j.brachy.2015.03.004 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK9JH UT WOS:000356555900012 PM 25887342 ER PT J AU Gutchess, AH Sokal, R Coleman, JA Gotthilf, G Grewal, L Rosa, N AF Gutchess, Angela H. Sokal, Rebecca Coleman, Jennifer A. Gotthilf, Gina Grewal, Lauren Rosa, Nicole TI Age differences in self-referencing: Evidence for common and distinct encoding strategies SO BRAIN RESEARCH LA English DT Review DE self; fMRI; aging; memory ID MEDIAL PREFRONTAL CORTEX; EVENT-RELATED FMRI; EMOTIONAL MEMORY; OLDER-ADULTS; NEURAL BASIS; METAANALYSIS; INFORMATION; RELEVANCE; VALENCE; AROUSAL AB Although engagement of medial prefrontal cortex (MPFC) underlies self-referencing of information for younger and older adults, the region has not consistently been implicated across age groups for the encoding of self-referenced information. We sought to determine whether making judgments about others as well as the self influenced findings in the previous study. During an fMRI session, younger and older adults encoded adjectives using only a self-reference task. For items later remembered compared to those later forgotten, both age groups robustly recruited medial prefrontal cortex, indicating common neural regions support encoding across younger and older adults when participants make only self-reference judgments. Focal age differences emerged in regions related to emotional processing and cognitive control, though these differences are more limited than in tasks in which judgments also are made about others. We conclude that making judgments about another person differently affects the ways that younger and older adults make judgments about the self, with results of a follow-up behavioral study supporting this interpretation. This article is part of a Special Issue entitled Memory and Aging. (C) 2014 Elsevier B.V. All rights reserved. C1 [Gutchess, Angela H.; Sokal, Rebecca; Coleman, Jennifer A.; Gotthilf, Gina; Grewal, Lauren; Rosa, Nicole] Brandeis Univ, Waltham, MA 02454 USA. [Gutchess, Angela H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr, Charlestown, MA USA. [Sokal, Rebecca] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Coleman, Jennifer A.] Virginia Commonwealth Univ, Richmond, VA USA. [Grewal, Lauren] Univ Pittsburgh, Pittsburgh, PA USA. [Rosa, Nicole] Harvard Univ, Cambridge, MA 02138 USA. RP Gutchess, AH (reprint author), Brandeis Univ, Dept Psychol, 415 South St,MS 062, Waltham, MA 02454 USA. EM gutchess@brandeis.edu OI Coleman, Jennifer/0000-0002-0158-2589 FU National Institute on Aging [R21AG032382]; National Center for Research Resources [P41 RR14075]; MIND Institute FX We gratefully acknowledge experimental assistance from Allie Indeck, Maya Siegel, Christine Hosey, Deborah Chamama, and Brian Dahlben. This research was funded by National Institute on Aging (Grant R21AG032382), and portions of the research were conducted while A.H.G. was a fellow of the American Federation for Aging Research. The Athinoula A. Martinos Center for Biomedical Imaging is supported by the National Center for Research Resources (Grant P41 RR14075) and by the MIND Institute. NR 37 TC 1 Z9 1 U1 1 U2 7 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 JUL 1 PY 2015 VL 1612 BP 118 EP 127 DI 10.1016/j.brainres.2014.08.033 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CK9HR UT WOS:000356551700010 PM 25223905 ER PT J AU Viswanathan, AN Moughan, J Miller, BE Xiao, Y Jhingran, A Portelance, L Bosch, WR Matulonis, UA Horowitz, NS Mannel, RS Souhami, L Erickson, BA Winter, KA Small, W Gaffney, DK AF Viswanathan, Akila N. Moughan, Jennifer Miller, Brigitte E. Xiao, Ying Jhingran, Anuja Portelance, Lorraine Bosch, Walter R. Matulonis, Ursula A. Horowitz, Neil S. Mannel, Robert S. Souhami, Luis Erickson, Beth A. Winter, Kathryn A. Small, William, Jr. Gaffney, David K. TI NRG Oncology/RTOG 0921: A phase 2 study of postoperative intensity-modulated radiotherapy with concurrent cisplatin and bevacizumab followed by carboplatin and paclitaxel for patients with endometrial cancer SO CANCER LA English DT Article DE endometrial cancer; radiation; bevacizumab; chemotherapy; intensity-modulated radiotherapy (IMRT) ID PELVIC RADIATION-THERAPY; III TRIAL; CISPLATIN/PACLITAXEL CHEMOTHERAPY; GASTROINTESTINAL TOXICITY; ADJUVANT CHEMOTHERAPY; CERVICAL-CANCER; RISK; CARCINOMA; IRRADIATION; SURGERY AB BACKGROUNDThe current study was conducted to assess acute and late adverse events (AEs), overall survival (OS), pelvic failure, regional failure, distant failure, and disease-free survival in a prospective phase 2 clinical trial of bevacizumab and pelvic intensity-modulated radiotherapy (IMRT) with chemotherapy in patients with high-risk endometrial cancer. METHODSPatients underwent a hysterectomy and lymph node removal, and had 1 of the following high-risk factors: grade 3 carcinoma with >50% myometrial invasion, grade 2 or 3 disease with any cervical stromal invasion, or known extrauterine extension confined to the pelvis. Treatment included pelvic IMRT and concurrent cisplatin on days 1 and 29 of radiation and bevacizumab (at a dose of 5 mg/kg on days 1, 15, and 29 of radiation) followed by adjuvant carboplatin and paclitaxel for 4 cycles. The primary endpoint was grade 3 AEs occurring within the first 90 days (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). RESULTSA total of 34 patients were accrued from November 2009 through December 2011, 30 of whom were eligible and received study treatment. Seven of 30 patients (23.3%; 1-sided 95% confidence interval, 10.6%-36.0%) developed grade 3 treatment-related nonhematologic toxicities within 90 days; an additional 6 patients experienced grade 3 toxicities between 90 and 365 days after treatment. The 2-year OS rate was 96.7% and the disease-free survival rate was 79.1%. No patient developed a within-field pelvic failure and no patients with International Federation of Gynecology and Obstetrics stage I to IIIA disease developed disease recurrence after a median follow-up of 26 months. CONCLUSIONSPostoperative bevacizumab added to chemotherapy and pelvic IMRT appears to be well tolerated and results in high OS rates at 2 years for patients with high-risk endometrial carcinoma. Cancer 2015;121:2156-2163. (c) 2015 American Cancer Society. C1 [Viswanathan, Akila N.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol,Med Sch, Boston, MA 02115 USA. [Moughan, Jennifer; Winter, Kathryn A.] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Miller, Brigitte E.] Carolinas Healthcare Syst NorthEast, Levine Canc Inst, Concord, NC USA. [Xiao, Ying] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Portelance, Lorraine] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Bosch, Walter R.] Washington Univ, St Louis, MO USA. [Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Horowitz, Neil S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02115 USA. [Mannel, Robert S.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Souhami, Luis] McGill Univ, Montreal, PQ, Canada. [Erickson, Beth A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Small, William, Jr.] Loyola Univ, Chicago, IL 60611 USA. [Gaffney, David K.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu FU National Cancer Institute [U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA81647, U24CA180803]; NIH [R21 167800] FX Supported by National Cancer Institute grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA81647, and U24CA180803. Dr. Viswanathan receives support through NIH R21 167800. Dr. Bosch has received a grant and other research support from Augmenix for work performed outside of the current study. Ms. Winter has acted as a paid statistical member of the Data Monitoring Committee for an ovarian trial performed for Roche outside of the current study. NR 19 TC 4 Z9 4 U1 1 U2 6 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 JUL 1 PY 2015 VL 121 IS 13 BP 2156 EP 2163 DI 10.1002/cncr.29337 PG 8 WC Oncology SC Oncology GA CK7SU UT WOS:000356433600012 PM 25847373 ER PT J AU Castillo, JJ Olszewski, AJ Hunter, ZR Kanan, S Meid, K Treon, SP AF Castillo, Jorge J. Olszewski, Adam J. Hunter, Zachary R. Kanan, Sandra Meid, Kirsten Treon, Steven P. TI Incidence of secondary malignancies among patients with Waldenstrom macroglobulinemia: An analysis of the SEER database SO CANCER LA English DT Article DE epidemiology; incidence; lymphoplasmacytic lymphoma; secondary malignancies; Waldenstrom macroglobulinemia ID CHRONIC LYMPHOCYTIC-LEUKEMIA; LYMPHOPLASMACYTIC LYMPHOMA; CANCER; POPULATION; RISK; CHLORAMBUCIL; FLUDARABINE; NEOPLASMS; ANTIBODY; THERAPY AB BACKGROUNDWaldenstrom macroglobulinemia (WM) is an indolent malignancy that predominantly affects older individuals who are at risk for secondary malignancies (SMs). The objective of this study was to characterize the incidence of SMs after a diagnosis of WM with the Surveillance, Epidemiology, and End Results (SEER) database. METHODSWith SEER-13 data (1992-2011), standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for the rates of solid and hematologic SMs in WM patients versus the general population. The analysis was stratified by age, sex, race, year of diagnosis, and latency from the WM diagnosis. RESULTSAmong 4676 patients with WM, 681 SMs were recorded. The overall SIR was 1.49 (95% CI, 1.38-1.61), and the median time to an SM was 3.7 years. The cumulative incidence of SMs was 10% at 5 years and 16% at 10 years. The risk was significantly increased for cancers of the lungs, urinary tract, and thyroid; melanoma; aggressive lymphoma; and acute leukemia. The SIR for SMs in patients with WM was increased, regardless of age, sex, race, or year of diagnosis. CONCLUSIONSPatients with WM had a 49% higher risk of SMs than the general population. The selectively increased risk for hematologic SMs and certain solid SMs may be associated with transformation, therapy, and immune dysregulation. Cancer 2015;121:2230-2236. (c) 2015 American Cancer Society. C1 [Castillo, Jorge J.; Hunter, Zachary R.; Kanan, Sandra; Meid, Kirsten; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstrom Macroglobulinemia, Boston, MA 02215 USA. [Castillo, Jorge J.; Treon, Steven P.] Harvard Univ, Sch Med, Boston, MA USA. [Olszewski, Adam J.] Brown Univ, Mem Hosp Rhode Isl, Warren Alpert Med Sch, Div Hematol & Oncol, Pawtucket, RI 02860 USA. RP Castillo, JJ (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstrom Macroglobulinemia, 450 Brookline Ave,M221, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Olszewski, Adam/0000-0002-6472-6658; Castillo, Jorge/0000-0001-9490-7532; Hunter, Zachary/0000-0002-1689-1691 NR 30 TC 8 Z9 8 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 JUL 1 PY 2015 VL 121 IS 13 BP 2230 EP 2236 DI 10.1002/cncr.29334 PG 7 WC Oncology SC Oncology GA CK7SU UT WOS:000356433600021 PM 25757851 ER PT J AU Hanna, NH Dahlberg, SE Kolesar, JM Aggarwal, C Hirsch, FR Ramalingam, SS Schiller, JH AF Hanna, Nasser H. Dahlberg, Suzanne E. Kolesar, Jill M. Aggarwal, Charu Hirsch, Fred R. Ramalingam, Suresh S. Schiller, Joan H. TI Three-arm, randomized, phase 2 study of carboplatin and paclitaxel in combination with cetuximab, cixutumumab, or both for advanced non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based therapy: An Eastern Cooperative Oncology Group (ECOG) study (E4508) SO CANCER LA English DT Article DE carboplatin; cetuximab; cixutumumab; non-small cell lung cancer; paclitaxel ID GROWTH-FACTOR-I; RECEPTOR MONOCLONAL-ANTIBODY; GENE COPY NUMBER; III TRIAL; BINDING PROTEIN-3; EGFR MUTATIONS; OPEN-LABEL; CHEMOTHERAPY; ADENOCARCINOMA; SENSITIVITY AB BACKGROUNDPreclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC). METHODSPatients with chemotherapy-naive, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test. RESULTSFrom September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively. CONCLUSIONSOn the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC. Cancer 2015;121:2253-2261. (c) 2015 American Cancer Society. C1 [Hanna, Nasser H.] Indiana Univ, Hlth Simon Canc Ctr, Indianapolis, IN 46202 USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kolesar, Jill M.] Univ Wisconsin, Sch Pharm, Madison, WI 53706 USA. [Aggarwal, Charu] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Hirsch, Fred R.] Univ Colorado, Sch Med, Div Med Oncol, Denver, CO USA. [Ramalingam, Suresh S.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Schiller, Joan H.] Univ Texas SW Med Ctr Dallas, Div Hematol Oncol, Dallas, TX 75390 USA. RP Hanna, NH (reprint author), Indiana Univ, Indiana Univ Sch Med, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. EM nhanna@iupui.edu FU Public Health Service Grants [CA180820, CA180794, CA180795, CA180799, CA180864, CA180834, CA180870]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This study was conducted by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA180795, CA180799, CA180864, CA180834, CA180870, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. NR 28 TC 8 Z9 8 U1 0 U2 8 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 JUL 1 PY 2015 VL 121 IS 13 BP 2253 EP 2261 DI 10.1002/cncr.29308 PG 9 WC Oncology SC Oncology GA CK7SU UT WOS:000356433600024 PM 25740387 ER PT J AU Cohen, JM Granter, SR Werchniak, AE AF Cohen, J. M. Granter, S. R. Werchniak, A. E. TI Risk stratification in extramammary Paget disease SO CLINICAL AND EXPERIMENTAL DERMATOLOGY LA English DT Review ID LYMPH-NODE BIOPSY; PROGNOSTIC-FACTORS; MANAGEMENT; EXPRESSION AB Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best-understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of >1mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki-67, cyclin D1, Mucin 5AC and E-cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research. C1 [Cohen, J. M.; Granter, S. R.; Werchniak, A. E.] Harvard Univ, Sch Med, Boston, MA USA. [Granter, S. R.] Brigham & Womens Hosp, Dept Pathol, Div Dermatopathol, Boston, MA 02115 USA. [Werchniak, A. E.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Werchniak, A. E.] Dana Farber Canc Inst, Ctr Cutaneous Oncol, Boston, MA 02115 USA. RP Werchniak, AE (reprint author), Brigham & Womens Hosp, Dept Dermatol, 221 Longwood Ave, Boston, MA 02115 USA. EM awerchniak@partners.org NR 16 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0307-6938 EI 1365-2230 J9 CLIN EXP DERMATOL JI Clin. Exp. Dermatol. PD JUL PY 2015 VL 40 IS 5 BP 473 EP 478 DI 10.1111/ced.12690 PG 6 WC Dermatology SC Dermatology GA CL0JL UT WOS:000356628600001 PM 26011765 ER PT J AU Toosi, KK Hogaboom, NS Oyster, ML Boninger, ML AF Toosi, Kevin K. Hogaboom, Nathan S. Oyster, Michelle L. Boninger, Michael L. TI Computer keyboarding biomechanics and acute changes in median nerve indicative of carpal tunnel syndrome SO CLINICAL BIOMECHANICS LA English DT Article DE Carpal tunnel syndrome; Computer keyboarding biomechanics; Ultrasound; Ergonomics ID FOREARM POSTURES; CANAL PRESSURES; WRIST; DIAGNOSIS; SONOGRAPHY; ULTRASOUND; MOVEMENT; WORKERS; USERS AB Background: Carpal tunnel syndrome is a common and costly peripheral neuropathy. Occupations requiring repetitive, forceful motions of the hand and wrist may play a role in the development of carpal tunnel syndrome. Computer keyboarding is one such task, and has been associated with upper-extremity musculoskeletal disorder development. The purpose of this study was to determine whether continuous keyboarding can cause acute changes in the median nerve and whether these changes correlate with wrist biomechanics during keyboarding. Methods: A convenience sample of 37 healthy individuals performed a 60-minute typing task. Ultrasound images were collected at baseline, after 30 and 60 min of typing, then after 30 min of rest. Kinematic data were collected during the typing task. Variables of interest were median nerve cross-sectional area, flattening ratio, and swelling ratio at the pisiform; subject characteristics (age, gender, BMI, wrist circumference, typing speed) and wrist joint angles. Findings: Cross-sectional area and swelling ratio increased after 30 and 60 min of typing, and then decreased to baseline after 30 min of rest. Peak ulnar deviation contributed to changes in cross-sectional area after 30 min of typing. Interpretation: Results from this study confirmed a typing task causes changes in the median nerve, and changes are influenced by level of ulnar deviation. Furthermore, changes in the median nerve are present until cessation of the activity. While it is unclear if these changes lead to long-term symptoms or nerve injury, their existence adds to the evidence of a possible link between carpal tunnel syndrome and keyboarding. Published by Elsevier Ltd. C1 [Toosi, Kevin K.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Toosi, Kevin K.; Hogaboom, Nathan S.; Oyster, Michelle L.; Boninger, Michael L.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. [Hogaboom, Nathan S.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Oyster, Michelle L.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. RP Boninger, ML (reprint author), Human Engn Res Labs, 6425 Penn Ave,Suite 400, Pittsburgh, PA 15206 USA. EM boninger@pitt.edu OI Hogaboom, Nathan/0000-0002-0601-5751; Boninger, Michael/0000-0001-6966-919X FU U.S. Department of Veterans Affairs [B3142C]; National Institutes of Health [T32HD049307] FX This material is the result of work supported with resources and the use of facilities at the Human Engineering Research Laboratories, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. This study was supported by the U.S. Department of Veterans Affairs (B3142C) and the National Institutes of Health (T32HD049307). NR 30 TC 0 Z9 0 U1 3 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 EI 1879-1271 J9 CLIN BIOMECH JI Clin. Biomech. PD JUL PY 2015 VL 30 IS 6 BP 546 EP 550 DI 10.1016/j.clinbiomech.2015.04.008 PG 5 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA CK9FI UT WOS:000356545600004 PM 25933812 ER PT J AU Oliveira, SEH Esteves, FG Pereira, EG Carvalho, M Boyd, JE AF Oliveira, Sandra E. H. Esteves, Francisco G. Pereira, Edgar G. Carvalho, Marina Boyd, Jennifer E. TI The Internalized Stigma of Mental Illness: Cross-Cultural Adaptation and Psychometric Properties of the Portuguese Version of the ISMI Scale SO COMMUNITY MENTAL HEALTH JOURNAL LA English DT Article DE ISMI; Self-stigma; Portuguese; Mental disorders; Diagnosis ID SCHIZOPHRENIA SPECTRUM DISORDERS; SELF-STIGMA; PERCEIVED DISCRIMINATION; EUROPEAN COUNTRIES; GAMIAN-EUROPE; PEOPLE; CONSEQUENCES; EMPOWERMENT; EXPERIENCES; OUTPATIENTS AB This study examined the psychometric properties of the Portuguese version of the ISMI scale in a sample of 253 adult psychiatric outpatients. The exploratory factor analysis replicated the five factor structure of the scale. The results revealed good internal consistency. Criterion-related validity supported the variability in response to stigma across clinical diagnoses. Thus, the Portuguese version of the ISMI scale can be considered appropriate to measure and differentiate between stigmatization experiences. Also, in order to design more focused approaches aimed to reduce the negative effects of internalized stigma, its use in institutional and in community-based mental health services is recommended. C1 [Oliveira, Sandra E. H.; Esteves, Francisco G.] Inst Univ Lisboa ISCTE IUL, CIS IUL, P-1649026 Lisbon, Portugal. [Pereira, Edgar G.; Carvalho, Marina] Univ Lusofona Humanidades & Tecnol, Fac Psicol, Lisbon, Portugal. [Carvalho, Marina] CHBA, Serv Psiquiatria, Algarve, Portugal. [Boyd, Jennifer E.] San Francisco VA Med Ctr, San Francisco, CA USA. [Boyd, Jennifer E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Oliveira, SEH (reprint author), Inst Univ Lisboa ISCTE IUL, CIS IUL, Av Forcas Armadas, P-1649026 Lisbon, Portugal. EM seholiveira@gmail.com NR 44 TC 4 Z9 4 U1 2 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0010-3853 EI 1573-2789 J9 COMMUNITY MENT HLT J JI Community Ment. Health J. PD JUL PY 2015 VL 51 IS 5 BP 606 EP 612 DI 10.1007/s10597-015-9828-x PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA CK9DX UT WOS:000356541900013 PM 25612794 ER PT J AU Pierrotti, LC Kotton, CN AF Pierrotti, Ligia C. Kotton, Camille N. TI Transplantation in the Tropics: Lessons on Prevention and Management of Tropical Infectious Diseases SO CURRENT INFECTIOUS DISEASE REPORTS LA English DT Article DE Transplant; Solid organ transplantation; Hematopoietic stem cell transplantation; Tropical infectious diseases; Tuberculosis; Chagas disease; Leishmaniasis ID SOLID-ORGAN TRANSPLANTATION; LATENT TUBERCULOSIS INFECTION; STEM-CELL TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; OF-THE-LITERATURE; REAL-TIME PCR; ALLOGENEIC HEMATOPOIETIC SCT; RENAL-ALLOGRAFT RECIPIENTS; LIPOSOMAL AMPHOTERICIN-B; DONOR-DERIVED INFECTIONS AB Tropical infectious diseases (IDs) remain a rare complication in transplant recipients even in tropical settings, but this topic has become increasingly important during the last decade due to multiple factors. Interestingly, non-tropical countries report most of the experiences with tropical diseases. The reported experience from non-endemic regions, however, does not always reflect the experience of endemic areas. Most of the guidelines and recommendations in the literature may not be applicable in tropical settings due to logistical difficulties, cost, and lack of proven benefit. In addition, certain post-transplant prevention measures, as prophylaxis and reducing exposure risk, are not feasible. Nonetheless, risk assessment and post-transplant management of tropical IDs in tropical areas should not be neglected, and clinicians need to have a higher clinical awareness for tropical ID occurring in this population. Herein, we review the more significant tropical ID in transplant patients, focusing on relevant experience reported by tropical settings. C1 [Pierrotti, Ligia C.] Univ Sao Paulo, Fac Med, Div Infect Dis, Hosp Clin, BR-05403900 Sao Paulo, SP, Brazil. [Kotton, Camille N.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Pierrotti, LC (reprint author), Univ Sao Paulo, Fac Med, Div Infect Dis, Hosp Clin, Av Dr Eneas de Carvalho Aguiar 255,4 Andar, BR-05403900 Sao Paulo, SP, Brazil. EM pierrot@usp.br NR 179 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3847 EI 1534-3146 J9 CURR INFECT DIS REP JI Curr. Infect. Dis. Rep. PD JUL PY 2015 VL 17 IS 7 AR 34 DI 10.1007/s11908-015-0492-7 PG 20 WC Infectious Diseases SC Infectious Diseases GA CK9DF UT WOS:000356540100004 ER PT J AU Deutsch, V Havens, A Snow, K AF Deutsch, Varda Havens, Andrew Snow, Karen TI International Society for Cell Therapy Facility Sanitization Survey Laboratory Practices Committee Report SO CYTOTHERAPY LA English DT Article DE classification; processing facilities; regulation; sanitization AB Background aims. Quality cell manufacturing processes require a clean laboratory environment. Methods. This report was aimed at describing current cleaning and sanitization practices reported by facilities that manufacture many types of cellular therapy products for clinical use. It is our hope that this report may provide the groundwork for guidance recommendations directed at developing consensus standards for cleaning and sanitization practices across the globe. Facility sanitization is a central issue to regulatory and accreditation bodies. Facilities are required to develop plans to assess sanitization practices and test cleaning effectiveness. Results. This document provides information on how this is performed in different facilities and may allow newer, smaller or less developed facilities to build, enhance or revise their current quality program by using experience and expertise in facility sanitization reported herein. Conclusions. This report summarizes the results of the latest survey and compares results with those previously reported. New and relevant trends in the field provide important information and will provide important information for establishing guidelines. C1 [Deutsch, Varda] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Hematol & Bone Marrow Transplant Lab, IL-69978 Tel Aviv, Israel. [Havens, Andrew] Univ Texas Houston, Evelyn H Griffin cGMP Facil, Program Regenerat Med, Houston, TX USA. [Havens, Andrew] Univ Texas Houston, Judith R Hoffberger cGMP Facil, Program Regenerat Med, Houston, TX USA. [Snow, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Snow, K (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ksnow1@mgh.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUL PY 2015 VL 17 IS 7 BP 850 EP 859 DI 10.1016/j.jcyt.2015.03.688 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CL0KS UT WOS:000356632200003 PM 25958337 ER PT J AU Edelman, EJ Tate, JP Fiellin, DA Brown, ST Bryant, K Gandhi, N Gibert, CL Goetz, MB Gordon, KS Rodriguez-Barradas, MC Braithwaite, RS Rimland, D Justice, AC AF Edelman, E. J. Tate, J. P. Fiellin, D. A. Brown, S. T. Bryant, K. Gandhi, N. Gibert, C. L. Goetz, M. B. Gordon, K. S. Rodriguez-Barradas, M. C. Braithwaite, R. S. Rimland, D. Justice, A. C. TI Impact of defined clinical population and missing data on temporal trends in HIV viral load estimation within a health care system SO HIV MEDICINE LA English DT Article DE community viral load; epidemiological methods; HIV; population surveillance; quality of health care ID OF-VETERANS-AFFAIRS; MEDICAL-CARE; COHORT; INFORMATION; ENGAGEMENT; MORTALITY; INDEX AB ObjectivesCommunity viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Health Administration (VA) to determine trends in the health care system viral load (HSVL) and its sensitivity to varying definitions of the clinical population and assumptions regarding missing data. MethodsWe included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with at least one documented CD4 count, HIV-1 RNA or antiretroviral prescription (n=37318). We created 6-month intervals including patients with at least one visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load. ResultsThe clinical population size varied by definition, increasing from 16000-19000 patients in 2000 to 23000-26000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or the past 2 years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97800 HIV-1 RNA copies/mL in 2000 to 2000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322300 to 9900 copies/mL. HSVL was underestimated when using only current data in each interval. ConclusionsThe CVL concept can be applied to a health care system, providing a measure of health care quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data. C1 [Edelman, E. J.; Tate, J. P.; Fiellin, D. A.; Justice, A. C.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Edelman, E. J.; Fiellin, D. A.; Justice, A. C.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT 06520 USA. [Tate, J. P.; Gordon, K. S.; Justice, A. C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Brown, S. T.] James J Peters VA Med Ctr, Bronx, NY USA. [Brown, S. T.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Bryant, K.] NIAAA, Bethesda, MD USA. [Gandhi, N.] Emory Rollins Sch Publ Hlth, Atlanta, GA USA. [Gandhi, N.; Rimland, D.] Emory Univ, Sch Med, Atlanta, GA USA. [Gibert, C. L.] Washington DC VA Med Ctr, Washington, DC USA. [Gibert, C. L.] George Washington Univ, Sch Med, Washington, DC USA. [Goetz, M. B.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Goetz, M. B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rodriguez-Barradas, M. C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, M. C.] Baylor Coll Med, Houston, TX 77030 USA. [Braithwaite, R. S.] NYU, Sch Med, New York, NY USA. [Rimland, D.] Atlanta Vet Affairs Med Ctr, Decatur, GA USA. RP Edelman, EJ (reprint author), Yale Univ, Sch Med, Gen Internal Med, POB 208025, New Haven, CT 06520 USA. EM ejennifer.edelman@yale.edu OI Goetz, Matthew/0000-0003-4542-992X; Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502 FU NIAAA NIH HHS [U01-AA020790, U10 AA013566, U10-AA13566, U01 AA020790, U24 AA020794, U24-AA020794]; NIAID NIH HHS [K24 AI114444, P30AI050409]; NIDA NIH HHS [K12 DA033312, K12DA033312-01A1]; PHS HHS [K24114444-01] NR 38 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD JUL PY 2015 VL 16 IS 6 BP 346 EP 354 DI 10.1111/hiv.12219 PG 9 WC Infectious Diseases SC Infectious Diseases GA CK9XL UT WOS:000356592700003 PM 25688937 ER PT J AU Wu, WE Babb, JS Tal, A Kirov, II George, AE Ratai, EM Gonzalez, RG Gonen, O AF Wu, W. E. Babb, J. S. Tal, A. Kirov, I. I. George, A. E. Ratai, E-M Gonzalez, R. G. Gonen, O. TI Early glial activation precedes neurodegeneration in the cerebral cortex after SIV infection: A 3D, multivoxel proton magnetic resonance spectroscopy study SO HIV MEDICINE LA English DT Article DE cerebral cortex; magnetic resonance imaging; magnetic resonance spectroscopy; neuroglia; simian immunodeficiency virus ID WHITE-MATTER; IMMUNODEFICIENCY-VIRUS; MR SPECTROSCOPY; GRAY; SEGMENTATION; HIV/AIDS; BRAIN AB ObjectivesAs approximate to 40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging (H-1-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. MethodsThe brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T-2-weighted quantitative magnetic resonance imaging (MRI) and 16x16x4 multivoxel H-1-MRSI (echo time/repetition time=33/1440ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to H-1-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28cm(3) (approximate to 35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. ResultsThe mean (standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 +/- 0.9, 7.2 +/- 0.4 and 0.9 +/- 0.1mM, respectively; these concentrations increased 28% (p approximate to 0.06), 15% and 10% (both p<0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 +/- 0.6mM pre-infection vs. 7.3 +/- 0.8mM post-infection; p approximate to 0.37). The mean cortex volume was also unchanged (8.1 +/- 1.1 cm(3) pre-infection vs. 8.3 +/- 0.5 cm(3) post-infection; p approximate to 0.76). ConclusionsThese results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex. C1 [Wu, W. E.; Babb, J. S.; Kirov, I. I.; George, A. E.; Gonen, O.] NYU, Sch Med, Dept Radiol, New York, NY 10016 USA. [Tal, A.] Weizmann Inst Sci, Dept Chem Phys, IL-76100 Rehovot, Israel. [Ratai, E-M; Gonzalez, R. G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ratai, E-M; Gonzalez, R. G.] Massachusetts Gen Hosp, Neuroradiol Div, Charlestown, MA USA. RP Wu, WE (reprint author), NYU, Sch Med, Dept Radiol, 660 First Ave 2nd Floor, New York, NY 10016 USA. EM wew226@nyu.edu OI Wu, William/0000-0003-0990-4164; george, ajax/0000-0001-6355-2951; Kirov, Ivan/0000-0001-5641-8578; Gonen, Oded/0000-0002-3148-2028 FU NCRR NIH HHS [S10RR019933, S10RR022976]; NIBIB NIH HHS [EB01015]; NINDS NIH HHS [NS040237, NS050041, NS050520, NS059331] NR 23 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD JUL PY 2015 VL 16 IS 6 BP 381 EP 387 DI 10.1111/hiv.12222 PG 7 WC Infectious Diseases SC Infectious Diseases GA CK9XL UT WOS:000356592700008 PM 25689120 ER PT J AU Barron, DS Eickhoff, SB Clos, M Fox, PT AF Barron, Daniel S. Eickhoff, Simon B. Clos, Mareike Fox, Peter T. TI Human pulvinar functional organization and connectivity SO HUMAN BRAIN MAPPING LA English DT Article DE pulvinar; functional anatomy; fMRI; cognitive neuroscience; attention ID ACTIVATION-BASED PARCELLATION; HUMAN BRAIN; INFERIOR PULVINAR; ATTENTION SYSTEM; MEDIAL PULVINAR; CEREBRAL-CORTEX; HUMAN AMYGDALA; HUMAN THALAMUS; METAANALYSIS; NETWORKS AB The human pulvinar is the largest thalamic area in terms of size and cortical connectivity. Although much is known about regional pulvinar structural anatomy, relatively little is known about pulvinar functional anatomy in humans. Cooccurrence of experimentally induced brain activity is a traditional metric used to establish interregional brain connectivity and forms the foundation of functional neuroimaging connectivity analyses. Because functional neuroimaging studies report task-related coactivations within a standardized space, meta-analysis of many whole-brain studies can define the brain's interregional coactivation across many tasks. Such an analysis can also detect and define variations in functional coactivations within a particular region. Here we use coactivation profiles reported in approximate to 7,700 functional neuroimaging studies to parcellate and define the pulvinar's functional anatomy. Parcellation of the pulvinar's coactivation profile identified five clusters per pulvinar of distinct functional coactivation. These clusters showed a high degree of symmetry across hemispheres and correspondence with the human pulvinar's cytoarchitecture. We investigated the functional coactivation profiles of each resultant pulvinar cluster with meta-analytic methods. By referencing existent neuroimaging and lesion-deficit literature, these profiles make a case for regional pulvinar specialization within the larger human attention-controlling network. Reference to this literature also informs specific hypotheses that can be tested in subsequent studies in healthy and clinical populations. Hum Brain Mapp 36:2417-2431, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Barron, Daniel S.; Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Barron, Daniel S.] Yale Univ, Sch Med, New Haven, CT USA. [Eickhoff, Simon B.] Res Ctr Julich, INM 1, Julich, Germany. [Clos, Mareike] Univ Dusseldorf, Inst Clin Neurosci & Med Psychol, Dusseldorf, Germany. [Eickhoff, Simon B.; Clos, Mareike] Univ Med Ctr Hamburg Eppendorf, Dept Syst Neurosci, Hamburg, Germany. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Fox, Peter T.] South Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX USA. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Fox, Peter T.] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. [Fox, Peter T.] Shenzhen Univ, Neuroimaging Lab, Sch Med, Shenzhen, Peoples R China. RP Fox, PT (reprint author), 8407 Floyd Curl Dr, San Antonio, TX 78229 USA. EM fox@uthscsa.edu RI Eickhoff, Simon/K-2061-2013 OI Eickhoff, Simon/0000-0001-6363-2759 FU National Institute of Neurological Disorder Stroke [1-F31-NS083160-01]; National Institute of Mental Health [RO1-MH074457]; Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Systems Biology (Human Brain Model); DFG [IRTG 1328] FX Contract grant sponsor: National Institute of Neurological Disorder & Stroke; Contract grant number: 1-F31-NS083160-01(D.S.B.); Contract grant sponsor: National Institute of Mental Health; Contract grant sponsor: RO1-MH074457 (P.T.F.), Contract grant sponsor: Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Systems Biology (Human Brain Model) (S.B.E. and M.C.); Contract grant sponsor: DFG; Contract grant number: IRTG 1328 (S.B.E.) NR 62 TC 4 Z9 4 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2015 VL 36 IS 7 BP 2417 EP 2431 DI 10.1002/hbm.22781 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CL1QP UT WOS:000356719200001 PM 25821061 ER PT J AU Carmona, S Hoekzema, E Castellanos, FX Garcia-Garcia, D Lage-Castellanos, A Van Dijk, KRA Navas-Sanchez, FJ Martinez, K Desco, M Sepulcre, J AF Carmona, Susana Hoekzema, Elseline Castellanos, Francisco X. Garcia-Garcia, David Lage-Castellanos, Agustin Van Dijk, Koene R. A. Navas-Sanchez, Francisco J. Martinez, Kenia Desco, Manuel Sepulcre, Jorge TI Sensation-to-cognition cortical streams in attention-deficit/hyperactivity disorder SO HUMAN BRAIN MAPPING LA English DT Article DE attention-deficit; hyperactivity disorder; resting-state functional magnetic resonance imaging; ventral attention network; default mode network; sensorimotor network ID DEFICIT HYPERACTIVITY DISORDER; INTRINSIC FUNCTIONAL CONNECTIVITY; BRAIN-DYSFUNCTION; NAIVE BOYS; ADHD; NETWORK; CORTEX; CHILDREN; FMRI; SYSTEMS AB We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortexvisual, auditory, and somatosensorywe used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naive children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. Hum Brain Mapp 36:2544-2557, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Carmona, Susana; Van Dijk, Koene R. A.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Carmona, Susana; Garcia-Garcia, David; Martinez, Kenia; Desco, Manuel] Inst Invest Sanitaria Gregorio Maranon, Unidad Med & Cirugia Expt, Madrid, Spain. [Carmona, Susana; Garcia-Garcia, David; Navas-Sanchez, Francisco J.; Desco, Manuel] Univ Carlos III Madrid, Dept Bioingn & Ingn Aeroespacial, Madrid, Spain. [Hoekzema, Elseline] Netherlands Inst Neurosci, Neuroendocrinol Bakker Grp, Amsterdam, Netherlands. [Castellanos, Francisco X.] NYU, Langone Med Ctr, Ctr Child Study, Ctr Neurodev Disorders, New York, NY USA. [Castellanos, Francisco X.] Nathan S Kline Inst Psychiat Res, Div Child & Adolescent Psychiat Res, Orangeburg, NY 10962 USA. [Lage-Castellanos, Agustin] Cuba Neurosci Ctr, Dept Neurostat, Havana, Cuba. [Van Dijk, Koene R. A.; Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Van Dijk, Koene R. A.; Sepulcre, Jorge] Harvard Univ, Sch Med, Charlestown, MA USA. [Navas-Sanchez, Francisco J.; Desco, Manuel] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain. [Sepulcre, Jorge] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sepulcre, Jorge] Harvard Univ, Sch Med, Boston, MA USA. RP Carmona, S (reprint author), Harvard Univ, Dept Psychol, Ctr Brain Sci, Northwest Lab Bldg 290,52 Oxford St, Cambridge, MA 02138 USA. EM susannacarmona@gmail.com RI Garcia-Garcia, David/I-2105-2015; Desco, Manuel/D-2822-2009; Van Dijk, Koene/G-3317-2012; OI Garcia-Garcia, David/0000-0001-5224-3280; Desco, Manuel/0000-0003-0989-3231; Van Dijk, Koene/0000-0001-6137-4282; Castellanos, Francisco/0000-0001-9192-9437 FU Consejeria de Educacion, Juventud y Deporte of Comunidad de Madrid; European Union [291820]; NIH-NIBIB [1K23EB019023-01RM] FX Contract grant sponsors: The 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); Contract grant number: REA grant agreement no 291820 (SC).; Contract grant sponsors: NIH-NIBIB 1K23EB019023-01RM grant (JS) NR 60 TC 4 Z9 4 U1 0 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2015 VL 36 IS 7 BP 2544 EP 2557 DI 10.1002/hbm.22790 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CL1QP UT WOS:000356719200010 PM 25821110 ER PT J AU Xu, M Wang, TF Chen, SP Fox, PT Tan, LH AF Xu, Min Wang, Tianfu Chen, Siping Fox, Peter T. Tan, Li Hai TI Effective connectivity of brain regions related to visual word recognition: An fMRI study of Chinese reading SO HUMAN BRAIN MAPPING LA English DT Article DE connectivity; functional magnetic resonance imaging; reading; Chinese reading; dynamic causal modeling; ventral pathway; dorsal pathway; writing systems ID VENTRAL OCCIPITOTEMPORAL CORTEX; INFERIOR PREFRONTAL CORTEX; DEVELOPMENTAL DYSLEXIA; FUNCTIONAL SPECIALIZATION; ALPHABETIC WORDS; NEURAL SYSTEMS; WRITTEN WORDS; CHARACTERS; LANGUAGE; METAANALYSIS AB Past neuroimaging studies have focused on identifying specialized functional brain systems for processing different components of reading, such as orthography, phonology, and semantics. More recently, a few experiments have been performed to look into the integration and interaction of distributed neural systems for visual word recognition, suggesting that lexical processing in alphabetic languages involves both ventral and dorsal neural pathways originating from the visual cortex. In the present functional magnetic resonance imaging study, we tested the multiple pathways model with Chinese character stimuli and examined how the neural systems interacted in reading Chinese. Using dynamic causal modeling, we demonstrated that visual word recognition in Chinese engages the ventral pathway from the visual cortex to the left ventral occipitotemporal cortex, but not the dorsal pathway from the visual cortex to the left parietal region. The ventral pathway, however, is linked to the superior parietal lobule and the left middle frontal gyrus (MFG) so that a dynamic neural network is formed, with information flowing from the visual cortex to the left ventral occipitotemporal cortex to the parietal lobule and then to the left MFG. The findings suggest that cortical dynamics is constrained by the differences in how visual orthographic symbols in writing systems are linked to spoken language. Hum Brain Mapp 36:2580-2591, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Xu, Min; Wang, Tianfu; Chen, Siping; Fox, Peter T.; Tan, Li Hai] Shenzhen Univ, Sch Med, Dept Biomed Engn, Shenzhen 518060, Peoples R China. [Xu, Min; Wang, Tianfu; Chen, Siping; Tan, Li Hai] Guangdong Key Lab Biomed Informat Detect & Ultras, Shenzhen, Peoples R China. [Xu, Min] Univ Hong Kong, Sch Humanities, Hong Kong, Hong Kong, Peoples R China. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Fox, Peter T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Tan, LH (reprint author), Shenzhen Univ, Sch Med, Dept Biomed Engn, Shenzhen 518060, Peoples R China. EM fox@uthscsa.edu; tanlh@szu.edu.cn FU National Strategic Basic Research Program ("973" Program) of the Ministry of Science and Technology of China [2012CB720701]; National Natural Science Foundation of China [61372006] FX Contract grant sponsor: National Strategic Basic Research Program ("973" Program) of the Ministry of Science and Technology of China; Contract grant number: 2012CB720701; Contract grant sponsor: National Natural Science Foundation of China; Contract grant number: 61372006. NR 74 TC 3 Z9 3 U1 15 U2 53 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2015 VL 36 IS 7 BP 2580 EP 2591 DI 10.1002/hbm.22792 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CL1QP UT WOS:000356719200012 PM 25788100 ER PT J AU Petersen, N Touroutoglou, A Andreano, JM Cahill, L AF Petersen, Nicole Touroutoglou, Alexandra Andreano, Joseph M. Cahill, Larry TI Oral contraceptive pill use is associated with localized decreases in cortical thickness SO HUMAN BRAIN MAPPING LA English DT Article DE cortical thickness; hormonal contraception; morphometric analysis; neuroendocrinology ID MENSTRUAL-CYCLE PHASE; HUMAN CEREBRAL-CORTEX; PREMENSTRUAL DYSPHORIC DISORDER; DIFFERENT ENDOCRINE STATES; ESTROGEN-RECEPTOR-ALPHA; BRAINS DEFAULT NETWORK; CENTRAL-NERVOUS-SYSTEM; HUMAN FEMALE BRAIN; CINGULATE CORTEX; NEGATIVE EMOTION AB Oral contraceptive pills (OCs), which are used to prevent pregnancy by the majority of women in the United States, contain steroid hormones that may affect the brain's structure and function. In this investigation, we tested the hypothesis that OC use is associated with differences in brain structure using a hypothesis-driven, surface-based approach. In 90 women, (44 OC users, 46 naturally-cycling women), we compared the cortical thickness of brain regions that participate in the salience network and the default mode network, as well as the volume of subcortical regions in these networks. We found that OC use was associated with significantly lower cortical thickness measurements in the lateral orbitofrontal cortex and the posterior cingulate cortex. These regions are believed to be important for responding to rewards and evaluating internal states/incoming stimuli, respectively. Further investigations are needed to determine if cortical thinning in these regions are associated with behavioral changes, and also to identify whether OC use is causally or only indirectly related to these changes in brain morphology. Hum Brain Mapp 36:2644-2654, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Petersen, Nicole] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Semel Inst, Los Angeles, CA 90024 USA. [Petersen, Nicole; Cahill, Larry] Univ Calif Irvine, Dept Neurobiol & Behav, Bonney Res Lab, Irvine, CA USA. [Touroutoglou, Alexandra] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Touroutoglou, Alexandra; Andreano, Joseph M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Touroutoglou, Alexandra; Andreano, Joseph M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Boston, MA 02114 USA. [Touroutoglou, Alexandra; Andreano, Joseph M.] Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neuroimaging, Boston, MA 02114 USA. RP Petersen, N (reprint author), Westwood Plaza C8-539, Los Angeles, CA 90095 USA. EM npetersen@ucla.edu FU NIH [R01MH57508] FX Contract grant sponsor: NIH; Contract grant number: R01MH57508 (to L.C.) NR 64 TC 3 Z9 3 U1 9 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2015 VL 36 IS 7 BP 2644 EP 2654 DI 10.1002/hbm.22797 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CL1QP UT WOS:000356719200017 PM 25832993 ER PT J AU Wang, ZM Rajaraman, P Melin, BS Chung, CC Zhang, WJ McKean-Cowdin, R Michaud, D Yeager, M Ahlbom, A Albanes, D Andersson, U Freeman, LEB Buring, JE Butler, MA Carreon, T Feychting, M Gapstur, SM Gaziano, JM Giles, GG Hallmans, G Henriksson, R Hoffman-Bolton, J Inskip, PD Kitahara, CM Marchand, LL Linet, MS Li, SC Peters, U Purdue, MP Rothman, N Ruder, AM Sesso, HD Severi, G Stampfer, M Stevens, VL Visvanathan, K Wang, SS White, E Zeleniuch-Jacquotte, A Hoover, R Fraumeni, JF Chatterjee, N Hartge, P Chanock, SJ AF Wang, Zhaoming Rajaraman, Preetha Melin, Beatrice S. Chung, Charles C. Zhang, Weijia McKean-Cowdin, Roberta Michaud, Dominique Yeager, Meredith Ahlbom, Anders Albanes, Demetrius Andersson, Ulrika Freeman, Laura E. Beane Buring, Julie E. Butler, Mary Ann Carreon, Tania Feychting, Maria Gapstur, Susan M. Gaziano, J. Michael Giles, Graham G. Hallmans, Goran Henriksson, Roger Hoffman-Bolton, Judith Inskip, Peter D. Kitahara, Cari M. Marchand, Loic Le Linet, Martha S. Li, Shengchao Peters, Ulrike Purdue, Mark P. Rothman, Nathaniel Ruder, Avima M. Sesso, Howard D. Severi, Gianluca Stampfer, Meir Stevens, Victoria L. Visvanathan, Kala Wang, Sophia S. White, Emily Zeleniuch-Jacquotte, Anne Hoover, Robert Fraumeni, Joseph F. Chatterjee, Nilanjan Hartge, Patricia Chanock, Stephen J. TI Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data SO HUMAN MUTATION LA English DT Article DE glioma; TP53; rare SNP; TCGA ID GENOME-WIDE ASSOCIATION; SQUAMOUS-CELL CARCINOMA; NERVOUS-SYSTEM TUMORS; POLYADENYLATION SIGNAL; CANCER SUSCEPTIBILITY; SNPS; RARE AB We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10(-11)), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximate to 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. (C) 2015 Wiley Periodicals, Inc. C1 [Wang, Zhaoming; Rajaraman, Preetha; Chung, Charles C.; Yeager, Meredith; Albanes, Demetrius; Freeman, Laura E. Beane; Inskip, Peter D.; Kitahara, Cari M.; Linet, Martha S.; Li, Shengchao; Purdue, Mark P.; Rothman, Nathaniel; Hoover, Robert; Fraumeni, Joseph F.; Chatterjee, Nilanjan; Hartge, Patricia; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Wang, Zhaoming; Chung, Charles C.; Yeager, Meredith; Li, Shengchao] Leidos Biomed Res Inc, Canc Genom Res Lab, Gaithersburg, MD USA. [Melin, Beatrice S.; Andersson, Ulrika; Henriksson, Roger] Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden. [Zhang, Weijia] Icahn Sch Med Mt Sinai, Dept Med Bioinformat Core, New York, NY 10029 USA. [McKean-Cowdin, Roberta] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Michaud, Dominique] Brown Univ, Dept Epidemiol, Div Biol & Med, Providence, RI 02912 USA. [Michaud, Dominique] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Ahlbom, Anders; Feychting, Maria] Karolinska Inst, Inst Environm Med, Div Epidemiol, S-10401 Stockholm, Sweden. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Harvard Univ, Sch Med, Boston, MA USA. [Butler, Mary Ann; Carreon, Tania; Ruder, Avima M.] NIOSH, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Ctr Geriatr Res Educ & Clin, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med Nutr Res, Umea, Sweden. [Hoffman-Bolton, Judith; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Marchand, Loic Le] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Peters, Ulrike; White, Emily] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Peters, Ulrike; White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Stampfer, Meir] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Visvanathan, Kala] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Zeleniuch-Jacquotte, Anne] NYU Sch Med, Dept Environm Med, Div Epidemiol, New York, NY USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr Rm 7E412,MSC 9776, Bethesda, MD 20892 USA. EM wangzha@mail.nih.gov; chanocks@mail.nih.gov RI Purdue, Mark/C-9228-2016; Kitahara, Cari/R-8267-2016; OI Purdue, Mark/0000-0003-1177-3108; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU NCI; NIH [N01-CO-12400]; Department of Health and Human Services FX Contract grant sponsors: NCI; NIH; Department of Health and Human Services; NCI; NIH (N01-CO-12400). NR 18 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUL PY 2015 VL 36 IS 7 BP 684 EP 688 DI 10.1002/humu.22799 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CK8NT UT WOS:000356495700005 PM 25907361 ER PT J AU Sharma, PK Wong, EB Napier, RJ Bishai, WR Ndung'u, T Kasprowicz, VO Lewinsohn, DA Lewinsohn, DM Gold, MC AF Sharma, Prabhat K. Wong, Emily B. Napier, Ruth J. Bishai, William R. Ndung'u, Thumbi Kasprowicz, Victoria O. Lewinsohn, Deborah A. Lewinsohn, David M. Gold, Marielle C. TI High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells SO IMMUNOLOGY LA English DT Article DE bacteria; cell surface molecules; human; MHC; MR1 and MAIT cells; T cells ID INVARIANT T-CELLS; ACTIVATION ANTIGEN; ALPHA-CHAIN; COMPLEX; MR1; LYMPHOCYTES; PATHWAY; DEFINES AB Mucosa-associated invariant T (MAIT) cells express the semi-invariant T-cell receptor TRAV1-2 and detect a range of bacteria and fungi through the MHC-like molecule MR1. However, knowledge of the function and phenotype of bacteria-reactive MR1-restricted TRAV1-2(+) MAIT cells from human blood is limited. We broadly characterized the function of MR1-restricted MAIT cells in response to bacteria-infected targets and defined a phenotypic panel to identify these cells in the circulation. We demonstrated that bacteria-reactive MR1-restricted T cells shared effector functions of cytolytic effector CD8(+) T cells. By analysing an extensive panel of phenotypic markers, we determined that CD26 and CD161 were most strongly associated with these T cells. Using FACS to sort phenotypically defined CD8(+) subsets we demonstrated that high expression of CD26 on CD8(+)TRAV1-2(+) cells identified with high specificity and sensitivity, bacteria-reactive MR1-restricted T cells from human blood. CD161(hi) was also specific for but lacked sensitivity in identifying all bacteria-reactive MR1-restricted T cells, some of which were CD161(dim). Using cell surface expression of CD8, TRAV1-2, and CD26(hi) in the absence of stimulation we confirm that bacteria-reactive T cells are lacking in the blood of individuals with active tuberculosis and are restored in the blood of individuals undergoing treatment for tuberculosis. C1 [Sharma, Prabhat K.; Napier, Ruth J.; Lewinsohn, David M.; Gold, Marielle C.] Oregon Hlth & Sci Univ, Pulm & Crit Care Med, Portland, OR 97239 USA. [Wong, Emily B.; Ndung'u, Thumbi; Kasprowicz, Victoria O.] KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Wong, Emily B.; Bishai, William R.; Ndung'u, Thumbi] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bishai, William R.] Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD USA. [Kasprowicz, Victoria O.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Kasprowicz, Victoria O.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, HIV Pathogenesis Programme, Durban, South Africa. [Lewinsohn, Deborah A.] Oregon Hlth & Sci Univ, Pediat, Portland, OR 97239 USA. [Lewinsohn, Deborah A.; Lewinsohn, David M.; Gold, Marielle C.] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol, Portland, OR 97239 USA. [Lewinsohn, David M.; Gold, Marielle C.] Portland VA Med Ctr, Portland, OR USA. RP Gold, MC (reprint author), Oregon Hlth & Sci Univ, Pulm & Crit Care Med, 3181 SW Sam Jackson Pk Rd,Mail Code VA R&D 11, Portland, OR 97239 USA. EM lewinsod@ohsu.edu; goldm@ohsu.edu RI Lewinsohn, David/I-4936-2013; OI Ndung'u, Thumbi/0000-0003-2962-3992; Lewinsohn, David/0000-0001-9906-9494; Gold, Marielle/0000-0003-2505-3291 FU National Institutes of Health (NIH) under the NIAID funded MIST Consortium [AI095776]; National Institutes of Health (NIH) [T32AI007387]; Burroughs Wellcome Fund/ASTMH Postdoctoral Fellowship in Tropical Infectious Diseases and Merit Review from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development [I01 BX001231, I01 BX000533] FX Funding was provided by National Institutes of Health (NIH) grant AI095776, under the NIAID funded MIST Consortium (mucosal.org) and T32AI007387, and in part by the Burroughs Wellcome Fund/ASTMH Postdoctoral Fellowship in Tropical Infectious Diseases and Merit Review Awards # I01 BX001231 and I01 BX000533 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development and resources and the use of facilities at the VA Portland Health Care System. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 34 TC 14 Z9 14 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD JUL PY 2015 VL 145 IS 3 BP 443 EP 453 DI 10.1111/imm.12461 PG 11 WC Immunology SC Immunology GA CL1JR UT WOS:000356699200012 PM 25752900 ER PT J AU Cluzet, VC Gerber, JS Nachamkin, I Metlay, JP Zaoutis, TE Davis, MF Julian, KG Linkin, DR Coffin, SE Margolis, DJ Hollander, JE Bilker, WB Han, XY Mistry, RD Gavin, LJ Tolomeo, P Wise, JA Wheeler, MK Hu, BF Fishman, NO Royer, D Lautenbach, E AF Cluzet, Valerie C. Gerber, Jeffrey S. Nachamkin, Irving Metlay, Joshua P. Zaoutis, Theoklis E. Davis, Meghan F. Julian, Kathleen G. Linkin, Darren R. Coffin, Susan E. Margolis, David J. Hollander, Judd E. Bilker, Warren B. Han, Xiaoyan Mistry, Rakesh D. Gavin, Laurence J. Tolomeo, Pam Wise, Jacqueleen A. Wheeler, Mary K. Hu, Baofeng Fishman, Neil O. Royer, David Lautenbach, Ebbing CA Ctr Dis Control Prevention CDC TI Risk Factors for Recurrent Colonization With Methicillin-Resistant Staphylococcus aureus in Community-Dwelling Adults and Children SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID HOUSEHOLD CONTACTS; SKIN INFECTIONS; EMERGENCY-DEPARTMENT; HIGH PREVALENCE; SWAB SPECIMENS; CARRIAGE; MRSA; TRANSMISSION; ERADICATION; SURVEILLANCE AB OBJECTIVE. To identify risk factors for recurrent methicillin-resistant Staphylococcus aureus (MRSA) colonization. DESIGN. Prospective cohort study conducted from January 1, 2010, through December 31, 2012. SETTING. Five adult and pediatric academic medical centers. PARTICIPANTS. Subjects (ie, index cases) who presented with acute community-onset MRSA skin and soft-tissue infection. METHODS. Index cases and all household members performed self-sampling for MRSA colonization every 2 weeks for 6 months. Clearance of colonization was defined as 2 consecutive sampling periods with negative surveillance cultures. Recurrent colonization was defined as any positive MRSA surveillance culture after clearance. Index cases with recurrent MRSA colonization were compared with those without recurrence on the basis of antibiotic exposure, household demographic characteristics, and presence of MRSA colonization in household members. RESULTS. The study cohort comprised 195 index cases; recurrent MRSA colonization occurred in 85 (43.6%). Median time to recurrence was 53 days (interquartile range, 36-84 days). Treatment with clindamycin was associated with lower risk of recurrence (odds ratio, 0.52; 95% CI, 0.29-0.93). Higher percentage of household members younger than 18 was associated with increased risk of recurrence (odds ratio, 1.01; 95% CI, 1.00-1.02). The association between MRSA colonization in household members and recurrent colonization in index cases did not reach statistical significance in primary analyses. CONCLUSION. A large proportion of patients initially presenting with MRSA skin and soft-tissue infection will have recurrent colonization after clearance. The reduced rate of recurrent colonization associated with clindamycin may indicate a unique role for this antibiotic in the treatment of such infection. C1 [Cluzet, Valerie C.; Linkin, Darren R.; Fishman, Neil O.; Lautenbach, Ebbing] Univ Penn, Dept Med, Perelman Sch Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Gerber, Jeffrey S.; Zaoutis, Theoklis E.; Linkin, Darren R.; Coffin, Susan E.; Margolis, David J.; Bilker, Warren B.; Han, Xiaoyan; Tolomeo, Pam; Wise, Jacqueleen A.; Wheeler, Mary K.; Lautenbach, Ebbing] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gerber, Jeffrey S.; Zaoutis, Theoklis E.; Coffin, Susan E.; Margolis, David J.; Bilker, Warren B.; Han, Xiaoyan; Lautenbach, Ebbing] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gerber, Jeffrey S.; Zaoutis, Theoklis E.; Coffin, Susan E.] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Div Infect Dis,Perelman Sch Med, Philadelphia, PA 19104 USA. [Nachamkin, Irving; Hu, Baofeng] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Metlay, Joshua P.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Davis, Meghan F.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Julian, Kathleen G.] Penn State Hershey Med Ctr, Div Infect Dis, Hershey, PA USA. [Linkin, Darren R.] Philadelphia Vet Adm Med Ctr, Philadelphia, PA USA. [Margolis, David J.] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hollander, Judd E.] Thomas Jefferson Univ Hosp, Dept Emergency Med, Philadelphia, PA 19107 USA. [Mistry, Rakesh D.] Childrens Hosp Colorado, Sect Emergency Med, Aurora, CO USA. [Gavin, Laurence J.] Penn Presbyterian Med Ctr, Dept Emergency Med, Philadelphia, PA USA. [Royer, David] Lincoln Univ, Dept Biol, Lincoln Univ, PA USA. RP Cluzet, VC (reprint author), Hosp Univ Penn, Dept Med, Div Infect Dis, 3400 Spruce St,3rd Fl,Silverstein Bldg,Ste E, Philadelphia, PA 19104 USA. EM valeriec@mail.med.upenn.edu OI Davis, Meghan/0000-0002-3475-4578 FU Pennsylvania State Department of Health (Commonwealth Universal Research Enhancement Program); National Institutes of Health [K24-AI080942]; Centers for Disease Control and Prevention Epicenters Program [U54-CK000163] FX Pennsylvania State Department of Health (Commonwealth Universal Research Enhancement Program grant to E.L.); the National Institutes of Health (grant K24-AI080942 to E.L.); and the Centers for Disease Control and Prevention Epicenters Program (grant U54-CK000163 to E.L.). The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. NR 40 TC 4 Z9 4 U1 0 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2015 VL 36 IS 7 BP 786 EP 793 DI 10.1017/ice.2015.76 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CK8UE UT WOS:000356513400005 PM 25869756 ER PT J AU Sillesen, NH Greene, ME Nebergall, AK Nielsen, PT Laursen, MB Troelsen, A Malchau, H AF Sillesen, Nanna H. Greene, Meridith E. Nebergall, Audrey K. Nielsen, Poul T. Laursen, Mogens B. Troelsen, Anders Malchau, Henrik TI Three Year RSA Evaluation of Vitamin E Diffused Highly Cross-linked Polyethylene Liners and Cup Stability SO JOURNAL OF ARTHROPLASTY LA English DT Article DE hip arthroplasty; RSA; liner; vitamin E; polyethylene ID TOTAL HIP-ARTHROPLASTY; RADIOSTEREOMETRIC ANALYSIS; STEPWISE INTRODUCTION; WEAR AB Vitamin E diffusion into highly cross-linked polyethylene (E-XLPE) is a method for enhancing oxidative stability of acetabular liners. The purpose of this study was to evaluate in vivo penetration of E-XLPE using radiostereometric analysis (RSA). Eighty-four hips were recruited into a prospective 10-year RSA. This is the first evaluation of the multicenter cohort after 3-years. All patients received E-XLPE liners (E1, Biomet) and porous-titanium coated cups (Regenerex, Biomet). There was no difference (P = 0.450) in median femoral head penetration into the E-XLPE liners at 3-years comparing cobalt-chrome heads (-0.028 mm; inter-quartile range (IQR) -0.065 to 0.047) with ceramic heads (-0.043 mm, IQR -0.143 to 0.042). The 3-year follow-up indicates minimal E-XLPE liner penetration regardless of head material and minimal early cup movement. (C) 2015 Elsevier Inc. All rights reserved. C1 [Sillesen, Nanna H.; Greene, Meridith E.; Nebergall, Audrey K.; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Nielsen, Poul T.; Laursen, Mogens B.] Aalborg Univ Hosp, Dept Orthopaed, Aalborg, Denmark. [Sillesen, Nanna H.; Troelsen, Anders] Copenhagen Univ Hosp, Dept Orthoped, Clin Orthoped Res Hvidovre, DK-2650 Hvidovre, Denmark. RP Sillesen, NH (reprint author), Copenhagen Univ Hosp, Dept Orthoped, Clin Orthoped Res Hvidovre, Kettegaards 30,Afd 333, DK-2650 Hvidovre, Denmark. OI Laursen, Mogens/0000-0002-2791-3921 NR 17 TC 2 Z9 2 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD JUL PY 2015 VL 30 IS 7 BP 1260 EP 1264 DI 10.1016/j.arth.2015.02.018 PG 5 WC Orthopedics SC Orthopedics GA CK4HG UT WOS:000356184300035 PM 25754257 ER PT J AU Warfield, ME Crossman, MK Delahaye, J Weerd, ED Kuhlthau, KA AF Warfield, Marji Erickson Crossman, Morgan K. Delahaye, Jennifer Weerd, Emma Der Kuhlthau, Karen A. TI Physician Perspectives on Providing Primary Medical Care to Adults with Autism Spectrum Disorders (ASD) SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Adults with autism spectrum disorders; Health care; Physician perspectives; Physician training ID HEALTH-CARE; YOUNG-ADULTS; DISABILITIES; TRANSITION; PEOPLE; NEEDS; CHILDREN; STUDENTS; PERFORMANCE; ATTITUDES AB We conducted in-depth case studies of 10 health care professionals who actively provide primary medical care to adults with autism spectrum disorders. The study sought to understand their experiences in providing this care, the training they had received, the training they lack and their suggestions for encouraging more physicians to provide this care. Qualitative data were gathered by phone using a structured interview guide and analyzed using the framework approach. Challenges to providing care were identified at the systems, practice and provider, and education and training levels. Solutions and interventions targeting needed changes at each level were also proposed. The findings have implications for health care reform, medical school and residency training programs, and the development of best practices. C1 [Warfield, Marji Erickson; Crossman, Morgan K.] Brandeis Univ, Starr Ctr Intellectual & Dev Disabil, Heller Sch Social Policy & Management, Waltham, MA 02453 USA. [Delahaye, Jennifer; Weerd, Emma Der; Kuhlthau, Karen A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Boston, MA USA. RP Warfield, ME (reprint author), Brandeis Univ, Starr Ctr Intellectual & Dev Disabil, Heller Sch Social Policy & Management, MS035,415 South St, Waltham, MA 02453 USA. EM mew@brandeis.edu FU U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program [R40 MC 19925] FX This project was supported with funding from a Grant, R40 MC 19925 through the U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program. We thank the providers who participated in the study. NR 46 TC 3 Z9 3 U1 2 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JUL PY 2015 VL 45 IS 7 BP 2209 EP 2217 DI 10.1007/s10803-015-2386-9 PG 9 WC Psychology, Developmental SC Psychology GA CK6QD UT WOS:000356351800025 PM 25724445 ER PT J AU Bernard, KRL Rivera, M AF Bernard, Kenneth R. L. Rivera, Morris TI REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE headache; thunderclap; subarachnoid hemorrhage; reversible cerebrovasconstriction syndrome ID CRANIAL COMPUTED-TOMOGRAPHY; SUBARACHNOID HEMORRHAGE; THUNDERCLAP HEADACHE; DIAGNOSIS AB Background: Reversible cerebral vasoconstriction syndrome (RCVS) is an underappreciated and poorly understood cause of thunderclap headache (TCH). Although self-limited in the majority of patients, incidence is increasing, with presentations overlapping considerably with life-threatening conditions, such as aneurysmal subarachnoid hemorrhage and stroke. In addition, radiographic findings seen in RCVS are also present in primary angiitis of the central nervous system (PACNS). Misdiagnosis of RCVS might subject patients to unnecessary invasive testing and immunosuppressive therapy. Furthermore, the recommended treatment of glucocorticoids used in PACNS can be harmful in RCVS. RCVS is not a benign condition, as patients can have ischemic or hemorrhagic complications leading to persistent neurologic deficits and even death. Current treatments, guided only by expert consensus, have no proven effect on these complications, which argues the need for accurate identification of patients with RCVS and prospective studies to validate treatment and inform prognoses. Case Report: We describe a previously healthy male who presented to the emergency department after 2 episodes of TCH and angiography consistent with RCVS. Why Should An Emergency Physician Be Aware of This?: RCVS is a common but underappreciated cause of TCH. The likelihood of misdiagnosing RCVS following the accepted diagnostic algorithm of acute headache in the emergency department is high due to a lack of clinical awareness and common features shared with other headache syndromes. Emergency department physicians must broaden the differential in patients presenting to the emergency department with TCH to include RCVS and be familiar with the accepted treatments and appropriate follow-up. (C) 2015 Elsevier Inc. C1 [Bernard, Kenneth R. L.] Brigham & Womens Massachusetts Gen Hosp, Dept Emergency Med, Harvard Affiliated Emergency Med Progam, Boston, MA 02115 USA. [Rivera, Morris] Marthas Vineyard Hosp, Partners Healthcare, Oak Bluffs, MA USA. RP Bernard, KRL (reprint author), Brigham & Womens Massachusetts Gen Hosp, Dept Emergency Med, Harvard Affiliated Emergency Med Progam, 75 Francis St,Neville House, Boston, MA 02115 USA. NR 17 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JUL PY 2015 VL 49 IS 1 BP 26 EP 31 DI 10.1016/j.jemermed.2015.01.012 PG 6 WC Emergency Medicine SC Emergency Medicine GA CK7YA UT WOS:000356451600018 PM 25858343 ER PT J AU Lam, SHF Bailitz, J Blehar, D Becker, BA Hoffmann, B Liteplo, AS Rajan, KB Lambert, M AF Lam, Samuel H. F. Bailitz, John Blehar, David Becker, Brent A. Hoffmann, Beatrice Liteplo, Andrew S. Rajan, Kumar B. Lambert, Michael TI MULTI-INSTITUTION VALIDATION OF AN EMERGENCY ULTRASOUND IMAGE RATING SCALE-A PILOT STUDY SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE ultrasound education; competency; image rating scale; bedside ultrasound ID LEARNING-CURVE; ULTRASONOGRAPHY; MEDICINE; SONOGRAPHY; PHYSICIANS; PERFORMANCE; QUALITY; TRAUMA; MODEL AB Background: As bedside ultrasound (BUS) is being increasingly taught and incorporated into emergency medicine practice, measurement of BUS competency is becoming more important. The commonly adopted experiential approach to BUS competency has never been validated on a large scale, and has some limitations by design. Objective: Our aim was to introduce and report preliminary testing of a novel emergency BUS image rating scale (URS). Methods: Gallbladder BUS was selected as the test case. Twenty anonymous BUS image sets (still images and clips) were forwarded electronically to 16 reviewers (13 attendings, 3 fellows) at six training sites across the United States. Each reviewer rated the BUS sets using the pilot URS that consisted of three components, with numerical values assigned to each of the following aspects: Landmarks, Image Quality, and Annotations. Reviewers also decided whether or not each BUS set would be "Clinically Useful." Kendall tau s were calculated as a measure of concordance among the reviewers. Results: Among the 13 attendings, image review experience ranged from 2-15 years, 5-300 scans per week, and averaged 7.8 years and 60 images. Kendall tau s for each aspect of the URS were: Landmarks: 0.55; Image Quality: 0.57; Annotation: 0.26; Total Score: 0.63, and Clinical Usefulness: 0.45. All URS elements correlated significantly with clinical usefulness (p < 0.001). The correlation coefficient between each attending reviewer and the entire group ranged from 0.48-0.69, and was independent of image review experience beyond fellowship training. Conclusion: Our novel URS had moderate-to-good inter-rater agreement in this pilot study. Based on these results, the URS will be modified for use in future investigations. (C) 2015 Elsevier Inc. C1 [Lam, Samuel H. F.; Lambert, Michael] Advocate Christ Med Ctr, Dept Emergency Med, Oak Lawn, IL 60453 USA. [Lam, Samuel H. F.] Univ Illinois, Dept Emergency Med, Chicago, IL USA. [Bailitz, John] Cook Cty Stroger Hosp, Dept Emergency Med, Chicago, IL USA. [Blehar, David] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA USA. [Becker, Brent A.] York Hosp Wellspan Health, Dept Emergency Med, York, PA USA. [Hoffmann, Beatrice] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. [Liteplo, Andrew S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Rajan, Kumar B.] Rush Univ, Rush Inst Hlth Aging, Dept Internal Med, Chicago, IL 60612 USA. RP Lam, SHF (reprint author), Advocate Christ Med Ctr, Dept Emergency Med, 4440 W 95th St, Oak Lawn, IL 60453 USA. OI Rajan, Kumar/0000-0003-1268-4617 FU Advocate Christ Medical Center Med Fund FX Grant support was provided to Dr. Lam by the Advocate Christ Medical Center Med Fund. We thank Mark Mycyk, MD, Rebecca R. Roberts, MD, P. John Konicki, DO, and Martha Villalba, MD, for reviewing the manuscript and providing insightful comments for revision. We also thank Ibrar Ahmed, BS for his statistical support. NR 26 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 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JUL PY 2015 VL 49 IS 1 BP 32 EP 39 DI 10.1016/j.jemermed.2015.01.010 PG 8 WC Emergency Medicine SC Emergency Medicine GA CK7YA UT WOS:000356451600019 PM 25907634 ER PT J AU Kline, JA Kabrhel, C AF Kline, Jeffrey A. Kabrhel, Christopher TI EMERGENCY EVALUATION FOR PULMONARY EMBOLISM, PART 2: DIAGNOSTIC APPROACH SO JOURNAL OF EMERGENCY MEDICINE LA English DT Review DE pulmonary embolism; medicolegal; defensive medicine; decision making; venous thromboembolism; pregnancy; diagnosis; pregnancy ID DEEP-VEIN THROMBOSIS; RULE-OUT CRITERIA; CONTRAST-INDUCED NEPHROPATHY; ACUTE VENOUS THROMBOEMBOLISM; REVISED GENEVA SCORE; LOW-RISK PATIENTS; D-DIMER CUTOFF; COMPUTED-TOMOGRAPHY; DEPARTMENT PATIENTS; PRETEST PROBABILITY AB Background: In part 1 of this two-part review, we discussed which risk factors, historical features, and physical findings increase risk for pulmonary embolism (PE) in symptomatic emergency department (ED) patients. Objectives: Use published evidence to describe criteria that a reasonable and prudent clinician can use to initiate and guide the process of excluding and diagnosing PE. Discussion: The careful and diligent emergency physician can use clinical criteria to safely obviate a formal evaluation of PE, including the use of gestalt reasoning and the pulmonary embolism rule-out criteria (PERC rule, Table 2, part 1). We present published clinical and radiographic features of patients with PE who eluded diagnosis in the ED. D-dimer can be used to exclude PE in many patients, and employing age-based adjustments to the threshold to define an abnormal value can further reduce patient exposure to pulmonary vascular imaging. Moreover, we discuss benefits, limitations, and potential harms of computed tomographic pulmonary vascular imaging relevant to patients and the practice of emergency care. We present algorithms to guide exclusion and diagnosis of PE in patients with suspected PE, including those who are pregnant. Conclusions: Reasonable and prudent emergency clinicians can exclude PE in symptomatic ED patients on clinical grounds alone in many patients, and many more can have PE ruled out by use of the D-dimer. (C) 2015 Elsevier Inc. C1 [Kline, Jeffrey A.] Indiana Univ Sch Med, Dept Emergency Med, Indianapolis, IN 46202 USA. [Kline, Jeffrey A.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Kabrhel, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Vasc Emergencies,Dept Emergency Med, Boston, MA USA. [Kabrhel, Christopher] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. RP Kline, JA (reprint author), Indiana Univ Sch Med, Dept Emergency Med, 720 Eskanazi Ave, Indianapolis, IN 46202 USA. OI Kabrhel, Christopher/0000-0002-8699-7176 NR 117 TC 3 Z9 3 U1 4 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JUL PY 2015 VL 49 IS 1 BP 104 EP 117 DI 10.1016/j.jemermed.2014.12.041 PG 14 WC Emergency Medicine SC Emergency Medicine GA CK7YA UT WOS:000356451600034 PM 25800524 ER PT J AU Fisichella, PM DeMeester, SR Hungness, E Perretta, S Soper, NJ Rosemurgy, A Torquati, A Sachdeva, AK Patti, MG AF Fisichella, P. Marco DeMeester, Steven R. Hungness, Eric Perretta, Silvana Soper, Nathaniel J. Rosemurgy, Alexander Torquati, Alfonso Sachdeva, Ajit K. Patti, Marco G. TI Emerging Techniques in Minimally Invasive Surgery. Pros and Cons SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Review DE Esophageal achalasia; Pneumatic dilatation; Laparoscopic Heller myotomy; Dor fundoplication; Per oral endoscopic myotomy; POEM; Transvaginal access; Transgastric access; Single-site surgery; Laparoscopy ID PERORAL ENDOSCOPIC MYOTOMY; LAPAROSCOPIC HELLER MYOTOMY; RANDOMIZED CONTROLLED-TRIAL; SITE LESS CHOLECYSTECTOMY; LEARNING-CURVE; ESOPHAGEAL ACHALASIA; SINGLE-INCISION; CONSENSUS STATEMENT; FUNDOPLICATION; MULTICENTER AB New trends have emerged regarding the best minimally invasive access approaches to perform gastrointestinal surgery. However, these newer approaches are seen critically by those who demand a more strict assessment of outcomes and safety. An international panel of expert gathered at the 2014 American College of Surgeons Meeting with the goal of providing an evidence-based understanding of the real value of these approaches in gastrointestinal surgery. The panel has compared the efficacy and safety of most established approaches to gastrointestinal diseases to those of new treatment modalities: peroral esophageal myotomy vs. laparoscopic myotomy for achalasia, transgastric vs. transvaginal approach, and single-incision vs. multi-port access minimally invasive surgery. The panel found that (1) the outcome of these new approaches was not superior to that of established surgical procedures; (2) the new approaches are generally performed in few highly specialized centers; and (3) transgastric and transvaginal approaches might be safe and feasible in very experienced hands, but cost, training, operative time, and tools seem to limit their application for the treatment of common procedures such as cholecystectomy and appendectomy. Because the expected advantages of new approaches have yet to be proven in controlled trials, new approaches should be considered for adoption into practice only after thorough analyses of their efficacy and effectiveness and appropriate training. C1 [Fisichella, P. Marco] Brigham & Womens Hosp, Dept Surg, Boston, MA 02132 USA. [Fisichella, P. Marco] Harvard Univ, Boston VA Healthcare Syst, Sch Med, Boston, MA 02132 USA. [DeMeester, Steven R.] Univ So Calif, Dept Surg, Los Angeles, CA USA. [Hungness, Eric; Soper, Nathaniel J.] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Perretta, Silvana] Univ Strasbourg, Dept Digest & Endocrine Surg, IRCAD, Strasbourg, France. [Rosemurgy, Alexander] Florida Hosp, Dept Surg, Tampa, FL USA. [Torquati, Alfonso] Duke Univ, Dept Surg, Durham, NC USA. [Sachdeva, Ajit K.] Amer Coll Surg, Div Educ, Chicago, IL USA. [Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Dept Surg, Chicago, IL 60637 USA. [Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Ctr Esophageal Dis, Chicago, IL 60637 USA. RP Fisichella, PM (reprint author), Brigham & Womens Hosp, Dept Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM marco6370@yahoo.com FU Division of Education, Committee on Emergent Surgical Technologies (CESTE), American College of Surgeons FX This paper is sponsored by the Division of Education, Committee on Emergent Surgical Technologies (CESTE), American College of Surgeons. NR 61 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD JUL PY 2015 VL 19 IS 7 BP 1355 EP 1362 DI 10.1007/s11605-015-2766-7 PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CK8AH UT WOS:000356458900019 PM 25678255 ER PT J AU Kaiser, AM Hogen, R Bordeianou, L Alavi, K Wise, PE Sudan, R AF Kaiser, Andreas M. Hogen, Rachel Bordeianou, Liliana Alavi, Karim Wise, Paul E. Sudan, Ranjan CA SSAT TI Clostridium Difficile Infection from a Surgical Perspective SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Clostridium difficile; Antibiotic-associated colitis; Antibiotic-associated diarrhea; Pseudo-membranous colitis; Toxic colitis; Total colectomy; Fecal microbiota transfer ID INFLAMMATORY-BOWEL-DISEASE; INTENSIVE-CARE-UNIT; RISK-FACTORS; MICROBIOTA TRANSPLANTATION; HOSPITALIZED-PATIENTS; DIAGNOSTIC YIELD; RANDOMIZED-TRIAL; FOLLOW-UP; COLITIS; DIARRHEA AB The incidence and the severity of Clostridium difficile infection (CDI) have increased significantly over the last decade, especially in high-risk populations such as patients with inflammatory bowel disease (IBD). Surgeons must be able to both identify and minimize the risk of CDI in their own surgical patients and determine which CDI patients will benefit from surgery. We sought to define the risk factors, compare the treatment options, define the surgical indications, and identify factors that affect surgical outcomes for CDI based on the currently available literature. Antibiotic use, exposure to the C. difficile bacteria, IBD, and higher levels of co-morbidity are all risk factors for CDI. The majority of CDI can be treated with antibiotics. Severe or fulminant colitis, however, has a high potential for poor outcome, but experience and some data suggest a lower mortality rate with colectomy rather than with continued medical treatment. Open total abdominal colectomy with end ileostomy is typically the preferred surgical strategy. It is often difficult to determine which patients will fail medical management as some may not manifest clinical signs of severe infection. Surrogate parameters of failure of medical therapy include respiratory and/or renal insufficiency, age greater than 60 years, peripheral vascular disease, congestive heart failure, and coagulopathy, all of which have been associated with worse surgical outcomes. Evidence suggests that in appropriately selected patients, colectomy performed before the development of shock requiring vasopressors, respiratory failure, renal failure, multi-organ dysfunction, and mental status changes may reduce mortality of the most severe forms of colitis. For less severe or recurrent presentations, creation of a loop ileostomy with intra-operative colonic lavage, fecal microbiota transfer, and C. difficile vaccinations are being discussed but have only been studied in small case-controlled series. Prevention, containment, and non-surgical treatment are the cornerstone of management for CDI. However, the most severe forms with toxic colitis benefit from involvement of a surgical team. Swift open total abdominal colectomy with end ileostomy in patients with severe or fulminant C. difficile colitis has the best chance to reduce mortality if it is not delayed until shock, end organ damage, vasopressor requirement, mental status changes develop. Less aggressive approaches may be appropriate for milder and refractory forms but require further study before their applicability can be determined. C1 [Kaiser, Andreas M.; Hogen, Rachel] Univ So Calif, Keck Sch Med, Div Colorectal Surg, Dept Surg, Los Angeles, CA 90033 USA. [Bordeianou, Liliana] Massachusetts Gen Hosp, Dept Surg, Colorectal Surg Program, Boston, MA 02114 USA. [Alavi, Karim] UMass Mem Med Ctr, Dept Surg, Worcester, MA USA. [Wise, Paul E.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Sudan, Ranjan] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Kaiser, AM (reprint author), Univ So Calif, Keck Sch Med, Div Colorectal Surg, Dept Surg, 1441 Eastlake Ave,Suite 7418, Los Angeles, CA 90033 USA. EM akaiser@usc.edu OI Wise, Paul/0000-0003-3798-7913 FU GI Health Foundation FX Disclosure Information: Authors: Karim Alavi, M.D., MPH has nothing to disclose; Sook Yee Chan, M.D. has nothing to disclose. Paul Wise, M.D. has nothing to disclose. Andreas M. Kaiser, M.D. receives speaker fees from GI Health Foundation, and royalties from Uptodate and McGraw Hill Publisher. Ranjan Sudan, M.D. has nothing to disclose. Liliana Bordeianou, M.D. has nothing to disclose. Editors-in-Chief: Jeffrey B. Matthews, M.D., has nothing to disclose; Charles Yeo, M.D., has nothing to disclose. CME Overseers: Arbiter: Jeffrey B. Matthews, M.D., has nothing to disclose; Vice-Arbiter: Guilherme M. Campos, M.D., Ph.D., has nothing to disclose; Question Reviewers: Deepa Taggarshe, M.D. has nothing to disclose; I. Michael Leitman, M.D., has nothing to disclose. NR 117 TC 4 Z9 4 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD JUL PY 2015 VL 19 IS 7 BP 1363 EP 1377 DI 10.1007/s11605-015-2785-4 PG 15 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CK8AH UT WOS:000356458900020 PM 25917533 ER PT J AU Kaminetzky, CP Nelson, KM AF Kaminetzky, Catherine P. Nelson, Karin M. TI In the Office and In-Between: The Role of Panel Management in Primary Care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID HEALTH; OUTCOMES C1 [Kaminetzky, Catherine P.] VA Puget Sound Hlth Care Syst, Ctr Educ & Dev, Seattle, WA 98108 USA. [Kaminetzky, Catherine P.; Nelson, Karin M.] Univ Washington, Sch Med, Div Gen Internal Med, Seattle, WA USA. [Nelson, Karin M.] VA Puget Sound Hlth Care Syst, VA Hlth Serv Res & Dev, Seattle, WA 98108 USA. RP Kaminetzky, CP (reprint author), VA Puget Sound Hlth Care Syst, Ctr Educ & Dev, 1660 South Columbian Way, Seattle, WA 98108 USA. EM catherine.kaminetzky@va.gov NR 12 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2015 VL 30 IS 7 BP 876 EP 877 DI 10.1007/s11606-015-3310-x PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CK8AL UT WOS:000356459400005 PM 25851305 ER PT J AU Berkowitz, SA Percac-Lima, S Ashburner, JM Chang, YC Zai, AH He, W Grant, RW Atlas, SJ AF Berkowitz, Seth A. Percac-Lima, Sanja Ashburner, Jeffrey M. Chang, Yuchiao Zai, Adrian H. He, Wei Grant, Richard W. Atlas, Steven J. TI Building Equity Improvement into Quality Improvement: Reducing Socioeconomic Disparities in Colorectal Cancer Screening as Part of Population Health Management SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE colorectal cancer; cancer screening; health status disparities; socioeconomic factors; quality improvement ID RANDOMIZED-CONTROLLED-TRIAL; INTERRUPTED TIME-SERIES; UNITED-STATES; PATIENT NAVIGATION; PRIMARY-CARE; COLONOSCOPY; INTERVENTIONS; IMPACT; ORGANIZATIONS AB Improving colorectal cancer (CRC) screening rates for patients from socioeconomically disadvantaged backgrounds is a recognized public health priority. Our aim was to determine if implementation of a system-wide screening intervention could reduce disparities in the setting of improved overall screening rates. This was an interrupted time series (ITS) analysis before and after a population management intervention. Patients eligible for CRC screening (age 52-75 years without prior total colectomy) in an 18-practice research network from 15 June 2009 to 15 June 2012 participated in the study. The Technology for Optimizing Population Care (TopCare) intervention electronically identified patients overdue for screening and facilitated contact by letter or telephone scheduler, with or without physician involvement. Patients identified by algorithm as high risk for non-completion entered into intensive patient navigation. Patients were dichotomized as a parts per thousand currency signaEuro parts per thousand high school diploma (a parts per thousand currency sign HS), an indicator of socioeconomic disadvantage, vs. > HS diploma (> HS). The monthly disparity between a parts per thousand currency signaEuro parts per thousand HS and > HS with regard to CRC screening completion was examined. At baseline, 72 % of 47,447 eligible patients had completed screening, compared with 75 % of 51,442 eligible patients at the end of follow-up (p < 0.001). CRC screening completion was lower in a parts per thousand currency signaEuro parts per thousand HS vs. > HS patients in June 2009 (65.7 % vs. 74.5 %, p < 0.001) and remained lower in June 2012 (69.4 % vs. 76.7 %, p < 0.001). In the ITS analysis, which accounts for secular trends, TopCare was associated with a significant decrease in the CRC screening disparity (0.7 %, p < 0.001). The effect of TopCare represents approximately 99 additional a parts per thousand currency signaEuro parts per thousand HS patients screened above prevailing trends, or 26 life-years gained had these patients remained unscreened. A multifaceted population management intervention sensitive to the needs of vulnerable patients modestly narrowed disparities in CRC screening, while also increasing overall screening rates. Embedding interventions for vulnerable patients within larger population management systems represents an effective approach to increasing overall quality of care while also decreasing disparities. C1 [Berkowitz, Seth A.; Percac-Lima, Sanja; Ashburner, Jeffrey M.; Chang, Yuchiao; He, Wei; Atlas, Steven J.] Massachusetts Gen Hosp, Med Serv, Div Gen Internal Med, Boston, MA USA. [Berkowitz, Seth A.; Percac-Lima, Sanja; Chang, Yuchiao; Zai, Adrian H.; Atlas, Steven J.] Harvard Univ, Sch Med, Boston, MA 02138 USA. [Zai, Adrian H.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Grant, Richard W.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Berkowitz, SA (reprint author), Harvard Univ, Sch Med, Boston, MA 02138 USA. EM SABerkowitz@partners.org OI Berkowitz, Seth/0000-0003-1030-4297 FU Agency for Healthcare Research and Quality [AHRQ R18-HS018161]; Controlled Risk Insurance Company/Risk Management Foundation; Massachusetts General Hospital Primary Care Operations Improvement Program; Massachusetts General Physicians Organization; Institutional National Research Service Award [T32HP10251]; Ryoichi Sasakawa Fellowship Fund; Division of General Internal Medicine at Massachusetts General Hospital FX This study was supported by grants from the Agency for Healthcare Research and Quality (AHRQ R18-HS018161), the Controlled Risk Insurance Company/Risk Management Foundation, and institutional funding through the Massachusetts General Hospital Primary Care Operations Improvement Program and the Massachusetts General Physicians Organization. Seth A. Berkowitz was supported by an Institutional National Research Service Award #T32HP10251, the Ryoichi Sasakawa Fellowship Fund, and by the Division of General Internal Medicine at Massachusetts General Hospital. NR 39 TC 8 Z9 8 U1 4 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2015 VL 30 IS 7 BP 942 EP 949 DI 10.1007/s11606-015-3227-4 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CK8AL UT WOS:000356459400017 PM 25678378 ER PT J AU Soley-Bori, M Soria-Saucedo, R Ryan, CM Schneider, JC Haynes, AB Gerrard, P Cabral, HJ Lillemoe, KD Kazis, LE AF Soley-Bori, Marina Soria-Saucedo, Rene Ryan, Colleen M. Schneider, Jeffrey C. Haynes, Alex B. Gerrard, Paul Cabral, Howard J. Lillemoe, Keith D. Kazis, Lewis E. TI Functional Status and Hospital Readmissions Using the Medical Expenditure Panel Survey SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE functional status; physical status; medical expenditure panel survey; hospital admission; readmission ID QUALITY-OF-LIFE; HEART-FAILURE PATIENTS; RISK-FACTORS; ACUTE-CARE; DISCHARGE; OLDER; REHOSPITALIZATION; REHABILITATION; PREDICTORS; PROGRAM AB Hospital readmissions are expensive and they may signal poor quality of care. Whether functional status is related to hospital readmissions using a representative U.S sample remains unexplored . We aimed to assess the relationship between functional status and all-cause 30-day hospital readmissions using a representative sample of the US population. This was a retrospective observational study (2003-2011). The study included 3,772 patients who completed the SF-12 before being hospitalized. Three hundred and eighteen (8.4 %) were readmitted within 30 days after being discharged. The Medical Expenditure Panel Survey (MEPS) was employed. Functional status was measured with the Short-Form 12-Item Health Survey Version 2A (R) (SF-12). The probability of being readmitted was estimated using a logistic model controlling for demographic characteristics, comorbid conditions, insurance coverage, physical (PCS) and mental (MCS) summaries of the SF-12, reason for hospitalization, length of hospital stay, region, and residential area. A one-unit difference in PCS reduced the odds of readmission by 2 % (odds ratio 0.98 [95 % CI, 0.97 to 0.99]; p < 0.001), which implies an 18 % reduction in the odds of readmissions for a ten-unit difference (one standard deviation) in PCS. The c-statistic of the model was 0.72. Baseline physical function is associated with hospital readmissions. The SF-12 improves the ability to identify patients at high risk of hospital readmission. C1 [Soley-Bori, Marina; Soria-Saucedo, Rene; Kazis, Lewis E.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, CAPP, Boston, MA 02138 USA. [Cabral, Howard J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ryan, Colleen M.; Haynes, Alex B.; Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Ryan, Colleen M.; Schneider, Jeffrey C.] Harvard Univ, Sch Med, Boston, MA USA. [Ryan, Colleen M.] Shriners Hosp Children, Boston, MA USA. [Schneider, Jeffrey C.] Spaulding Rehabil Hosp, Charlestown, MA USA. [Haynes, Alex B.] Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, Boston, MA 02114 USA. [Haynes, Alex B.] Harvard Univ, Sch Publ Hlth, Ariadne Labs, Boston, MA 02115 USA. [Haynes, Alex B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gerrard, Paul] New England Rehabil Hosp Portland, Portland, ME USA. RP Kazis, LE (reprint author), Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, CAPP, Boston, MA 02138 USA. EM lek@bu.edu NR 45 TC 5 Z9 5 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2015 VL 30 IS 7 BP 965 EP 972 DI 10.1007/s11606-014-3170-9 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CK8AL UT WOS:000356459400020 PM 25691236 ER PT J AU Liu, QL Rehman, H Krishnasamy, Y Schnellmann, RG Lemasters, JJ Zhong, Z AF Liu, Qinlong Rehman, Hasibur Krishnasamy, Yasodha Schnellmann, Rick G. Lemasters, John J. Zhong, Zhi TI Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice SO JOURNAL OF HEPATOLOGY LA English DT Article DE c-Jun N-terminal kinase; Inducible nitric oxide synthase; Liver transplantation; Mitochondrial permeability transition; Non-heart-beating donors; Primary non-function; Sab ID MITOCHONDRIAL PERMEABILITY TRANSITION; NITRIC-OXIDE SYNTHASE; HEART-BEATING DONORS; N-TERMINAL KINASE; HEPATIC ISCHEMIA-REPERFUSION; GRAFT INJURY; ISCHEMIA/REPERFUSION INJURY; SIGNALING PATHWAYS; OXIDATIVE STRESS; INHIBITION AB Background & Aims: Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Methods: Livers explanted from wild-type, inducible nitric oxide synthase knockout (iNOS(-/-)), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. Results: After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS deficiency. JNK inhibition and JNK2 deficiency, but not JNK1 deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS deficiency, JNK inhibition and JNK2 deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. Conclusion: The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization, and is an attractive target to improve liver function and survival in CDD liver transplantation recipients. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Schnellmann, Rick G.; Lemasters, John J.; Zhong, Zhi] Med Univ S Carolina, Dept Drug Discovery & Biol Sci, Charleston, SC 29425 USA. [Liu, Qinlong] Dalian Med Univ, Affiliated Hosp 2, Dalian, Liaoning, 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 29403 USA. RP Zhong, Z (reprint author), Med Univ S Carolina, Dept Drug Discovery & Biol Sci, 280 Calhoun St,MSC140, Charleston, SC 29425 USA. EM zhong@musc.edu FU National Institute of Health [DK70844, DK037034]; Chinese National Natural Foundation [81470878] FX This study was supported, in part, by Grant DK70844 and DK037034 from the National Institute of Health and Grant #81470878 from Chinese National Natural Foundation. NR 49 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2015 VL 63 IS 1 BP 68 EP 74 DI 10.1016/j.jhep.2015.02.017 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CK6CC UT WOS:000356314400011 PM 25703084 ER PT J AU Simon, TG King, LY Chung, RT AF Simon, Tracey G. King, Lindsay Y. Chung, Raymond T. TI Reply to: "Coagulation and fibrosis: A potential non-negligible target of statins in chronic hepatitis'' SO JOURNAL OF HEPATOLOGY LA English DT Letter C1 [Simon, Tracey G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Simon, Tracey G.; King, Lindsay Y.; Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA USA. [King, Lindsay Y.; Chung, Raymond T.] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [King, Lindsay Y.; Chung, Raymond T.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. EM rtchung@partners.org NR 9 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2015 VL 63 IS 1 BP 279 EP 279 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CK6CC UT WOS:000356314400031 PM 25728638 ER PT J AU Peterson, DS Fling, BW Mancini, M Cohen, RG Nutt, JG Horak, FB AF Peterson, Daniel S. Fling, Brett W. Mancini, Martina Cohen, Rajal G. Nutt, John G. Horak, Fay B. TI Dual-task interference and brain structural connectivity in people with Parkinson's disease who freeze SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; PEDUNCULOPONTINE NUCLEUS; BASAL GANGLIA; GAIT; NETWORK; MOTOR AB Background Freezing of gait in people with Parkinson's disease (PD) is likely related to attentional control (ie, ability to divide and switch attention). However, the neural pathophysiology of altered attentional control in individuals with PD who freeze is unknown. Structural connectivity of the pedunculopontine nucleus has been related to freezing and may play a role in altered attentional control; however, this relationship has not been investigated. We measured whether dual-task interference, defined as the reduction in gait performance during dual-task walking, is more pronounced in individuals with PD who freeze, and whether dual-task interference is associated with structural connectivity and/or executive function in this population. Methods We measured stride length in 13 people with PD with and 12 without freezing of gait during normal and dual-task walking. We also assessed asymmetry of pedunculopontine nucleus structural connectivity via diffusion tensor imaging and performance on cognitive tests assessing inhibition and set-shifting, cognitive domains related to freezing. Results Although stride length was not different across groups, change in stride length between normal and dual-task gait (ie, dual-task interference) was more pronounced in people with PD who freeze compared to non-freezers. Further, in people with PD who freeze, dual-task interference was correlated with asymmetry of pedunculopontine nucleus structural connectivity, Go-NoGo target accuracy (ability to release a response) and simple reaction time. Conclusions These results support the hypothesis that freezing is related to altered attentional control during gait, and suggest that differences in pedunculopontine nucleus connectivity contribute to poorer attentional control in people with PD who freeze. C1 [Peterson, Daniel S.; Fling, Brett W.; Mancini, Martina; Nutt, John G.; Horak, Fay B.] Oregon Hlth & Sci Univ, Sch Med, Dept Neurol, Portland, OR 97239 USA. [Peterson, Daniel S.; Fling, Brett W.; Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. [Cohen, Rajal G.] Univ Idaho, Dept Psychol & Commun Studies, Moscow, ID 83843 USA. RP Peterson, DS (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM petedani@ohsu.edu OI Peterson, Daniel/0000-0002-4639-6544 FU National Institutes of Health via the Morris K. Udall Center for Excellence in Parkinson's Disease Research at the University of Washington; Portland Veterans Affairs Medical Center (VA Merit Award) [E1075-R]; NIH [AG006457]; Medical Research Foundation of Oregon FX This work was supported by grants from National Institutes of Health via the Morris K. Udall Center for Excellence in Parkinson's Disease Research at the University of Washington, Portland Veterans Affairs Medical Center (VA Merit Award: E1075-R), NIH (AG006457) and the Medical Research Foundation of Oregon. NR 39 TC 13 Z9 13 U1 7 U2 23 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUL PY 2015 VL 86 IS 7 BP 786 EP 792 DI 10.1136/jnnp-2014-308840 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA CK4FU UT WOS:000356179000016 PM 25224677 ER PT J AU Tsoukas, MA Ko, BJ Witte, TR Dincer, F Hardman, WE Mantzoros, CS AF Tsoukas, Michael A. Ko, Byung-Joon Witte, Theodore R. Dincer, Fadime Hardman, W. Elaine Mantzoros, Christos S. TI Dietary walnut suppression of colorectal cancer in mice: Mediation by miRNA patterns and fatty acid incorporation SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Walnut; Colon cancer; miRNA; Fatty acids; Anti-inflammation; Apoptosis; Angiogenesis ID ALPHA-LINOLENIC ACID; MAMMARY-GLAND TUMORIGENESIS; COLON-CANCER; ELLAGIC ACID; EXPRESSION PROFILES; MICRORNA EXPRESSION; BETA-SITOSTEROL; DOWN-REGULATION; RISK-FACTORS; RAT COLON AB Colorectal cancer, unlike many other malignancies, may be preventable. Recent studies have demonstrated an inverse association between nut consumption and incidence of colon cancer; however, the underlying mechanisms are not fully understood. An emerging concept suggests that microribonucleic acids (miRNAs) may help explain the relationship between walnut consumption and decreased colorectal neoplasia risk. Seven days after HT-29 colon cancer cell injection, mice were randomized to either control or walnut diets for 25 days of diet treatment. Thirty samples of tumor and of omental adipose were analyzed to determine changes in lipid composition in each dietary group. In the tumors of the walnut-containing diet, we found significant increases in alpha-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid, as compared to the control diet. Final tumor size measured at sacrifice was negatively associated with percentage of total omega-3 fatty acid composition (r=-0.641, P=.001). MicroRNA expression analysis of colorectal tumor tissue revealed decreased expression of miRNAs 1903, 467c and 3068 (P<.05) and increased expression of miRNA 297a* (P=.0059) in the walnut-treated group as compared to control diet. Our results indicate that changes in the miRNA expression profiles likely affect target gene transcripts involved in pathways of anti-inflammation, antivascularization, antiproliferation and apoptosis. We also demonstrate the incorporation of protective fatty acids into colonic epithelium of walnut-fed mice, which may independently alter miRNA expression profiles itself. Future studies of the mechanism of widespread miRNA regulation by walnut consumption are needed to offer potential prognostic and therapeutic targets. (C) 2015 Elsevier Inc. All rights reserved. C1 [Tsoukas, Michael A.; Ko, Byung-Joon; Dincer, Fadime; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Sch Med, Boston, MA 02215 USA. [Tsoukas, Michael A.] Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA USA. [Witte, Theodore R.; Hardman, W. Elaine] Marshall Univ, Sch Med, Dept Biochem & Microbiol, Huntington, WV USA. RP Tsoukas, MA (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Sch Med, Boston, MA 02215 USA. EM mtsouka1@bidmc.harvard.edu FU American Institute for Cancer Research [276688]; California Walnut Commission FX This study was supported from a grant by the American Institute for Cancer Research (276688) and the California Walnut Commission. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Institute for Cancer Research and the California Walnut Commission; sponsors had no input on interpretation or reporting of findings. NR 70 TC 6 Z9 7 U1 4 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD JUL PY 2015 VL 26 IS 7 BP 776 EP 783 DI 10.1016/j.jnutbio.2015.02.009 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA CK9LM UT WOS:000356561600012 PM 25882694 ER PT J AU Friedlander, AH Chang, TI Hazboun, RC Aghazadehsanai, N AF Friedlander, Arthur H. Chang, Tina I. Hazboun, Renna C. Aghazadehsanai, Nona TI Critique of American Dental Association Council on Scientific Affairs Clinical Practice Guideline: Use of Prophylactic Antibiotics Before Dental Procedures in Patients With Prosthetic Joints SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Editorial Material ID INFECTIONS C1 [Friedlander, Arthur H.] Vet Affairs Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA 90073 USA. [Friedlander, Arthur H.] Ronald Reagan UCLA Med Ctr, Hosp Dent Serv, Qual Assurance, Los Angeles, CA USA. [Friedlander, Arthur H.; Chang, Tina I.] Univ Calif Los Angeles, Sch Dent, Dept Oral & Maxillofacial Surg, Los Angeles, CA 90024 USA. [Chang, Tina I.] Vet Affairs Greater Los Angeles Healthcare Syst, Res Fellowship & Inpatient Oral & Maxillofacial S, Los Angeles, CA 90073 USA. [Hazboun, Renna C.; Aghazadehsanai, Nona] Vet Affairs Greater Los Angeles Healthcare Syst, Oral & Maxillofacial Surg Sect, Dent Serv, Los Angeles, CA 90073 USA. RP Friedlander, AH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM arthur.friedlander@va.gov NR 5 TC 1 Z9 1 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUL PY 2015 VL 73 IS 7 BP 1242 EP 1243 DI 10.1016/j.joms.2015.03.052 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CK5ZI UT WOS:000356306900007 PM 25896570 ER PT J AU Busch, RA Curtis, CS Leverson, GE Kudsk, KA AF Busch, Rebecca A. Curtis, Caitlin S. Leverson, Glen E. Kudsk, Kenneth A. TI Use of Piggyback Electrolytes for Patients Receiving Individually Prescribed vs Premixed Parenteral Nutrition SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE parenteral nutrition; nutrition; parenteral formulas; compounding; outcomes research; quality; nutrition support practice; reimbursement ID BLOOD-STREAM INFECTIONS; OUTBREAK AB Background: Parenteral nutrition (PN) is available as individualized prescriptions frequently prepared with an automated compounding device or as commercially prepared premixed solutions. Our institution exclusively used individualized PN until an amino acid shortage forced a temporary switch to premixed solutions. In general, premixed solutions contain lower electrolyte levels than individualized formulations prescribed for patients with normal organ function. We aimed to quantify supplemental intravenous piggyback (IVPB) electrolyte use in adult patients receiving individualized and premixed PN and to quantify any effect on difference in the cost of therapy. Methods: We compared use of supplemental IVPB electrolytes administered to patients receiving PN during consecutive periods prior to and during the amino acid shortage. Electrolyte IVPBs tabulated were potassium chloride, 10 and 20 mEq; magnesium sulfate, 2 g and 4 g; potassium phosphate, 7.5 and 15 mmol; and sodium phosphate, 7.5 and 15 mmol IVPB. Results: There was no statistical difference in the number of PN formulations administered per day during each period (14.7 +/- 3.9 vs 14.0 +/- 2.6, individualized vs premixed, respectively). Total IVPB electrolytes prescribed per day increased significantly from the individualized PN period to the premixed PN period (7.03 +/- 3.8 vs 13.8 +/- 6.8; P < .0001). The additional IVPB electrolyte supplementation required in patients receiving premixed PN was associated with an additional $11,855.74 cost per 30 days of therapy compared with those who received individualized PN. Conclusion: Inpatient use of premixed PN results in a significant increase in IVPB electrolyte supplementation and cost compared with individualized PN use. C1 [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. [Busch, Rebecca A.; Leverson, Glen E.; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Curtis, Caitlin S.] Univ Wisconsin Hosp & Clin, Dept Pharm, Madison, WI 53792 USA. RP Kudsk, KA (reprint author), Univ Wisconsin, G5-341 Clin Sci Ctr,600 Highland Ave, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU Surgical Oncology Research Training Program [T32CA090217-13] FX The project described was supported by the Surgical Oncology Research Training Program (grant number T32CA090217-13). NR 17 TC 3 Z9 3 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD JUL PY 2015 VL 39 IS 5 BP 586 EP 590 DI 10.1177/0148607113518583 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CK8SE UT WOS:000356507600010 PM 24390715 ER PT J AU Horan, WP Reise, SP Kern, RS Lee, J Penn, DL Green, MF AF Horan, William P. Reise, Steven P. Kern, Robert S. Lee, Junghee Penn, David L. Green, Michael F. TI Structure and correlates of self-reported empathy in schizophrenia SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Schizophrenia; Empathy; Social functioning; Social cognition; QCAE ID SOCIAL NEUROSCIENCE MEASURES; EMOTION REGULATION; COGNITIVE EMPATHY; CLINICAL-TRIALS; ACCURACY; PERSPECTIVE; SUPPRESSION; COMPETENCE; PSYCHOSIS; DEFICITS AB Research on empathy in schizophrenia has relied on dated self-report scales that do not conform to contemporary social neuroscience models of empathy. The current study evaluated the structure and correlates of the recently-developed Questionnaire of Cognitive and Affective Empathy (QCAE) in schizophrenia. This measure, whose structure and validity was established in healthy individuals, includes separate scales to assess the two main components of empathy: Cognitive Empathy (assessed by two subscales) and Affective Empathy (assessed by three subscales). Stable outpatients with schizophrenia (n = 145) and healthy individuals (n = 45) completed the QCAE, alternative measures of empathy, and assessments of clinical symptoms, neurocognition, and functional outcome. Exploratory and confirmatory factor analyses provided consistent support for a two-factor solution in the schizophrenia group, justifying the use of separate cognitive and affective empathy scales in this population. However, one of the three Affective Empathy subscales was not psychometrically sound and was excluded from further analyses. Patients reported significantly lower Cognitive Empathy but higher Affective Empathy than controls. Among patients, the QCAE scales showed significant correlations with an alternative self-report empathy scale, but not with performance on an empathic accuracy task. The QCAE Cognitive Empathy subscales also showed significant, though modest, correlations with negative symptoms and functional outcome. These findings indicate that structure of self-reported empathy is similar in people with schizophrenia and healthy subjects, and can be meaningfully compared between groups. They also contribute to emerging evidence that some aspects of empathy may be intact or hyper-responsive in schizophrenia. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Horan, William P.; Kern, Robert S.; Lee, Junghee; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Horan, William P.; Kern, Robert S.; Lee, Junghee; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Reise, Steven P.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Penn, David L.] Univ N Carolina, Chapel Hill, NC USA. [Penn, David L.] Australian Catholic Univ, Melbourne, Vic, Australia. RP Horan, WP (reprint author), VA Greater Los Angeles Healthcare Syst, MIRECC 210A,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM horan@ucla.edu RI Lee, Junghee/C-5226-2014 OI Lee, Junghee/0000-0001-9567-8700 FU National Institute of Mental Health [MH087618, MH043292, MH065707] FX National Institute of Mental Health (MH087618, MH043292, and MH065707 to M.F.G.) NR 51 TC 6 Z9 6 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL-AUG PY 2015 VL 66-67 BP 60 EP 66 DI 10.1016/j.jpsychires.2015.04.016 PG 7 WC Psychiatry SC Psychiatry GA CL2AT UT WOS:000356746700008 PM 25985922 ER PT J AU Tsai, J Armour, C Southwick, SM Pietrzak, RH AF Tsai, Jack Armour, Cherie Southwick, Steven M. Pietrzak, Robert H. TI Dissociative subtype of DSM-5 posttraumatic stress disorder in US veterans SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Posttraumatic stress disorder; Dissociation; Veterans; Substance abuse ID QUALITY-OF-LIFE; AFGHANISTAN VETERANS; NATIONAL-HEALTH; LATENT PROFILE; PTSD TREATMENT; IRAQ; RESILIENCE; DEPRESSION; VALIDATION; HOSTILITY AB The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) formally introduced a dissociative subtype of posttraumatic stress disorder (PTSD). This study examined the proportion of U.S. veterans with DSM-5 PTSD that report dissociative symptoms; and compared veterans with PTSD with and without the dissociative subtype and trauma-exposed controls on sociodemographics, clinical characteristics, and quality of life. Multivariable analyses were conducted on a nationally representative sample of 1484 veterans from the National Health and Resilience in Veterans Study (second baseline survey conducted September October, 2013). Of the 12.0% and 5.2% of veterans who screened positive for lifetime and past-month DSM-5 PTSD, 19.2% and 16.1% screened positive for the dissociative subtype, respectively. Among veterans with PTSD, those with the dissociative subtype reported more severe PTSD symptoms, comorbid depressive and anxiety symptoms, alcohol use problems, and hostility than those without the dissociative subtype. Adjusting for PTSD symptom severity, those with the dissociative subtype continued to report more depression and alcohol use problems. These results underscore the importance of assessing, monitoring, and treating the considerable proportion of veterans with PTSD and dissociative symptoms. Published by Elsevier Ltd. C1 [Tsai, Jack] US Dept Vet Affairs, New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. [Tsai, Jack; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Armour, Cherie] Univ Ulster, Psychol Res Inst, Coleraine BT52 1SA, Londonderry, North Ireland. [Southwick, Steven M.; Pietrzak, Robert H.] VA Connecticut Healthcare Syst, US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, West Haven, CT USA. RP Tsai, J (reprint author), 950 Campbell Ave,151D, West Haven, CT 06516 USA. EM jack.Tsai@yale.edu OI Tsai, Jack/0000-0002-0329-648X; Armour, Cherie/0000-0001-7649-3874 FU U.S. Department of Veterans Affairs, National Center for Posttraumatic Stress Disorder; U.S. Department of Veterans Affairs, Health Services Research and Development FX This work received no specific grant from any funding agency, commercial or not-for-profit sectors. This work was supported by the U.S. Department of Veterans Affairs, National Center for Posttraumatic Stress Disorder and the U.S. Department of Veterans Affairs, Health Services Research and Development. The views presented here are those of the authors alone and do not represent the position of the United States Government. NR 52 TC 5 Z9 5 U1 7 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL-AUG PY 2015 VL 66-67 BP 67 EP 74 DI 10.1016/j.jpsychires.2015.04.017 PG 8 WC Psychiatry SC Psychiatry GA CL2AT UT WOS:000356746700009 PM 25969340 ER PT J AU Andersson, MI Rajbhandari, R Kew, MC Vento, S Preiser, W Hoepelman, AIM Theron, G Cotton, M Cohn, J Glebe, D Lesi, O Thursz, M Peters, M Chung, R Wiysonge, C AF Andersson, Monique I. Rajbhandari, Ruma Kew, Michael C. Vento, Sandro Preiser, Wolfgang Hoepelman, Andy I. M. Theron, Gerhard Cotton, Mark Cohn, Jennifer Glebe, Dieter Lesi, Olufunmilayo Thursz, Mark Peters, Marion Chung, Raymond Wiysonge, Charles TI Mother-to-child transmission of hepatitis B virus in sub-Saharan Africa: time to act SO LANCET GLOBAL HEALTH LA English DT Editorial Material ID PREVENT PERINATAL TRANSMISSION; TENOFOVIR DISOPROXIL FUMARATE; PREGNANT-WOMEN; INFECTION; IMMUNIZATION; INFANTS; HIV; EFFICACY; VACCINE; SAFETY C1 [Andersson, Monique I.] Univ Stellenbosch, Div Med Virol, ZA-7505 Cape Town, South Africa. [Rajbhandari, Ruma; Chung, Raymond] Massachusetts Gen Hosp, Dept Hepatol, Boston, MA 02114 USA. [Rajbhandari, Ruma; Chung, Raymond] Harvard Univ, Boston, MA 02115 USA. [Kew, Michael C.] Univ Cape Town, Dept Med, ZA-7700 Rondebosch, South Africa. [Vento, Sandro] Univ Botswana, Gaborone, Botswana. [Preiser, Wolfgang] Univ Stellenbosch, Div Med Virol, ZA-7600 Stellenbosch, South Africa. [Theron, Gerhard] Univ Stellenbosch, Dept Obstet & Gynaecol, ZA-7600 Stellenbosch, South Africa. [Cotton, Mark] Univ Stellenbosch, Dept Child Hlth, ZA-7600 Stellenbosch, South Africa. [Wiysonge, Charles] Univ Stellenbosch, Dept Evidence Based Med, ZA-7600 Stellenbosch, South Africa. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Hoepelman, Andy I. M.] Univ Utrecht, Dept Med, Utrecht, Netherlands. [Glebe, Dieter] Univ Giessen, Inst Med Virol, D-35390 Giessen, Germany. [Lesi, Olufunmilayo] Univ Lagos, Dept Hepatol, Lagos, Nigeria. [Thursz, Mark] Univ London Imperial Coll Sci Technol & Med, Dept Hepatol, London, England. [Peters, Marion] Univ Calif San Francisco, Dept Hepatol, San Francisco, CA 94143 USA. RP Andersson, MI (reprint author), Univ Stellenbosch, Div Med Virol, Francie van Zijl Ave, ZA-7505 Cape Town, South Africa. EM andersson_m@sun.ac.za RI Preiser, Wolfgang/J-4875-2016 OI Preiser, Wolfgang/0000-0002-0254-7910 FU Poliomyelitis Research Foundation; National Health Laboratory Service Research Trust FX We declare no competing interests. We acknowledge funding from the Poliomyelitis Research Foundation and National Health Laboratory Service Research Trust. NR 15 TC 5 Z9 6 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD JUL PY 2015 VL 3 IS 7 BP E358 EP E359 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK6CH UT WOS:000356314900010 PM 26087980 ER PT J AU Lee, MS Liu, CY Su, L Christiani, DC AF Lee, Mi-Sun Liu, Chen-yu Su, Li Christiani, David C. TI Polymorphisms in ERCC1 and ERCC2/XPD genes and carcinogen DNA adducts in human lung SO LUNG CANCER LA English DT Article DE ERCC1; ERCC2/XPD; DNA repair; DNA adduct; Non-small cell lung cancer ID NUCLEOTIDE EXCISION-REPAIR; CANCER SUSCEPTIBILITY; CHINESE POPULATION; RISK; XPD; SMOKING; DAMAGE; GENOTYPES; METAANALYSIS; CAPACITY AB Objectives: In this exploratory study, we aimed to investigate whether polymorphisms in excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways associated with DNA adducts in human lung tissue. We also analyzed the association stratified by the major histologic subtypes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). Methods: The study population consisted of 107 early stage NSCLC patients from the Massachusetts General Hospital (MGH) in Boston who underwent curative surgical resection. Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C11 8T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using a PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (Taqman). DNA adduct levels were measured as relative adduct levels per 10(10) nucleotides by P-32-postlabeling in non-tumor lung tissue. Results: After adjusting for potential confounders, lung DNA adduct levels increased by 103.2% [95% confidence interval (CI), -11.5 to 366.6] for ERCC2/XPD rs1799793AA genotype compared with their corresponding wild type homozygous genotypes in overall NSCLC, but the difference did not reach statistical significance. When we stratified by the subtypes of NSCLC, we found that DNA adducts levels in lung increased by 204.9% (95% CI, 0.8 to 822.2, P=0.059) for ERCC2/XPD rs1799793AA genotype in subjects with SQCC and the trend was statistically significant (P for trend = 0.0489). Conclusions: Polymorphisms in ERCC2/XPD Asp312Asn may be associated with increased DNA adduct levels in the lung, especially among subjects with SQCC. Further large scale studies are needed to confirm our findings. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Lee, Mi-Sun; Su, Li; Christiani, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Liu, Chen-yu] Natl Taiwan Univ, Coll Publ Hlth, Inst Environm Hlth, Taipei 10764, Taiwan. [Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Christiani, David C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Christiani, DC (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave,Bldg 1 Room 1401, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu OI LIU, CHEN-YU/0000-0002-4693-5667 FU National Institutes of Health [CA074386, CA092824, CA090578] FX The authors gratefully acknowledge the patients and physicians from the Massachusetts General Hospital in Boston, Drs. John Wain and Eugene Mark, and Dr. John Wiencke. This study was supported by grants from National Institutes of Health (CA074386, CA092824, CA090578). NR 32 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JUL PY 2015 VL 89 IS 1 BP 8 EP 12 DI 10.1016/j.lungcan.2015.05.001 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CK9FP UT WOS:000356546300003 PM 26001533 ER PT J AU Owonikoko, TK Dahlberg, SE Khan, SA Gerber, DE Dowell, J Moss, RA Belani, CP Hann, CL Aggarwal, C Ramalingam, SS AF Owonikoko, Taofeek K. Dahlberg, Suzanne E. Khan, Saad A. Gerber, David E. Dowell, Jonathan Moss, Rebecca A. Belani, Chandra P. Hann, Christine L. Aggarwal, Charu Ramalingam, Suresh S. TI A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E2511) SO LUNG CANCER LA English DT Article DE Small cell; Veliparib; PARP; Phase I ID REFRACTORY SOLID TUMORS; I COMBINATION; III TRIAL; CHEMOTHERAPY; ADULTS; IRINOTECAN/CISPLATIN; ETOPOSIDE/CISPLATIN; INHIBITOR; LYMPHOMAS; ABT-888 AB Objectives: Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects. Materials and methods: The study employed the 3 +3 dose escalation design to establish the safety and recommended phase 2 dose (RP2D) of V when combined with fixed doses of C (75 mg/m(2) on day 1) and E (100 mg/m(2) on days 1-3) in a 21-day cycle. The starting dose of V was 60 mg (bid days 1-7) with plan to escalate to 100 mg (days 1-7) or de-escalate to 40 mg (days 1-7) depending on the dose limiting toxicity (DLT) experience during cycle 1. Patients with treatment-naive, extensive stage SCLC were included. Results: The study enrolled 9 patients: M/F (4/5); median age (60); White/African American (8/1). V was tolerated at the 60 mg (DLT in 0 of 3 patients) and 100 mg dose (DLT in 1 of 6 patients; grade 5 cardiac failure). Veliparib at 100 mg in combination with standard doses of C and E was established as the RP2D. Grades 3-5 adverse events irrespective of attribution during cycle 1 included: dehydration (1), diarrhea (1), fatigue (1), febrile neutropenia (1), heart failure (1), leukopenia (6), lymphopenia (1), nausea (2), neutropenia (8), respiratory failure (1), and thrombocytopenia (2). Investigator-assessed efficacy outcome in 7 evaluable patients were stable disease in 2/7 (28.6%), partial response in 4/7 (57.1%), and complete response in 1/7 (14.3%) patients. Conclusions: This study demonstrated the safety of combining veliparib with cisplatin and etoposide in previously untreated SCLC patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Owonikoko, Taofeek K.; Ramalingam, Suresh S.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Khan, Saad A.; Gerber, David E.; Dowell, Jonathan] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Moss, Rebecca A.] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Moss, Rebecca A.] Rutgers State Univ, Robert Wood Johnson Med Sch, New Brunswick, NJ 08903 USA. [Belani, Chandra P.] Penn State Hershey Canc Inst, Hershey, PA USA. [Hann, Christine L.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Aggarwal, Charu] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Owonikoko, TK (reprint author), Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Room C380,3rd Floor,1365C Clifton Rd NE, Atlanta, GA 30322 USA. EM towonik@emory.edu OI Moss, Rebecca/0000-0002-0139-5396 FU Public Health Service Grants [CA180820, CA180794, CA180864, CA180870, CA180802]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; NIH/NCI grant [5K23CA164015] FX This study was conducted by the ECOG ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA180864, CA180870, CA180802, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. T.K. Owonikoko was supported by NIH/NCI grant 5K23CA164015. NR 21 TC 17 Z9 17 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JUL PY 2015 VL 89 IS 1 BP 66 EP 70 DI 10.1016/j.lungcan.2015.04.015 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CK9FP UT WOS:000356546300013 PM 25985977 ER PT J AU Chatnuntawech, I Gagoski, B Bilgic, B Cauley, SF Setsompop, K Adalsteinsson, E AF Chatnuntawech, Itthi Gagoski, Borjan Bilgic, Berkin Cauley, Stephen F. Setsompop, Kawin Adalsteinsson, Elfar TI Accelerated H-1 MRSI using randomly undersampled spiral-based k-space trajectories SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance spectroscopic imaging (MRSI); random undersampling; spiral trajectory; compressed sensing; parallel imaging ID SPECTROSCOPIC IMAGING PEPSI; OUTER-VOLUME SUPPRESSION; N-ACETYL ASPARTATE; HUMAN-BRAIN; MAGNETIC-RESONANCE; CHEMICAL-SHIFT; MULTIPLE-SCLEROSIS; MRI RECONSTRUCTION; ARRAY COIL; SENSE AB PurposeTo develop and evaluate the performance of an acquisition and reconstruction method for accelerated MR spectroscopic imaging (MRSI) through undersampling of spiral trajectories. Theory and MethodsA randomly undersampled spiral acquisition and sensitivity encoding (SENSE) with total variation (TV) regularization, random SENSE+TV, is developed and evaluated on single-slice numerical phantom, in vivo single-slice MRSI, and in vivo three-dimensional (3D)-MRSI at 3 Tesla. Random SENSE+TV was compared with five alternative methods for accelerated MRSI. ResultsFor the in vivo single-slice MRSI, random SENSE+TV yields up to 2.7 and 2 times reduction in root-mean-square error (RMSE) of reconstructed N-acetyl aspartate (NAA), creatine, and choline maps, compared with the denoised fully sampled and uniformly undersampled SENSE+TV methods with the same acquisition time, respectively. For the in vivo 3D-MRSI, random SENSE+TV yields up to 1.6 times reduction in RMSE, compared with uniform SENSE+TV. Furthermore, by using random SENSE+TV, we have demonstrated on the in vivo single-slice and 3D-MRSI that acceleration factors of 4.5 and 4 are achievable with the same quality as the fully sampled data, as measured by RMSE of reconstructed NAA map, respectively. ConclusionWith the same scan time, random SENSE+TV yields lower RMSEs of metabolite maps than other methods evaluated. Random SENSE+TV achieves up to 4.5-fold acceleration with comparable data quality as the fully sampled acquisition. Magn Reson Med 74:13-24, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Chatnuntawech, Itthi; Adalsteinsson, Elfar] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Gagoski, Borjan] Harvard Univ, Sch Med, Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA USA. [Bilgic, Berkin; Cauley, Stephen F.; Setsompop, Kawin] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Setsompop, Kawin] Harvard Univ, Sch Med, Boston, MA USA. [Adalsteinsson, Elfar] MIT, Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA. [Adalsteinsson, Elfar] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Chatnuntawech, I (reprint author), MIT, Room 36-776A,77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ichatnun@mit.edu FU NIH [R01 EB017337] FX Grant sponsor: NIH; Grant number: R01 EB017337. NR 53 TC 4 Z9 4 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2015 VL 74 IS 1 BP 13 EP 24 DI 10.1002/mrm.25394 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK7XZ UT WOS:000356451500003 ER PT J AU Miloslavsky, EM McSparron, JI Richards, JB Puig, A Sullivan, AM AF Miloslavsky, Eli M. McSparron, Jakob I. Richards, Jeremy B. Puig, Alberto Sullivan, Amy M. TI Teaching during consultation: factors affecting the resident-fellow teaching interaction SO MEDICAL EDUCATION LA English DT Article ID EMERGENCY-DEPARTMENT; QUALITATIVE DATA; COMMUNICATION; FRAMEWORK AB ObjectivesThe subspecialty consultation represents a potentially powerful opportunity for resident learning, but barriers may limit the educational exchanges between fellows (subspecialty registrars) and residents (house officers). We conducted a focus group study of internal medicine (IM) residents and subspecialty fellows to determine barriers against and factors facilitating resident-fellow teaching interactions on the wards, and to identify opportunities for maximising teaching and learning. MethodsWe conducted four focus groups of IM residents (n=18) and IM subspecialty fellows (n=16) at two academic medical centres in the USA during February and March 2013. Participants represented trainees in all 3years of residency training and seven IM subspecialties. Four investigators analysed the transcripts using a structured qualitative framework approach, which was informed by literature on consultation and the theoretical framework of activity theory. ResultsWe identified two domains of barriers and facilitating factors: personal and systems-based. Sub-themes in the personal domain included fellows' perceived resistance to consultations, residents' willingness to engage in teaching interactions, and perceptions and expectations. Sub-themes in the systems-based domain included the process of requesting the consult, the quality of the consult request, primary team structure, familiarity between residents and fellows, workload, work experience, culture of subspecialty divisions, and fellows' teaching skills. These barriers differentially affected the two stages of the consult identified in the focus groups (initial interaction and follow-up interaction). ConclusionsResidents and fellows want to engage in positive teaching interactions in the context of the clinical consult; however, multiple barriers influence both parties in the hospital environment. Many of these barriers are amenable to change. Interventions aimed at reducing barriers to teaching in the setting of consultation hold promise for improving teaching and learning on the wards. Discuss ideas arising from the article at discuss. C1 [Miloslavsky, Eli M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol,Dept Med, Boston, MA USA. [McSparron, Jakob I.; Richards, Jeremy B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Dept Med,Med Sch, Boston, MA 02215 USA. [Puig, Alberto] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clinician Educ Serv,Dept Med, Boston, MA USA. [Sullivan, Amy M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Shapiro Inst Educ & Res, Sch Med, Boston, MA 02215 USA. RP Miloslavsky, EM (reprint author), Massachusetts Gen Hosp, Dept Med, Div Rheumatol, 55 Fruit St,Suite 2C, Boston, MA 02114 USA. EM emiloslavsky@mgh.harvard.edu FU Partners Center of Expertise in Medical Education Research Grant FX This research was supported by a Partners Center of Expertise in Medical Education Research Grant (2012). NR 30 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0308-0110 EI 1365-2923 J9 MED EDUC JI Med. Educ. PD JUL PY 2015 VL 49 IS 7 BP 717 EP 730 DI 10.1111/medu.12760 PG 14 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA CK7CM UT WOS:000356388100011 PM 26077219 ER PT J AU Boehm, JS Golub, TR AF Boehm, Jesse S. Golub, Todd R. TI An ecosystem of cancer cell line factories to support a cancer dependency map SO NATURE REVIEWS GENETICS LA English DT Editorial Material ID DRUG-SENSITIVITY C1 [Boehm, Jesse S.; Golub, Todd R.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Golub, Todd R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Boehm, JS (reprint author), Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA. EM boehm@broadinstitute.org OI Boehm, Jesse/0000-0002-6795-6336 FU Howard Hughes Medical Institute NR 5 TC 7 Z9 7 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD JUL PY 2015 VL 16 IS 7 BP 373 EP 374 DI 10.1038/nrg3967 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CK7WV UT WOS:000356447500001 PM 26077369 ER PT J AU Barrett, LF Simmons, WK AF Barrett, Lisa Feldman Simmons, W. Kyle TI Interoceptive predictions in the brain SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID MEDIAL PREFRONTAL CORTEX; ANTERIOR INSULAR CORTEX; OLD-WORLD MONKEY; INTRINSIC FUNCTIONAL CONNECTIVITY; LARGE-SCALE BRAIN; CORTICAL STRUCTURE; RESTING-STATE; MOTOR CORTEX; CINGULATE CORTEX; MACAQUE MONKEYS AB Intuition suggests that perception follows sensation and therefore bodily feelings originate in the body. However, recent evidence goes against this logic: interoceptive experience may largely reflect limbic predictions about the expected state of the body that are constrained by ascending visceral sensations. In this Opinion article, we introduce the Embodied Predictive Interoception Coding model, which integrates an anatomical model of corticocortical connections with Bayesian active inference principles, to propose that agranular visceromotor cortices contribute to interoception by issuing interoceptive predictions. We then discuss how disruptions in interoceptive predictions could function as a common vulnerability for mental and physical illness. C1 [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Barrett, Lisa Feldman] Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Simmons, W. Kyle] Laureate Inst Brain Res, Tulsa, OK 74133 USA. [Simmons, W. Kyle] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. EM l.barrett@neu.edu; wksimmons@laureateinstitute.org RI Simmons, William/K-8925-2015 OI Simmons, William/0000-0002-0399-9003 FU US National Institute on Aging [R01AG030311]; US National Science Foundation grant [BCS-1052790]; US Army Research Institute for the Behavioural and Social Sciences [W5J9CQ-12-C-0049, W5J9CQ-11-C-0046]; US National Institute of Mental Health grant [K01MH096175-01]; US National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award; Oklahoma Tobacco Research Center FX The authors thank M.A. Garcia-Cabezas for helpful discussions and advice in preparing figure 1. They also thank K. Friston, H. Barbas, B. Finlay, H. Mayberg, J. Feinstein, S. Khalsa, J. Avery, M. Paulus, A. Satpute, L. Chanes, A. Touroutoglou and I. Kleckner for helpful discussions about the EPIC model and comments offered on the manuscript. In addition, they thank L. Chanes, A. Touroutoglou and J. Zhang for their assistance in summarizing the interoceptive system from the macaque tract-tracing literature. This work was supported by a US National Institute on Aging grant (R01AG030311), a US National Science Foundation grant (BCS-1052790) and contracts from the US Army Research Institute for the Behavioural and Social Sciences (contracts W5J9CQ-12-C-0049 and W5J9CQ-11-C-0046) to L.F.B., as well as a US National Institute of Mental Health grant (K01MH096175-01), a US National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award, and funding from the Oklahoma Tobacco Research Center to W.K.S. The views, opinions and findings contained in this article are those of the authors and should not be construed as an official position, policy or decision of the US National Institutes of Health or Department of the Army unless so designated by other documents. NR 149 TC 67 Z9 67 U1 10 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2015 VL 16 IS 7 BP 419 EP 429 DI 10.1038/nrn3950 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CK9UV UT WOS:000356585900009 PM 26016744 ER PT J AU Janes, AC Pedrelli, P Whitton, AE Pechtel, P Douglas, S Martinson, MA Huz, I Fava, M Pizzagalli, DA Evins, AE AF Janes, Amy C. Pedrelli, Paola Whitton, Alexis E. Pechtel, Pia Douglas, Samuel Martinson, Max A. Huz, Ilana Fava, Maurizio Pizzagalli, Diego A. Evins, A. Eden TI Reward Responsiveness Varies by Smoking Status in Women with a History of Major Depressive Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID GENDER-DIFFERENCES; DOPAMINE NEURONS; HEDONIC CAPACITY; SEX-DIFFERENCES; NICOTINE; CESSATION; BUPROPION; ANHEDONIA; MODEL; MOOD AB Major depressive disorder (MDD) and nicotine dependence are highly comorbid, with studies showing that similar to 50% of individuals with MDD smoke. The link between these disorders persists even after the clinical symptoms of depression subside, as indicated by high levels of nicotine dependence among individuals with remitted depression (rMDD). Recent evidence indicates that individuals with rMDD show blunted responses to reward as measured by a probabilistic reward task (PRT), which assesses the ability to modify behavior as a function of reward history. Given nicotine's ability to enhance reward responsiveness, individuals with rMDD might smoke to address this persistent reward deficit. However, it is unclear whether smokers with rMDD show enhanced reward responsiveness relative to rMDD individuals who do not smoke. To test this hypothesis, we evaluated reward responsiveness on the PRT in four groups (N = 198): individuals with and without rMDD who were or were not nicotine dependent. As hypothesized, rMDD nonsmokers had lower reward responsiveness relative to both control nonsmokers and rMDD smokers; conversely, smokers with rMDD showed behavioral patterns comparable to those without a history of depression. Given nicotine's ability to enhance reward sensitivity, it is possible that nicotine normalizes the otherwise blunted reward responsiveness in individuals with rMDD. Therapies aimed at enhancing this reward-based deficit may be beneficial in the treatment of both nicotine dependence and MDD. C1 [Janes, Amy C.; Pizzagalli, Diego A.] Harvard Univ, McLean Hosp, Sch Med, McLean Imaging Ctr, Belmont, MA USA. [Janes, Amy C.; Pedrelli, Paola; Whitton, Alexis E.; Pechtel, Pia; Fava, Maurizio; Pizzagalli, Diego A.; Evins, A. Eden] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Pedrelli, Paola; Martinson, Max A.; Huz, Ilana; Fava, Maurizio; Pizzagalli, Diego A.] Massachusetts Gen Hosp, Depress Clin Res Program, Boston, MA 02114 USA. [Whitton, Alexis E.; Pechtel, Pia; Douglas, Samuel; Pizzagalli, Diego A.] Harvard Univ, McLean Hosp, Sch Med, Ctr Depress Anxiety & Stress Res, Belmont, MA USA. [Evins, A. Eden] Massachusetts Gen Hosp, Ctr Addict Med, Boston, MA 02114 USA. RP Janes, AC (reprint author), McLean Hosp, Brain Imaging Ctr, Mail Stop 310,115 Mill St, Belmont, MA 02478 USA. EM ajanes@mclean.harvard.edu RI Janes, Amy/A-5322-2013; Whitton, Alexis/H-4098-2016 OI Janes, Amy/0000-0002-3749-5006; Whitton, Alexis/0000-0002-7944-2172 FU National Institute of Health [U01DA019378, K01DA029645, K24DA030443, R10MH68376, R21MH078979, K23AA020064, R01MH068376]; GlaxoSmithKline; Pfizer; Forum Pharmaceuticals; Otsuka America Pharmaceutical; Servier; Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen RD, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories FX This work was supported by National Institute of Health Grants U01DA019378 (MF), K01DA029645 (AJ), K24DA030443 (AEE) R10MH68376 (DP), R21MH078979 (DP), K23AA020064 (PP), and R01MH068376. Dr Evins has received research support in the form of funding and/or study supplies from GlaxoSmithKline, Pfizer, and Forum Pharmaceuticals. Over the past 2 years, Dr Pizzagalli has received honoraria/consulting fees from Otsuka America Pharmaceutical, Pfizer, and Servier for activities unrelated to this project. Maurizio Fava, M.D., Research Support: Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite LLC;PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst LaboratoriesAdvisory/Consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite (R) LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Puretech Ventures; Psycho-Genics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; ; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc. Speaking/Publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource, Corp.; Wyeth-Ayerst Laboratories. Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: Patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolters Kluwer; World Scientific Publishing Co. Pte. Ltd. The remaining authors declare no conflict of interest. NR 49 TC 4 Z9 4 U1 3 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 JUL PY 2015 VL 40 IS 8 BP 1940 EP 1946 DI 10.1038/npp.2015.43 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CK4IE UT WOS:000356186700014 PM 25662839 ER PT J AU Yu, DK Zheng, J Zhu, RL Wu, N Guan, A Cho, KS Chen, DF Luo, G AF Yu, Dekuang Zheng, Jin Zhu, Ruilin Wu, Nan Guan, Alex Cho, Kin-Sang Chen, Dong Feng Luo, Gang TI Computer-aided analyses of mouse retinal OCT images - an actual application report SO OPHTHALMIC AND PHYSIOLOGICAL OPTICS LA English DT Article DE image segmentation; mouse study; optical coherence tomography; photoreceptor degeneration ID OPTICAL COHERENCE TOMOGRAPHY; SEGMENTATION; LAYERS AB PurposeThere is a need for automated retinal optical coherence tomography (OCT) image analysis tools for quantitative measurements in small animals. Some image processing techniques for retinal layer analysis have been developed, but reports about how useful those techniques are in actual animal studies are rare. This paper presents the use of a retinal layer detection method we developed in an actual mouse study that involves wild type and mutated mice carrying photoreceptor degeneration. MethodsSpectral domain OCT scanning was performed by four experimenters over 12months on 45 mouse eyes that were wild-type, deficient for ephrin-A2 and ephrin-A3, deficient for rhodopsin, or deficient for rhodopsin, ephrin-A2 and ephrin-A3. The thickness of photoreceptor complex between the outer plexiform layer and retinal pigment epithelium was measured on two sides of the optic disc as the biomarker of retinal degeneration. All the layer detection results were visually confirmed. ResultsOverall, 96% (8519 out of 9000) of the half-side images were successfully processed using our technique in a semi-automatic manner. There was no significant difference in success rate between mouse lines (p=0.91). Based on a human observer's rating of image quality for images successfully and unsuccessfully processed, the odds ratios for easily visible' images and not clear' images to be successfully processed is 62 and 4, respectively, against indistinguishable' images. Thickness of photoreceptor complex was significantly different across the quadrants compared (p<0.001). It was also found that the average thickness based on 4-point sparse sampling was not significantly different from the full analysis, while the range of differences between the two methods could be up to about 6m or 16% for individual eyes. Differences between mouse lines and progressive thickness reduction were revealed by both sampling measures. ConclusionsAlthough the thickness of the photoreceptor complex layer is not even, manual sparse sampling may be as sufficiently accurate as full analysis in some studies such as ours, where the error of sparse sampling was much smaller than the effect size of rhodopsin deficiency. It is also suggested that the image processing method can be useful in actual animal studies. Even for images poorly visible to human eyes the image processing method still has a good chance to extract the complex layer. C1 [Yu, Dekuang] Southern Med Univ, Guangzhou, Guangdong, Peoples R China. [Zheng, Jin; Zhu, Ruilin; Wu, Nan; Guan, Alex; Cho, Kin-Sang; Chen, Dong Feng; Luo, Gang] Harvard Univ, Schepens Eye Res Inst, Sch Med, Massachusetts Eye & Ear, Boston, MA 02163 USA. [Zheng, Jin] Beihang Univ, Beijing Key Lab Digital Media, Sch Comp Sci & Engn, Beijing 100191, Peoples R China. [Zhu, Ruilin] Peking Univ, Dept Ophthalmol, Hosp 1, Beijing 100871, Peoples R China. [Zhu, Ruilin] Minist Educ, Key Lab Vis Loss & Restorat, Beijing, Peoples R China. [Wu, Nan] Third Mil Med Univ, Southwest Eye Hosp, Dept Ophthalmol, Chongqing, Peoples R China. [Chen, Dong Feng] VA Boston Healthcare Syst, Boston, MA USA. RP Luo, G (reprint author), Harvard Univ, Schepens Eye Res Inst, Sch Med, Massachusetts Eye & Ear, Boston, MA 02163 USA. EM Gang_Luo@meei.harvard.edu FU NIH [R01 EY017641]; Department of Veterans Affairs [VA241-P-2285]; National Youth Natural Science Foundation of China [30901645]; National Science Foundation of China [61370124]; National Scholarship Foundation of China [201303070205] FX This work is supported in part by NIH grant R01 EY017641 to DFC, the Department of Veterans Affairs grant VA241-P-2285 to DFC, National Youth Natural Science Foundation of China (#30901645), National Science Foundation of China (#61370124), and National Scholarship Foundation of China (#201303070205). NR 14 TC 0 Z9 0 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-5408 EI 1475-1313 J9 OPHTHAL PHYSL OPT JI Ophthalmic Physiol. Opt. PD JUL PY 2015 VL 35 IS 4 BP 442 EP 449 DI 10.1111/opo.12213 PG 8 WC Ophthalmology SC Ophthalmology GA CL0JA UT WOS:000356627100010 PM 25959043 ER PT J AU Nair, A Gan, J Bush-Joseph, C Verma, N Tetreault, MW Saha, K Margulis, A Fogg, L Scanzello, CR AF Nair, A. Gan, J. Bush-Joseph, C. Verma, N. Tetreault, M. W. Saha, K. Margulis, A. Fogg, L. Scanzello, C. R. TI Synovial chemokine expression and relationship with knee symptoms in patients with meniscal tears SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Osteoarthritis; Synovitis; Relative expression; Knee disability; KOOS ID GENE-EXPRESSION; CARTILAGE LOSS; OSTEOARTHRITIS; PAIN; INFLAMMATION; PROGRESSION; BIOMARKERS; FEATURES; SURGERY; INJURY AB Objective: In patients with knee OA, synovitis is associated with knee pain and symptoms. We previously identified synovial mRNA expression of a set of chemokines (CCL19, IL-8, CCL5, XCL-1, CCR7) associated with synovitis in patients with meniscal tears but without radiographic OA. CCL19 and CCR7 were also associated with knee symptoms. This study sought to validate expression of these chemokines and association with knee symptoms in more typical patients presenting for meniscal arthroscopy, many who have pre-existing OA. Design: Synovial fluid (SF) and biopsies were collected from patients undergoing meniscal arthroscopy. Synovial mRNA expression was measured using quantitative RT-PCR. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was administered preoperatively. Regression analyses determined if associations between chemokine mRNA levels and KOOS scores were independent of other factors including radiographic OA. CCL19 in SF was measured by ELISA, and compared to patients with advanced knee OA and asymptomatic organ donors. Results: 90% of patients had intra-operative evidence of early cartilage degeneration. CCL19, IL-8, CCL5, XCL1, CCR7 transcripts were detected in all patients. Synovial CCL19 mRNA levels independently correlated with KOOS Activities of Daily Living (ADL) scores (95% CI [-8.071, -0.331], P = 0.036), indicating higher expression was associated with more knee-related dysfunction. SF CCL19 was detected in 7 of 10 patients, compared to 4 of 10 asymptomatic donors. Conclusion: In typical patients presenting for meniscal arthroscopy, synovial CCL19 mRNA expression was associated with knee-related difficulty with ADL, independent of other factors including presence of radiographic knee OA. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Nair, A.; Gan, J.; Saha, K.] Rush Univ, Med Ctr, Div Rheumatol, Chicago, IL 60612 USA. [Bush-Joseph, C.; Verma, N.; Tetreault, M. W.] Rush Univ, Med Ctr, Dept Orthoped, Chicago, IL 60612 USA. [Margulis, A.] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Fogg, L.] Rush Univ, Med Ctr, Dept Community Syst & Mental Hlth Nursing, Chicago, IL 60612 USA. [Scanzello, C. R.] Univ Penn, Perelman Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Scanzello, C. R.] Univ Penn, Perelman Sch Med, Dept Orthoped, Philadelphia, PA 19104 USA. [Scanzello, C. R.] Philadelphia Vet Affairs Med Ctr, Dept Med, Rheumatol Sect, Philadelphia, PA USA. RP Scanzello, CR (reprint author), Univ Penn, Perelman Sch Med, Div Rheumatol, 3400 Spruce St,8th Floor Penn Tower, Philadelphia, PA 19104 USA. EM cscanz@upenn.edu OI Tetreault, Matthew/0000-0003-3584-9285 FU NIAMS NIH HHS [K08 AR057859, K08AR057859] NR 32 TC 3 Z9 3 U1 2 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUL PY 2015 VL 23 IS 7 BP 1158 EP 1164 DI 10.1016/j.joca.2015.02.016 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA CK7WM UT WOS:000356446300017 PM 25724256 ER PT J AU Kobayashi, T Papaioannou, G Mirzamohammadi, F Kozhemyakina, E Zhang, M Blelloch, R Chong, MW AF Kobayashi, T. Papaioannou, G. Mirzamohammadi, F. Kozhemyakina, E. Zhang, M. Blelloch, R. Chong, M. W. TI Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE microRNA; Drosha; Prg4; Chondrocyte; Osteoarthritis; Articular cartilage ID TRANSGENIC MICE; OSTEOARTHRITIS; EXPRESSION; MOUSE; DIFFERENTIATION; PATHWAYS; CELLS AB Objective: In growth plate chondrocytes, loss of Dicer, a microRNA (miRNA)-processing enzyme, causes defects in proliferation and differentiation, leading to a lethal skeletal dysplasia. However roles of miRNAs in articular chondrocytes have not been defined in vivo. To investigate the role of miRNAs in articular chondrocytes and to explore the possibility of generating a novel mouse osteoarthritis (OA) model caused by intrinsic cellular dysfunction, we ablated Drosha, another essential enzyme for miRNA biogenesis, exclusively in articular chondrocytes of postnatal mice. Design: First, to confirm that the essential role of miRNAs in skeletal development, we ablated the miRNA biogenesis pathway by deleting Drosha or DGCR8 in growth plate chondrocytes. Next, to investigate the role of miRNAs in articular cartilage, we deleted Drosha using Prg4-CreERT transgenic mice expressing a tamoxifen-activated Cre recombinase (CreERT) exclusively in articular chondrocytes. Tamoxifen was injected at postnatal days, 7, 14, 21, and 28 to ablate Drosha. Results: Deletion of Drosha or DGCR8 in growth plate chondrocytes caused a lethal skeletal defect similar to that of Dicer deletion, confirming the essential role of miRNAs in normal skeletogenesis. Early postnatal Drosha deletion in articular chondrocytes significantly increased cell death and decreased SafraninO staining. Mild OA-like changes, including surface erosion and cleft formation, were found in male mice at 6 months of age; however such changes in females were not observed even at 9 months of age. Conclusions: Early postnatal Drosha deficiency induces articular chondrocyte death and can cause a mild OA-like pathology. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Kobayashi, T.; Papaioannou, G.; Mirzamohammadi, F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. [Kozhemyakina, E.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhang, M.] Boston Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Zhang, M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Blelloch, R.] Univ Calif San Francisco, Ctr Reprod Sci, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Chong, M. W.] St Vincents Inst Med Res, Genom & Immunol Lab, Fitzroy, Vic 3065, Australia. [Chong, M. W.] Univ Melbourne, Dept Med, Fitzroy, Vic 3065, Australia. RP Kobayashi, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. EM tkobayashi1@mgh.harvard.edu; GPAPAIOANNOU@mgh.harvard.edu; FMIRZAMOHAMMADI@mgh.harvard.edu; eKozhemyakina@dresourcesgroup.com; Minjie.Zhang@childrens.harvard.edu; blellochr@stemcell.ucsf.edu; mchong@svi.edu.au RI Chong, Mark/H-6684-2016; OI Kobayashi, Tatsuya/0000-0003-4264-5117; Chong, Mark/0000-0002-3701-7397 FU NIAMS NIH HHS [R01 AR056645, P30 AR066261, AR056645] NR 30 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUL PY 2015 VL 23 IS 7 BP 1214 EP 1220 DI 10.1016/j.joca.2015.02.015 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA CK7WM UT WOS:000356446300023 PM 25707934 ER PT J AU Jermoumi, M Korideck, H Bhagwat, M Zygmanski, P Makrigiogos, GM Berbeco, RI Cormack, RC Ngwa, W AF Jermoumi, M. Korideck, H. Bhagwat, M. Zygmanski, P. Makrigiogos, G. M. Berbeco, R. I. Cormack, R. C. Ngwa, W. TI Comprehensive quality assurance phantom for the small animal radiation research platform (SARRP) SO PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS LA English DT Article DE SARRP; QA phantom; Micro-irradiator ID RADIOTHERAPY; CT; SYSTEM; CALIBRATION; VALIDATION; DOSIMETRY AB Purpose: To develop and test the suitability and performance of a comprehensive quality assurance (QA) phantom for the Small Animal Radiation Research Platform (SARRP). Methods and materials: A QA phantom was developed for carrying out daily, monthly and annual QA tasks including: imaging, dosimetry and treatment planning system (TPS) performance evaluation of the SARRP. The QA phantom consists of 15 (60 x 60 x 5 mm(3)) kV-energy tissue equivalent solid water slabs. The phantom can incorporate optically stimulated luminescence dosimeters (OSLD), Mosfet or film. One slab, with inserts and another slab with hole patterns are particularly designed for image QA. Results: Output constancy measurement results showed daily variations within 3%. Using the Mosfet in phantom as target, results showed that the difference between TPS calculations and measurements was within 5%. Annual QA results for the Percentage depth dose (PDD) curves, lateral beam profiles, beam flatness and beam profile symmetry were found consistent with results obtained at commissioning. PDD curves obtained using film and OSLDs showed good agreement. Image QA was performed monthly, with image-quality parameters assessed in terms of CBCT image geometric accuracy, CT number accuracy, image spatial resolution, noise and image uniformity. Conclusions: The results show that the developed QA phantom can be employed as a tool for comprehensive performance evaluation of the SARRP. The study provides a useful reference for development of a comprehensive quality assurance program for the SARRP and other similar small animal irradiators, with proposed tolerances and frequency of required tests. (C) 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved. C1 [Jermoumi, M.; Ngwa, W.] Univ Massachusetts, Dept Appl Phys, Med Phys Program, Lowell, MA USA. [Jermoumi, M.; Korideck, H.; Bhagwat, M.; Zygmanski, P.; Makrigiogos, G. M.; Berbeco, R. I.; Cormack, R. C.; Ngwa, W.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Jermoumi, M.; Korideck, H.; Bhagwat, M.; Zygmanski, P.; Makrigiogos, G. M.; Berbeco, R. I.; Cormack, R. C.; Ngwa, W.] Harvard Univ, Sch Med, Boston, MA USA. RP Jermoumi, M (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM mohammed_jermoumi@dfci.harvard.edu FU NCI NIH HHS [K01 CA172478] NR 25 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1120-1797 EI 1724-191X J9 PHYS MEDICA JI Phys. Medica PD JUL PY 2015 VL 31 IS 5 BP 529 EP 535 DI 10.1016/j.ejmp.2015.04.010 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK4WD UT WOS:000356223100014 PM 25964129 ER PT J AU Nisavic, M Shuster, JL Gitlin, D Worley, L Stern, TA AF Nisavic, Mladen Shuster, John L. Gitlin, David Worley, Linda Stern, Theodore A. TI Readings on Psychosomatic Medicine: Survey of Resources for Trainees SO PSYCHOSOMATICS LA English DT Review ID CONSULTATION-LIAISON PSYCHIATRY; INTENSIVE-CARE-UNIT; INTRAVENOUS HALOPERIDOL; MEDICALLY ILL; TASK-FORCE; DELIRIUM; DEPRESSION; GUIDELINES; MANAGEMENT; DIAGNOSIS AB Background: As systems care become more complex and comorbid medical and psychiatric illness becomes more evident, it is essential to prepare psychiatric trainees for practice in more integrated models of care. Objective: We sought to identify readings available for residency training in consultation-liaison C-L) psychiatry/psychosomatic medicine with the intent to help educators and trainees identify appropriate and essential learning resources within the field. Methods: We reviewed readings available to the residents (including commonly used textbooks in C-L psychiatry and C-L training programs' required reading lists') and identified areas of consensus regarding the topics germane to the care of patients with comorbid medical and psychiatric illness (namely depression, dementia, and delirium) and the education of trainees. Results: There was considerable variation in the references cited by well-regarded textbooks and by reading lists created for trainees in C-L psychiatry. In the 4 textbooks reviewed, there were 83 shared citations on delirium (including 10 citations that were common to all 4 textbooks and 17 citations shared by 3 textbooks.). Markedly less overlap was noted in the chapters on depression (only 2 references cited in all of the textbooks with relevant content) and dementia (only 7 shared references). Conclusion: Given the paucity of overlap of citations in commonly used textbooks., we recommend that practical topical reviews or textbook chapters be used as core (required) or recommended readings for residents on C-L psychiatry rotations, supplemented by a small number of studies or case series that illustrate key tea lung points on each essential topic. C1 [Nisavic, Mladen; Stern, Theodore A.] Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA. [Shuster, John L.] Vanderbilt Univ, Dept Psychiat, Nashville, TN 37235 USA. [Gitlin, David] Brigham & Womens Hosp, Psychiat, Boston, MA 02115 USA. [Worley, Linda] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Worley, Linda] Vanderbilt Univ, Sch Med, Dept Obstet & Gynecol, Nashville, TN 37212 USA. RP Nisavic, M (reprint author), 55 Fruit St, Boston, MA 02114 USA. EM mnisavic@partners.org NR 56 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2015 VL 56 IS 4 BP 319 EP 328 PG 10 WC Psychiatry; Psychology SC Psychiatry; Psychology GA CL0IR UT WOS:000356626100001 PM 26002223 ER PT J AU Janssen, SJ ter Meulen, DP Nota, SPFT Hageman, MGJS Ring, D AF Janssen, Stein J. ter Meulen, Dirk P. Nota, Sjoerd P. F. T. Hageman, Michiel G. J. S. Ring, David TI Does Verbal and Nonverbal Communication of Pain Correlate With Disability? SO PSYCHOSOMATICS LA English DT Article ID QUALITY-OF-LIFE; LOW-BACK-PAIN; COPING STRATEGIES; HEALTH-STATUS; ITEM BANK; OUTCOMES; PROMIS; DEPRESSION; BEHAVIOR; PREDICTORS AB Background: Illness (symptoms and disability) consistently correlates more with coping strategies and symptoms of depression than with pathophysiology or impairment. Objective: This study tested the primary null hypothesis that there is no correlation between verbal and nonverbal communication of pain (pain behavior) and upper extremity specific disability in patients with hand and upper extremity illness. Methods: A total of 139 new and followed up adult patients completed the QuickDASH, an ordinal rating of pain, and 4 Patient-Reported Outcomes Measurement Information System (PROMIS) Computer Adaptive Testing instruments: (PROMIS pain behavior, (2) PROMIS pain interference (measuring the degree to which pain interferes with achieving ones physical goals), (3) PROIVIIS physical function., and (4) PROMIS depression. Results: Factors associated with a higher QuickDASH score in bivariate analysis included a higher PROMIS pain behavior score, not working, being separated/divorced or widowed, having sought treatment before, having other pain conditions, a higher PROMIS pain interference score, a higher PROMIS depression score, and lower education level. The final multivariable model of factors' associated with QuickDASH included PROMIS pain interference, having other pain conditions, and being separated/divorced or widowed, and it explained 64% of the variability. Conclusion: PROMIS pain behavior (verbal and nonverbal communication of pain) correlates with upper extremity disability, but PROMIS pain interference (the degree to which pain interferes with activity) is a more important,factor. Level of Evidence: Level IV cross-sectional study. C1 [Janssen, Stein J.; ter Meulen, Dirk P.; Nota, Sjoerd P. F. T.; Hageman, Michiel G. J. S.; Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu NR 27 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JUL-AUG PY 2015 VL 56 IS 4 BP 338 EP 344 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA CL0IR UT WOS:000356626100003 PM 25627313 ER PT J AU Maher, TM Piper, A Song, YL Restrepo, MI Eves, ND AF Maher, Toby M. Piper, Amanda Song, Yuanlin Restrepo, Marcos I. Eves, Neil D. TI Year in review 2014: Interstitial lung disease, physiology, sleep and ventilation, acute respiratory distress syndrome, cystic fibrosis, bronchiectasis and rare lung disease SO RESPIROLOGY LA English DT Review DE acute respiratory distress syndrome; bronchiectasis; interstitial lung disease; lung function; obstructive sleep apnoea ID IDIOPATHIC PULMONARY-FIBROSIS; POSITIVE AIRWAY PRESSURE; THORACIC GAS-COMPRESSION; OBESITY HYPOVENTILATION SYNDROME; MESENTERIC FAT THICKNESS; NON-CF BRONCHIECTASIS; SERUM CYSTATIN-C; HEART-FAILURE; TRANSBRONCHIAL CRYOBIOPSY; NONINVASIVE VENTILATION C1 [Maher, Toby M.] Royal Brompton Hosp, Natl Inst Hlth Res, Resp Biomed Res Unit, London SW3 6LY, England. [Maher, Toby M.] Univ London Imperial Coll Sci Technol & Med, Natl Heart Lung Inst, Ctr Leukocyte Biol, Fibrosis Res Grp, London SW7 2AZ, England. [Piper, Amanda] Royal Prince Alfred Hosp, Dept Resp & Sleep Med, Sydney, NSW, Australia. [Piper, Amanda] Univ Sydney, Woolcock Inst Med Res, Circadian Grp, Sydney, NSW 2006, Australia. [Song, Yuanlin] Fudan Univ, Zhongshan Hosp, Dept Pulm Med, Shanghai 200433, Peoples R China. [Song, Yuanlin] Fudan Univ, Qingpu Branch, Shanghai 200433, Peoples R China. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Eves, Neil D.] Univ British Columbia, Sch Hlth & Exercise Sci, Fac Hlth & Social Dev, Ctr Heart Lung & Vasc Hlth, Kelowna, BC, Canada. RP Maher, TM (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart Lung Inst, Ctr Leukocyte Biol, Fibrosis Res Grp, Sir Alexander Fleming Bldg, London SW7 2AZ, England. EM t.maher@imperial.ac.uk FU National Heart, Lung, and Blood Institute [K23HL096054] FX M.I.R.'s time is partially protected by Award Number K23HL096054 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health, nor the Department of Veteran Affairs. NR 117 TC 1 Z9 1 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD JUL PY 2015 VL 20 IS 5 BP 834 EP 845 DI 10.1111/resp.12532 PG 12 WC Respiratory System SC Respiratory System GA CK6XH UT WOS:000356371600023 PM 25824415 ER PT J AU Wilkinson, H AF Wilkinson, Harold TI ELECTRICAL MEDICINE SO SCIENTIFIC AMERICAN LA English DT Letter C1 Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Wilkinson, H (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD JUL PY 2015 VL 313 IS 1 BP 6 EP 6 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL0KY UT WOS:000356632800006 ER PT J AU Pusztaszeri, MP Faquin, WC AF Pusztaszeri, Marc P. Faquin, William C. TI Update in salivary gland cytopathology: Recent molecular advances and diagnostic applications SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Salivary gland; Fine-needle aspiration; PLAG1; MYB; CRTC1; ETV6 ID ADENOID CYSTIC CARCINOMA; FINE-NEEDLE-ASPIRATION; ANALOG SECRETORY CARCINOMA; CLEAR-CELL-CARCINOMA; IN-SITU HYBRIDIZATION; ETV6-NTRK3 GENE FUSION; MUCOEPIDERMOID CARCINOMA; PLEOMORPHIC ADENOMA; CRIBRIFORM ADENOCARCINOMA; WARTHINS TUMOR AB Salivary gland tumors (SGT) are notorious for their extraordinary diversity and for the morphological overlap that exists between many of these entities. Fine-needle aspiration biopsy (FNAB) has a well-established role in the evaluation of patients with a salivary gland lesion, helping to guide clinical management. However, salivary gland FNAB has several limitations and does not allow for a specific diagnosis in some cases. For these reasons, salivary gland FNAB is considered one of the most challenging areas in cytopathology. Over the last decade, new salivary gland entities have been recognized, enlarging SGT diversity and complexity even more. In addition, a subset of SGT, including common entities such as pleomorphic adenoma and uncommon new entities such as mammary analog secretory carcinoma, have been characterized cytogenetically by the presence of specific translocations. The molecular consequences of these translocations and their potential prognostic and therapeutic values are not yet well characterized. However, these translocations and their resulting fusion oncogenes and oncoproteins can be used as diagnostic clues in salivary gland FNAB material in order to overcome the limitations of cytomorphological evaluation alone. In this review, we focus on SGTs currently known to harbor translocations and fusion genes, including uncommon and recently recognized entities, and discuss their potential application to salivary gland FNAB. (C) 2015 Elsevier Inc. All rights reserved. C1 [Pusztaszeri, Marc P.] Univ Hosp Geneva, Dept Pathol, CH-1211 Geneva 14, Switzerland. [Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Faquin, William C.] Harvard Univ, Sch Med, Boston, MA USA. RP Pusztaszeri, MP (reprint author), Univ Hosp Geneva, Dept Pathol, 1 Rue Michel Servet, CH-1211 Geneva 14, Switzerland. EM Marc.Pusztaszeri@hcuge.ch NR 91 TC 5 Z9 5 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD JUL PY 2015 VL 32 IS 4 BP 264 EP 274 DI 10.1053/j.semdp.2014.12.008 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA CL0MB UT WOS:000356635700004 PM 25613003 ER PT J AU Mitchell, C Fredricks, D Agnew, K Hitti, J AF Mitchell, Caroline Fredricks, David Agnew, Kathy Hitti, Jane TI Hydrogen Peroxide-Producing Lactobacilli Are Associated With Lower Levels of Vaginal Interleukin-1 beta, Independent of Bacterial Vaginosis SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PRETERM DELIVERY; GENITAL-TRACT; IN-VITRO; BIRTH; INFLAMMATION; INFECTION; WOMEN; COLONIZATION; FLUID AB Background The presence of hydrogen peroxide (H2O2)-producing lactobacilli in the vagina is associated with decreased rates of preterm birth and HIV acquisition. We hypothesize that this is due to immunomodulatory effects of these species. Methods Concentrations of interleukin (IL)-1 beta, IL-6, IL-8, secretory leukocyte protease inhibitor, and human beta-defensin 2 were quantified from vaginal swabs from 4 groups of women: women with and without bacterial vaginosis (BV) by Nugent score, further stratified by detection of H2O2-producing lactobacilli by semiquantitative culture. Ten quantitative polymerase chain reaction assays characterized the presence and quantity of select Lactobacillus and BV-associated species in each group. Levels of immune markers and bacteria were compared between the 4 groups using analysis of variance, Kruskal-Wallis, Mann-Whitney U, or chi(2) tests. Results Swabs from 110 women from 4 groups were included: 26 had a normal Nugent score (BV-), and no H2O2-producing lactobacilli detected (H2O2-); 47 were BV-, H2O2+; 27 BV+, H2O2-; and 10 BV+, H2O2+. The groups were similar in age, marital status, and reproductive history, but not ethnicity: the BV-, H2O2- group had more white participants (P = 0.02). In women with and without BV, IL-1 beta was lower in the H2O2+ groups. Human beta-defensin 2 was lowest in BV+ H2O2- women and highest in BV-, H2O2-. Secretory leukocyte protease inhibitor was lower in women with BV and did not differ by the presence of H2O2-producing lactobacilli. In regression analysis, higher quantities of Lactobacillus crispatus were associated with lower quantities of IL-1 beta. Detection and quantity of BV-associated species by quantitative polymerase chain reaction was significantly different between women with and without BV, but not between women with and without H2O2-producing lactobacilli within those groups. Conclusions The presence of H2O2-producing lactobacilli is associated with lower levels of some vaginal proinflammatory cytokines, even in women with BV. C1 [Mitchell, Caroline] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Fredricks, David] Univ Washington, Dept Obstet & Gynecol, Boston, MA USA. [Agnew, Kathy; Hitti, Jane] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Mitchell, C (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, 55 Fruit St, Boston, MA 02114 USA. EM caroline.mitchell@mgh.harvard.edu FU National Institutes of Health [HD-41682]; K08 from the National Institute of Allergy and Infectious Diseases [1K08AI087969]; Clinical Scientist Development Award from the Doris Duke Foundation FX The data in this study were derived from a study supported by National Institutes of Health Grant HD-41682 (J.H.). Dr Mitchell is supported by a K08 from the National Institute of Allergy and Infectious Diseases (1K08AI087969) and a Clinical Scientist Development Award from the Doris Duke Foundation. NR 38 TC 3 Z9 3 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUL PY 2015 VL 42 IS 7 BP 358 EP 363 DI 10.1097/OLQ.0000000000000298 PG 6 WC Infectious Diseases SC Infectious Diseases GA CK8MH UT WOS:000356491700002 PM 26222747 ER PT J AU Zhong, WY Driscoll, SJ Tsai, TY Wang, SB Mao, HQ Cha, TD Wood, KB Li, GA AF Zhong, Weiye Driscoll, Sean J. Tsai, Tsung-Yuan Wang, Shaobai Mao, Haiqing Cha, Thomas D. Wood, Kirkham B. Li, Guoan TI In vivo dynamic changes of dimensions in the lumbar intervertebral foramen SO SPINE JOURNAL LA English DT Article DE Lumbar intervertebral foramen; Foramen area; Lumbar stenosis; Lumbar kinematics; Weight-lifting activity; In-vivo; Dual-fluoroscopy ID CONFIGURATION MR SYSTEM; IMAGE MATCHING METHOD; FORAMINAL STENOSIS; FLEXION-EXTENSION; KINEMATICS; SPINE; KNEE; COMPRESSION; VALIDATION; PATHOLOGY AB BACKGROUND CONTEXT: Previous studies have reported position-dependent changes of the lumbar intervertebral foramen (LIVF) dimensions at different static flexion-extension postures. However, the changes of the LIVF dimensions during dynamic body motion have not been reported. PURPOSE: The objective of this study was to investigate the in vivo dimensions of the LIVF during a dynamic weight-lifting activity. STUDY DESIGN/SETTING: This was a retrospective study. METHODS: Ten asymptomatic subjects were recruited for this study. Three-dimensional (3D) vertebral models of the lumbar segments from L2 to S1 were constructed for each subject using magnetic resonance images. The lumbar spine was then imaged using a dual fluoroscopic imaging system as the subject performed a dynamic weight-lifting activity from an upper body position of 45 degrees to a maximal extension position. The in vivo positions of the vertebrae along the motion path were reproduced using the 3D vertebral models and the fluoroscopic images. The minimal area, height, and width of each LIVF during the dynamic body motion were analyzed. RESULTS: The LIVF area and width monotonically decreased with lumbar extension at all levels except L5-S1 (p<05). On average, the LIVF area decreased by 7.4 +/- 6.7%, 10.8 +/- 7.7%, and 10.068.0% at the L2-L3, L3-L4, and L4-L5 levels, respectively, from the flexion to the upright standing position, and by 6.4 +/- 5.0%, 7.7 +/- 7.4%, and 5.1 +/- 5.1%, respectively, from the upright standing to the extension position. The LIVF height remained relatively constant at all segments during the dynamic activity. The foramen area, height, and width of the L5-S1 remained relatively constant throughout the activity. CONCLUSIONS: Human lumbar foramen dimensions show segment-dependent characteristics during the dynamic weight-lifting activity. (C) 2015 Elsevier Inc. All rights reserved. C1 [Zhong, Weiye; Driscoll, Sean J.; Tsai, Tsung-Yuan; Wang, Shaobai; Mao, Haiqing; Cha, Thomas D.; Wood, Kirkham B.; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02114 USA. [Zhong, Weiye] Cent S Univ, Changsha 410011, Hunan, Peoples R China. [Zhong, Weiye] Xiangya Hosp 2, Dept Spinal Surg, Changsha 410011, Hunan, Peoples R China. [Mao, Haiqing] Soochow Univ, Affiliated Hosp 1, Dept Orthoped Surg, Suzhou 215006, Jiangsu, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org OI Tsai, Tsung-Yuan/0000-0003-1522-2987 FU National Institutes of Health [R21AR057989]; Synthes, Inc.; China Scholarship Council [201306370122] FX The authors would like to gratefully acknowledge the financial support from the National Institutes of Health (R21AR057989), Synthes, Inc., and China Scholarship Council (201306370122). NR 30 TC 2 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD JUL 1 PY 2015 VL 15 IS 7 BP 1653 EP 1659 DI 10.1016/j.spinee.2015.03.015 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA CK6BY UT WOS:000356314000021 PM 25797808 ER PT J AU Meara, JG Leather, AJM Hagander, L Alkire, BC Alonso, N Ameh, EA Bickler, SW Conteh, L Dare, AJ Davies, J Merisier, ED El-Halabi, S Farmer, PE Gawande, A Gullies, R Greenberg, SLM Grimes, CE Gruen, RL Ismail, EA Kamara, TB Lavy, C Ganbold, L Mkandawire, NC Raykar, NP Riesel, JN Rodas, E Rose, J Roy, N Shrime, MG Sullivan, R Verguet, S Watters, D Weiser, TG Wilson, IH Yamey, G Yip, W AF Meara, John G. Leather, Andrew J. M. Hagander, Lars Alkire, Blake C. Alonso, Nivaldo Ameh, Emmanuel A. Bickler, Stephen W. Conteh, Lesong Dare, Anna J. Davies, Justine Merisier, Eunice Derivois El-Halabi, Shenaaz Farmer, Paul E. Gawande, Atul Gullies, Rowan Greenberg, Sarah L. M. Grimes, Canis E. Gruen, Russell L. Ismail, Edna Adan Kamara, Thaim Buya Lavy, Chris Ganbold, Lundeg Mkandawire, Nyengo C. Raykar, Nakul P. Riesel, Johanna N. Rodas, Edgar Rose, John Roy, Nobhojit Shrime, Mark G. Sullivan, Richard Verguet, Stephane Watters, David Weiser, Thomas G. Wilson, Iain H. Yamey, Gavin Yip, Winnie TI Global Surgery 2030: Evidence and solutions for achieving health, welfare, and economic development SO SURGERY LA English DT Article C1 [Meara, John G.; Greenberg, Sarah L. M.; Raykar, Nakul P.; Riesel, Johanna N.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA 02115 USA. [Shrime, Mark G.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Meara, John G.; Hagander, Lars; Raykar, Nakul P.; Riesel, Johanna N.] Boston Childrens Hosp, Boston, MA USA. [Leather, Andrew J. M.; Dare, Anna J.; Grimes, Canis E.] Kings Hlth Partners, Kings Ctr Global Hlth, London, England. [Leather, Andrew J. M.; Dare, Anna J.; Grimes, Canis E.] Kings Coll London, London, England. [Hagander, Lars] Lund Univ, Clin Sci Lund, Dept Pediat, Pediat Surg & Global Pediat, Lund, Sweden. [Alkire, Blake C.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. [Alonso, Nivaldo] Univ Sao Paulo, Dept Plast Surg, Sao Paulo, Brazil. [Ameh, Emmanuel A.] Natl Hosp, Dept Surg, Div Peadiat Surg, Abuja, Nigeria. [Bickler, Stephen W.] Univ Calif San Diego, Rady Childrens Hosp, San Diego, CA 92103 USA. [Rose, John] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [Conteh, Lesong] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Davies, Justine] Lancet, London, England. [Merisier, Eunice Derivois] Dept Minist Hlth, Grassier, Ouest, Haiti. [El-Halabi, Shenaaz] Minist Hlth, Gaborone, Botswana. [Farmer, Paul E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Div Global Hlth Equ, Boston, MA 02115 USA. [Farmer, Paul E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Farmer, Paul E.] Partners Hlth, Boston, MA USA. [Gawande, Atul; Rose, John] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Gawande, Atul] Ariadne Labs, Boston, MA USA. [Gullies, Rowan] Royal N Shore Hosp, St Leonards, NSW 2065, Australia. [Greenberg, Sarah L. M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Gruen, Russell L.] Alfred Hosp, Melbourne, Vic, Australia. [Gruen, Russell L.] Monash Univ, Melbourne, Vic 3004, Australia. Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 639798, Singapore. [Ismail, Edna Adan] Edna Adan Univ Hosp, Hargeisa, Somalia. [Kamara, Thaim Buya] Connaught Hosp, Freetown, Sierra Leone. [Kamara, Thaim Buya] Univ Sierra Leone, Dept Surg, Freetown, Sierra Leone. [Lavy, Chris] Univ Oxford, Nuffield Dept Orthopaed, Rheumatol & Musculoskeletal Sci, Oxford, England. [Ganbold, Lundeg] Mongolian Natl Univ Med Sci, Ulaanbaatar, Mongol Peo Rep. [Mkandawire, Nyengo C.] Univ Malawi, Coll Med, Dept Surg, Blantyre, Malawi. [Mkandawire, Nyengo C.] Flinders Univ S Australia, Sch Med, Adelaide, SA 5001, Australia. [Raykar, Nakul P.] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Riesel, Johanna N.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Rodas, Edgar] Univ Cuenca, Cinterandes Fdn, Cuenca, Ecuador. [Rodas, Edgar] Univ Azuay, Cuenca, Ecuador. [Rodas, Edgar] Univ Azuay, Cuenca, Ecuador. [Roy, Nobhojit] BARC Hosp, Mumbai, Maharashtra, India. [Shrime, Mark G.] Harvard Interfac Initiat Hlth Policy, Cambridge, MA USA. [Sullivan, Richard] Kings Coll London, Kings Ctr Global Hlth, Li Kings Hlth Partners Integrated Canc Ctr, Inst Canc Policy, London, England. [Verguet, Stephane] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Watters, David] Royal Australasian Coll Surg, East Melbourne, Vic, Australia. [Watters, David] Deakin Univ, Melbourne, Vic, Australia. [Weiser, Thomas G.] Stanford Univ, Sch Med, Dept Surg, Stanford, CA USA. [Wilson, Iain H.] Royal Devon & Exeter NHS Fdn Trust, Dept Anaesthesia, Exeter, Devon, England. [Yamey, Gavin] Univ Calif San Francisco, Global Hlth Grp, Evidence Policy Initiat, San Francisco, CA USA. [Yip, Winnie] Univ Oxford, Blavatnik Sch Govt, Oxford, England. RP Meara, JG (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA 02115 USA. EM john.meara@childrens.harvard.edu OI Sullivan, Richard/0000-0002-6435-1825 NR 1 TC 19 Z9 19 U1 1 U2 4 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 JUL PY 2015 VL 158 IS 1 BP 3 EP 6 DI 10.1016/j.surg.2015.04.011 PG 4 WC Surgery SC Surgery GA CK6ED UT WOS:000356320400002 PM 25987187 ER PT J AU Shrime, MG Daniels, KM Meara, JG AF Shrime, Mark G. Daniels, Kimberly M. Meara, John G. TI Half a billion surgical cases: Aligning surgical delivery with best-performing health systems SO SURGERY LA English DT Article ID CLEFT-LIP; SURGERY; BURDEN; PALATE; CARE AB Background. Surgical delivery varies 200-fold across countries. No direct correlation exists, however, between surgical delivery and health outcomes, making it difficult to pinpoint a goal for surgical scale-up. This report determines the amount of surgery that would be delivered worldwide if the world aligned itself with countries providing the best health outcomes. Methods. Annual rates of surgical delivery have been published previously for 129 countries. Five health outcomes were plotted against reported surgical delivery. Univariate and multivariate polynomial regression curves were fit, and the optimal point on each regression curve was determined by solving for first-order conditions. The country closest to the optimum for each health outcome was taken as representative of the best-performing health system. Monetary inputs to and surgical procedures provided by these systems were scaled to the global population. Results. For 3 of the 5 health outcomes, optima could be found. Globally, 315 million procedures currently are provided annually. If global delivery mirrored the 3 best-performing countries, between 360 million and 460 million cases would be provided annually. With population growth, this will increase to approximately half a billion cases by 2030. Health systems delivering these outcomes spend approximately 10% of their GDP on health. Conclusion. This is the first study to provide empirical evidence for the surgical output that an ideal health system would provide. Our results project ideal delivery worldwide of approximately 550 million annual surgical cases by 2030. C1 [Shrime, Mark G.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Shrime, Mark G.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. [Shrime, Mark G.; Meara, John G.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA USA. [Daniels, Kimberly M.; Meara, John G.] Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA USA. RP Shrime, MG (reprint author), Harvard Interfac Initiat Hlth Policy, 14 Story St,4th Floor, Cambridge, MA 02138 USA. EM shrime@mail.harvard.edu FU National Institutes of Health/National Cancer Institute [R25CA92203] FX M.G.S. received partial funding from National Institutes of Health/National Cancer Institute R25CA92203. NR 20 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUL PY 2015 VL 158 IS 1 BP 27 EP 32 DI 10.1016/j.surg.2015.03.025 PG 6 WC Surgery SC Surgery GA CK6ED UT WOS:000356320400005 PM 25934078 ER PT J AU Lainas, P Camerlo, A Conrad, C Shivathirthan, N Fuks, D Gayet, B AF Lainas, Panagiotis Camerlo, Antoine Conrad, Claudius Shivathirthan, Nayruthia Fuks, David Gayet, Brice TI Laparoscopic right hepatectomy combined with partial diaphragmatic resection for colorectal liver metastases: Is it feasible and reasonable? SO SURGERY LA English DT Article ID LONG-TERM OUTCOMES; HEPATOCELLULAR-CARCINOMA; HEPATIC RESECTION; MATCHED ANALYSIS; METAANALYSIS; INVASION; INVOLVEMENT; APPRAISAL; BENEFITS AB Background. The impact of diaphragmatic invasion in patients with colorectal liver metastases (CRLMs) remains poorly evaluated. We aimed to evaluate feasibility and safety of laparoscopic right hepatectomy (LRH) with or without diaphragmatic resection for CRLM. Methods. From 2002 to 2012, 52 patients underwent LRH for CRLM. Of them, 7 patients had combined laparoscopic partial diaphragmatic resection ("diaphragm" group). Data were retrospectively collected and short and long-term outcomes analyzed. Results. Operative time was lower in the control group (272 vs 345 min, P = .06). Six patients required conversion to open surgery. Blood loss and transfusion rate were similar. Portal triad clamping was used more frequently in the "diaphragm" group (42.8% vs 6.6%, P = .02). Maximum tumor size was greater in the "diaphragm" group (74.5 vs 37.1 mm, P = .002). Resection margin was negative in all cases. Mortality was nil and general morbidity similar in the 2 groups. Specific liver-related complications occurred in 2 patients in the "diaphragm" group and 17 in the control group (P = .69). Mean hospital stay was similar (P = 56). Twenty-two (42.3%) patients experienced recurrence. One-, 3-, and 5-year overall survival after surgery in "diaphragm" and control groups were 69%, 34%, 34%, and 97%, 83%, 59%, respectively (P = .103). One- and 3-year disease-free survival after surgery in "diaphragm" and control groups were 57%, 47% and 75%, 54%, respectively (P = .310). Conclusion. LRH with en-bloc diaphragmatic resection could be reasonably performed for selected patients in expert centers. Technical difficulties related to diaphragmatic invasion must be circumvented. Further experience must be gained to confirm our results. C1 [Lainas, Panagiotis; Camerlo, Antoine; Conrad, Claudius; Shivathirthan, Nayruthia; Fuks, David; Gayet, Brice] Univ Paris 05, Inst Mutualiste Montsouris, Dept Digest Pathol, F-75014 Paris, France. [Conrad, Claudius] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Gayet, B (reprint author), Univ Paris 05, Inst Mutualiste Montsouris, Dept Digest Dis, 42 Blvd Jourdan, F-75014 Paris, France. EM brice.gayet@imm.fr NR 32 TC 5 Z9 6 U1 0 U2 2 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 JUL PY 2015 VL 158 IS 1 BP 128 EP 134 DI 10.1016/j.surg.2015.02.003 PG 7 WC Surgery SC Surgery GA CK6ED UT WOS:000356320400018 PM 25799466 ER PT J AU Dzik, W Kyeyune, D Otekat, G Natukunda, B Hume, H Kasirye, PG Ddungu, H Kajja, I Dhabangi, A Mugyenyi, GR Seguin, C Barnes, L Delaney, M AF Dzik, Walter Sunny Kyeyune, Dorothy Otekat, Grace Natukunda, Bernard Hume, Heather Kasirye, Phillip G. Ddungu, Henry Kajja, Isaac Dhabangi, Aggrey Mugyenyi, Godfrey R. Seguin, Claire Barnes, Linda Delaney, Meghan TI Transfusion Medicine in Sub-Saharan Africa: Conference Summary SO TRANSFUSION MEDICINE REVIEWS LA English DT Review DE Transfusion medicine; Sub-Saharan Africa; Conference proceedings ID SICKLE-CELL-DISEASE; PLATELET-TRANSFUSION; DEVELOPING-COUNTRIES; BLOOD-TRANSFUSION; CLINICAL-TRIAL; EXPERT PANEL; HEMORRHAGE; UGANDA; MULTICENTER; PREVENTION AB In November 2014, a 3-day conference devoted to transfusion medicine in sub-Saharan Africa was held in Kampala, Uganda. Faculty from academic institutions in Uganda provided a broad overview of issues pertinent to transfusion medicine in Africa. The conference consisted of lectures, demonstrations, and discussions followed by 5 small group workshops held at the Uganda Blood Transfusion Service Laboratories, the Ugandan Cancer Institute, and the Mulago National Referral Hospital. Highlighted topics included the challenges posed by increasing clinical demands for blood, the need for better patient identification at the time of transfusion, inadequate application of the antiglobulin reagent during pretransfusion testing, concern regarding proper recognition and evaluation of transfusion reactions, the expanded role for nurse leadership as a means to improve patient outcomes, and the need for an epidemiologic map of blood usage in Africa. Specialty areas of focus included the potential for broader application of transcranial Doppler and hydroxyurea therapy in sickle cell disease, African-specific guidelines for transfusion support of cancer patients, the challenges of transfusion support in trauma, and the importance of African-centered clinical research in pediatric and obstetric transfusion medicine. The course concluded by summarizing the benefits derived from an organized quality program that extended from the donor to the recipient As an educational tool, the slide-audio presentation of the lectures will be made freely available at the International Society of Blood Transfusion Academy Web site: http://www.isbtweb.org/academy/. (C) 2015 Elsevier Inc. All rights reserved. C1 [Dzik, Walter Sunny; Seguin, Claire] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kyeyune, Dorothy; Otekat, Grace] Uganda Blood Transfus Serv, Kampala, Uganda. [Hume, Heather; Kasirye, Phillip G.; Ddungu, Henry; Kajja, Isaac; Dhabangi, Aggrey] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. [Natukunda, Bernard; Mugyenyi, Godfrey R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Barnes, Linda; Delaney, Meghan] Puget Sound Blood Ctr, Seattle, WA 98104 USA. RP Dzik, W (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. OI Kasirye, Phillip/0000-0001-6620-483X FU International Society of Blood Transfusion; American Association of Blood Banks; Puget Sound Blood Center; Fred Hutchinson Cancer Institute; Massachusetts General Hospital; NHLBI grant [1R21HL10918-01A1] FX The authors gratefully acknowledge Mr Jason Barrett of the Fred Hutchinson-Uganda Cancer Institute Alliance for his outstanding contribution as project manager of the conference. Financial support was provided by grants from the International Society of Blood Transfusion, the American Association of Blood Banks, the Puget Sound Blood Center, the Fred Hutchinson Cancer Institute, and the Massachusetts General Hospital. Additional support was provided in part by NHLBI grant 1R21HL10918-01A1. NR 37 TC 2 Z9 2 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0887-7963 EI 1532-9496 J9 TRANSFUS MED REV JI Transf. Med. Rev. PD JUL PY 2015 VL 29 IS 3 BP 195 EP 204 DI 10.1016/j.tmrv.2015.02.003 PG 10 WC Hematology SC Hematology GA CK6EU UT WOS:000356322100005 PM 25752939 ER PT J AU Dilwali, S Kao, SY Fujita, T Landegger, LD Stankovic, KM AF Dilwali, Sonam Kao, Shyan-Yuan Fujita, Takeshi Landegger, Lukas D. Stankovic, Konstantina M. TI Nonsteroidal anti-inflammatory medications are cytostatic against human vestibular schwannomas SO TRANSLATIONAL RESEARCH LA English DT Article ID KAPPA-B ACTIVATION; SODIUM-SALICYLATE; ASPIRIN; APOPTOSIS; GROWTH; CANCER; CELLS; INHIBITION; MECHANISMS; MESALAZINE AB Vestibular schwannomas (VSs) are the most common tumors of the cerebellopontine angle. Significant clinical need exists for pharmacotherapies against VSs. Motivated by previous findings that immunohistochemical expression of cyclooxygenase 2 (COX-2) correlates with VS growth rate, we investigated the role of COX-2 in VSs and tested COX-2 inhibiting salicylates against VSs. COX-2 was found to be aberrantly expressed in human VS and primary human VS cells in comparison with control human nerve specimens and primary Schwann cells (SCs), respectively. Furthermore, levels of prostaglandin E2, the downstream enzymatic product of COX-2, were correlated with primary VS culture proliferation rate. Because COX-2 inhibiting salicylates such as aspirin are well tolerated and frequently clinically used, we assessed their repurposing for VS. Changes in proliferation, cell death, and cell viability were analyzed in primary VS cultures treated with aspirin, sodium salicylate, or 5-aminosalicylic acid. These drugs neither increased VS cell death nor affected healthy SCs. The cytostatic effect of aspirin in vitro was in concurrence with our previous clinical finding that patients with VS taking aspirin demonstrate reduced tumor growth. Overall, this work suggests that COX-2 is a key modulator in VS cell proliferation and survival and highlights salicylates as promising pharmacotherapies against VS. C1 [Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Labs, Boston, MA 02114 USA. Harvard MIT Program Speech & Hearing Biosci & Tec, Cambridge, MA USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. EM konstantina_stankovic@meei.harvard.edu OI Landegger, Lukas D./0000-0002-9660-2625 FU National Institute on Deafness and Other Communication Disorders [T32 DC00038, K08DC010419]; Bertarelli Foundation; Department of Defense Grant [W81XWH-14-1-0091] FX This study was supported by the National Institute on Deafness and Other Communication Disorders Grants T32 DC00038 (S.D., K.M.S.), K08DC010419 (K.M.S.), the Bertarelli Foundation (K.M.S.) and the Department of Defense Grant W81XWH-14-1-0091 (K.M.S.). NR 38 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 EI 1878-1810 J9 TRANSL RES JI Transl. Res. PD JUL PY 2015 VL 166 IS 1 BP 1 EP 11 DI 10.1016/j.trsl.2014.12.007 PG 11 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA CK6DC UT WOS:000356317700001 PM 25616959 ER PT J AU Beckers, CML Knezevic, N Valent, ET Tauseef, M Krishnan, R Rajendran, K Hardin, CC Aman, J van Bezu, J Sweetnam, P van Hinsbergh, VWM Mehta, D Amerongen, GPV AF Beckers, Cora M. L. Knezevic, Nebojsa Valent, Erik T. Tauseef, Mohammad Krishnan, Ramaswamy Rajendran, Kavitha Hardin, C. Corey Aman, Jurjan van Bezu, Jan Sweetnam, Paul van Hinsbergh, Victor W. M. Mehta, Dolly Amerongen, Geerten P. van Nieuw TI ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension SO VASCULAR PHARMACOLOGY LA English DT Article DE Contraction; HUVEC; Endothelial; Permeability; Rho kinase ID CELL-CELL CONTACTS; VE-CADHERIN; RHO-KINASE; ACTOMYOSIN CONTRACTILITY; BARRIER FUNCTION; PERMEABILITY; ACTIVATION; INHIBITION; THROMBIN; GTPASES AB Rho kinase mediates the effects of inflammatory permeability factors by increasing actomyosin-generated traction forces on endothelial adherens junctions, resulting in disassembly of intercellular junctions and increased vascular leakage. In vitro, this is accompanied by the Rho kinase-driven formation of prominent radial F-actin fibers, but the in vivo relevance of those F-actin fibers has been debated, suggesting other Rho kinase-mediated events to occur in vascular leak. Here, we delineated the contributions of the highly homologous isoforms of Rho kinase (ROCK1 and ROCK2) to vascular hyperpermeability responses. We show that ROCK2, rather than ROCK1 is the critical Rho kinase for regulation of thrombin receptor-mediated vascular permeability. Novel traction force mapping in endothelial monolayers, however, shows that ROCK2 is not required for the thrombin-induced force enhancements. Rather, ROM is pivotal to baseline junctional tension as a novel mechanism by which Rho kinase primes the endothelium for hyperpermeability responses, independent from subsequent ROCK1-mediated contractile stress-fiber formation during the late phase of the permeability response. (C) 2015 Elsevier Inc. All rights reserved. C1 [Beckers, Cora M. L.; Valent, Erik T.; Aman, Jurjan; van Bezu, Jan; van Hinsbergh, Victor W. M.; Amerongen, Geerten P. van Nieuw] Vrije Univ Amsterdam, Med Ctr, Inst Cardiovasc Res, Dept Physiol, NL-1081 BT Amsterdam, Netherlands. [Knezevic, Nebojsa; Tauseef, Mohammad; Mehta, Dolly; Amerongen, Geerten P. van Nieuw] Univ Illinois, Dept Pharmacol, Coll Med, Ctr Lung & Vasc Biol, Chicago, IL 60612 USA. [Krishnan, Ramaswamy; Rajendran, Kavitha] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Hardin, C. Corey] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Sweetnam, Paul] Surface Logix, Cambridge, MA 02138 USA. RP Amerongen, GPV (reprint author), Vrije Univ Amsterdam, Med Ctr, Inst Cardiovasc Res, Dept Physiol, Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. EM nieuwamerongen@vumc.nl FU Netherlands Heart Foundation (NHF) (The Hague) [2003T032, 2011T072]; Parker B. Francis Foundation; National Institute of Health [HL71784]; National Institutes of Health (NIH) [1K25HL111212] FX GPvNA was supported by the Netherlands Heart Foundation (NHF) (The Hague, grants 2003T032 and 2011T072), RK in part by the Parker B. Francis Foundation, DM by National Institute of Health (HL71784) and CCH in part by the National Institutes of Health (NIH, 1K25HL111212). NR 53 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1537-1891 EI 1879-3649 J9 VASC PHARMACOL JI Vasc. Pharmacol. PD JUL PY 2015 VL 70 BP 45 EP 54 DI 10.1016/j.vph.2015.03.017 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK9ND UT WOS:000356565900006 PM 25869521 ER PT J AU Stein, TD Montenigro, PH Alvarez, VE Xia, WM Crary, JF Tripodis, Y Daneshvar, DH Mez, J Solomon, T Meng, GY Kubilus, CA Cormier, KA Meng, S Babcock, K Kiernan, P Murphy, L Nowinski, CJ Martin, B Dixon, D Stern, RA Cantu, RC Kowall, NW McKee, AC AF Stein, Thor D. Montenigro, Philip H. Alvarez, Victor E. Xia, Weiming Crary, John F. Tripodis, Yorghos Daneshvar, Daniel H. Mez, Jesse Solomon, Todd Meng, Gaoyuan Kubilus, Caroline A. Cormier, Kerry A. Meng, Steven Babcock, Katharine Kiernan, Patrick Murphy, Lauren Nowinski, Christopher J. Martin, Brett Dixon, Diane Stern, Robert A. Cantu, Robert C. Kowall, Neil W. McKee, Ann C. TI Beta-amyloid deposition in chronic traumatic encephalopathy SO ACTA NEUROPATHOLOGICA LA English DT Article DE Chronic traumatic encephalopathy; Alzheimer's disease; Beta-amyloid; Neurodegenerative disorders; Dementia; Tau ID SEVERE BRAIN-INJURY; ALZHEIMERS-DISEASE; HEAD-INJURY; PROTEIN DEPOSITION; DIFFUSE PLAQUES; PATHOLOGY; APOE; RISK; TAU; AGE AB Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid beta peptide (A beta) levels, the extent of A beta deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that A beta deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that A beta deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, A beta deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with A beta plaques and those without. A beta deposition was significantly associated with the presence of the APOE epsilon 4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (beta = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both A beta plaques and total levels of A beta 1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that A beta deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that A beta is associated with both pathological and clinical progression of CTE independent of age. C1 [Stein, Thor D.; Meng, Gaoyuan; Kowall, Neil W.; McKee, Ann C.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Stein, Thor D.; Xia, Weiming; McKee, Ann C.] Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA. [Stein, Thor D.; Montenigro, Philip H.; Alvarez, Victor E.; Daneshvar, Daniel H.; Mez, Jesse; Solomon, Todd; Kubilus, Caroline A.; Cormier, Kerry A.; Meng, Steven; Babcock, Katharine; Kiernan, Patrick; Murphy, Lauren; Nowinski, Christopher J.; Martin, Brett; Dixon, Diane; Stern, Robert A.; Kowall, Neil W.; McKee, Ann C.] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Stein, Thor D.; McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Montenigro, Philip H.; Stern, Robert A.; Cantu, Robert C.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Alvarez, Victor E.; Daneshvar, Daniel H.; Mez, Jesse; Solomon, Todd; Kubilus, Caroline A.; Cormier, Kerry A.; Kiernan, Patrick; Murphy, Lauren; Stern, Robert A.; Kowall, Neil W.; McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Crary, John F.] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Crary, John F.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Crary, John F.] Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA. [Tripodis, Yorghos] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Tripodis, Yorghos; Martin, Brett; Dixon, Diane] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Nowinski, Christopher J.; Cantu, Robert C.] Sports Legacy Inst, Waltham, MA 02451 USA. [Stern, Robert A.; Cantu, Robert C.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Cantu, Robert C.] Emerson Hosp, Dept Neurosurg, Concord, MA 01742 USA. RP Stein, TD (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA. EM tdstein@bu.edu RI Kowall, Neil/G-6364-2012; xia, weiming/E-5465-2016; OI Kowall, Neil/0000-0002-6624-0213; xia, weiming/0000-0002-7463-3295; Stein, Thor/0000-0001-6954-4477; Daneshvar, Daniel/0000-0003-3691-9513; Stern, Robert/0000-0002-5008-077X; Tripodis, Yorghos/0000-0003-2190-7608; Montenigro, Philip/0000-0003-4442-9207 FU Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award; Alzheimer's Association [NIRG-305779]; Veterans Affairs Biorepository [CSP 501]; Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B6796-C]; National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering [U01NS086659-01]; National Institute of Aging Boston University AD Center [P30AG13846, 0572063345-5]; Department of Defense Peer Reviewed Alzheimer's Research Program (DoD-PRARP) [13267017]; Sports Legacy Institute FX We gratefully acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA) as well as all the individuals whose participation and contributions made this work possible. This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award; Alzheimer's Association (NIRG-305779); Veterans Affairs Biorepository (CSP 501); Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C); National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering (U01NS086659-01); National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345-5); Department of Defense Peer Reviewed Alzheimer's Research Program (DoD-PRARP #13267017); Sports Legacy Institute. This work was also supported by unrestricted gifts from the Andlinger Foundation and WWE. NR 51 TC 32 Z9 32 U1 5 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUL PY 2015 VL 130 IS 1 BP 21 EP 34 DI 10.1007/s00401-015-1435-y PG 14 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CK5EQ UT WOS:000356245500002 PM 25943889 ER PT J AU Ananthakrishnan, AN AF Ananthakrishnan, A. N. TI Editorial: diabetes and the risk of infections with immunomodulator therapy in inflammatory bowel diseases - author's reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL PY 2015 VL 42 IS 1 BP 120 EP 120 DI 10.1111/apt.13241 PG 1 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA CK1EV UT WOS:000355950300014 PM 26040521 ER PT J AU Almli, LM Stevens, JS Smith, AK Kilaru, V Meng, Q Flory, J Abu-Amara, D Hammamieh, R Yang, RT Mercer, KB Binder, EB Bradley, B Hamilton, S Jett, M Yehuda, R Marmar, CR Ressler, KJ AF Almli, Lynn M. Stevens, Jennifer S. Smith, Alicia K. Kilaru, Varun Meng, Qian Flory, Janine Abu-Amara, Duna Hammamieh, Rasha Yang, Ruoting Mercer, Kristina B. Binder, Elizabeth B. Bradley, Bekh Hamilton, Steven Jett, Marti Yehuda, Rachel Marmar, Charles R. Ressler, Kerry J. TI A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE GWAS; PTSD; fMRI; meQTL; epigenetic ID POSTTRAUMATIC-STRESS-DISORDER; DNA METHYLATION; ASSOCIATION; SYMPTOMS; AMYGDALA; POLYMORPHISM; POPULATION; EXPRESSION; INVENTORY; RECEPTOR AB Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N=147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N=147, =31.34, P=1.28x10(-8)) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N=2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N=2006, P=0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N=157, P=0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N=53, P<0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder. (c) 2015 Wiley Periodicals, Inc. C1 [Almli, Lynn M.; Stevens, Jennifer S.; Smith, Alicia K.; Kilaru, Varun; Mercer, Kristina B.; Binder, Elizabeth B.; Bradley, Bekh; Ressler, Kerry J.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Meng, Qian] Univ Med Ctr, Dept Psychiat, New York, NY USA. [Flory, Janine; Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Mental Hlth Care Ctr, Bronx, NY USA. [Flory, Janine; Yehuda, Rachel] Traumat Stress Studies Div, New York, NY USA. [Abu-Amara, Duna; Marmar, Charles R.] NYU, Dept Psychiat, Steven & Alexandra Cohen Vet Ctr Posttraumat Stre, New York, NY 10016 USA. [Hammamieh, Rasha; Jett, Marti] US Army Ctr Environm Hlth Res, Integrat Syst Biol, Ft Detrick, MD USA. [Yang, Ruoting] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Binder, Elizabeth B.] Max Planck Inst Psychiat, Dept Translat Res Psychiat, D-80804 Munich, Germany. [Bradley, Bekh] Dept Vet Affairs Med Ctr, Mental Hlth Serv Line, Atlanta, GA USA. [Hamilton, Steven] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Ressler, Kerry J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Ressler, KJ (reprint author), Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. EM kressle@emory.edu FU National Institutes of Mental Health [MH071537, MH096764]; Department of Defense [W81XWH-09-2-0044, W911NF-09-1-0298]; Emory and Grady Memorial Hospital General Clinical Research Center; NIH National Centers for Research Resources [M01RR00039]; Howard Hughes Medical Institute; Steven and Alexandra Cohen Foundation; National Center for Advancing Translational Sciences [UL1TR000067] FX Grant sponsor: National Institutes of Mental Health; Grant numbers: MH071537, MH096764; Grant sponsor: Department of Defense; Grant numbers: W81XWH-09-2-0044, W911NF-09-1-0298; Grant sponsor: Emory and Grady Memorial Hospital General Clinical Research Center; Grant sponsor: NIH National Centers for Research Resources; Grant number: M01RR00039; Grant sponsor: Howard Hughes Medical Institute; Grant sponsor: Steven and Alexandra Cohen Foundation; Grant sponsor: National Center for Advancing Translational Sciences; Grant number: #UL1TR000067. NR 43 TC 12 Z9 12 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL PY 2015 VL 168 IS 5 BP 327 EP 336 DI 10.1002/ajmg.b.32315 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA CK2XW UT WOS:000356079700002 PM 25988933 ER PT J AU Admon, R Holsen, LM Aizley, H Remington, A Whitfield-Gabrieli, S Goldstein, JM Pizzagalli, DA AF Admon, Roee Holsen, Laura M. Aizley, Harlyn Remington, Anne Whitfield-Gabrieli, Susan Goldstein, Jill M. Pizzagalli, Diego A. TI Striatal Hypersensitivity During Stress in Remitted Individuals with Recurrent Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Caudate; Depression; fMRI; Psychophysiologic Interaction (PPI); Reward; Stress ID INDUCED DOPAMINE RELEASE; POSITRON-EMISSION-TOMOGRAPHY; REWARD SYSTEM ACTIVITY; CHRONIC MILD STRESS; MAJOR DEPRESSION; PSYCHOSOCIAL STRESS; NUCLEUS-ACCUMBENS; HPA-AXIS; PSYCHOPHYSIOLOGICAL INTERACTIONS; ANTIDEPRESSANT TREATMENT AB BACKGROUND: Increased sensitivity to stress and dysfunctional reward processing are two primary characteristics of major depressive disorder (MDD) that may persist after remission. Preclinical work has established the pivotal role of the striatum in mediating both stress and reward responses. Human neuroimaging studies have corroborated these preclinical findings and highlighted striatal dysfunction in MDD in response to reward but have yet to investigate striatal function during stress, in particular in individuals with recurrent depression. METHODS: A validated mild psychological stress task involving viewing of negative stimuli during functional magnetic resonance imaging was conducted in 33 remitted individuals with a history of recurrent major depressive disorder (rMDD) and 35 matched healthy control subjects. Cortisol and anxiety levels were assessed throughout scanning. Stress-related activation was investigated in three striatal regions: caudate, nucleus accumbens, and putamen. Psychophysiologic interaction analyses probed connectivity of regions with central structures of the neural stress circuitry, such as the amygdala and hippocampus. RESULTS: The task increased cortisol and anxiety levels, although to a greater extent in rMDD individuals than healthy control subjects. In response to the negative stimuli, rMDD individuals, but not controls, also exhibited significantly potentiated caudate, nucleus accumbens, and putamen activations and increased caudate-amygdala and caudate-hippocampus connectivity. CONCLUSIONS: The findings highlight striatal hypersensitivity in response to a mild psychological stress in rMDD, as manifested by hyperactivation and hyperconnectivity with the amygdala and hippocampus. Striatal hypersensitivity during stress might thus constitute a trait mark of depression, providing a potential neural substrate for the interaction between stress and reward dysfunction in MDD. C1 [Admon, Roee; Pizzagalli, Diego A.] McLean Hosp, Ctr Depress Anxiety & Stress Res, Belmont, MA 02478 USA. [Pizzagalli, Diego A.] McLean Hosp, McLean Imaging Ctr, Belmont, MA 02478 USA. [Admon, Roee; Holsen, Laura M.; Goldstein, Jill M.; Pizzagalli, Diego A.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Holsen, Laura M.; Aizley, Harlyn; Remington, Anne; Goldstein, Jill M.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Med, Div Womens Hlth, Boston, MA 02115 USA. [Holsen, Laura M.; Aizley, Harlyn; Goldstein, Jill M.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Whitfield-Gabrieli, Susan; Goldstein, Jill M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr, Charlestown, MA USA. MIT, Charlestown, MA USA. [Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Pizzagalli, DA (reprint author), McLean Hosp, Ctr Depress Anxiety & Stress Res, Room 233C,115 Mill St, Belmont, MA 02478 USA. EM dap@mclean.harvard.edu FU National Institutes of Health Office for Research on Women's Health and Mental Health [P50 MH082679]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center [UL1 RR025758]; National Institute of Mental Health [K01 MH091222, R01 MH068376, R01 MH095809]; Adam Corneel Young Investigator Award; Brain & Behavior Research Foundation Young Investigator Award; Advanced Neuro Technology North America; AstraZeneca; Pfizer FX This work was supported by the National Institutes of Health Office for Research on Women's Health and Mental Health Grant No. P50 MH082679 (JMG); Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center Grant No. UL1 RR025758; National Institute of Mental Health Grant No. K01 MH091222 (LMH); National Institute of Mental Health Grant Nos. R01 MH068376 and R01 MH095809 (DAP); and The Adam Corneel Young Investigator Award (McLean Hospital) and a Brain & Behavior Research Foundation Young Investigator Award (RA).; Over the past 3 years, DAP has received honoraria or consulting fees from Advanced Neuro Technology North America, AstraZeneca, Pfizer, and Servier for activities unrelated to this project. All other authors report no biomedical financial interests or potential conflicts of interest. NR 88 TC 12 Z9 12 U1 5 U2 19 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 JUL 1 PY 2015 VL 78 IS 1 BP 67 EP 76 DI 10.1016/j.biopsych.2014.09.019 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CK0WA UT WOS:000355924800012 PM 25483401 ER PT J AU Rose, BS Jiang, W Punglia, RS AF Rose, Brent S. Jiang, Wei Punglia, Rinaa S. TI Effect of lymph node metastasis size on breast cancer-specific and overall survival in women with node-positive breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Lymph node metastasis size; Breast cancer; Breast cancer-specific survival; SEER ID EXTRACAPSULAR EXTENSION; AXILLARY NODES; RECURRENCE; MACROMETASTASES; RADIOTHERAPY; INVOLVEMENT; MASTECTOMY; RISK AB We investigated whether increasing size of lymph nodes (LN) metastases is associated with lower breast cancer-specific survival (BCSS) and overall survival (OS) independent of the number of positive LNs. Using Surveillance, Epidemiology, and End Results registry data, we identified 8791 women diagnosed between 1990 and 2003 with node-positive, non-metastatic invasive breast cancer treated with surgery and axillary LN dissection. Size of the largest involved LN metastasis was categorized as a parts per thousand currency sign2 mm, > 2 mm to < 2 cm, and a parts per thousand yen2 cm. BCSS and OS were estimated using the Kaplan-Meier method and compared using log-rank statistics. Adjusted hazard ratios (HR) were calculated using Cox proportional hazards models. Median follow-up was 109 months. Largest LN size was a parts per thousand currency sign2 mm, > 2 mm to < 2 cm, and a parts per thousand yen2 cm in 2219 (25.2 %), 5047 (57.4 %), and 1525 (17.3 %) women, respectively. The 10-year BCSS for women with LNs a parts per thousand currency sign2 mm, > 2 mm to < 2 cm, and a parts per thousand yen2 cm was 82.9, 75.5, 64.8 %, respectively (p < 0.001). On multivariable analysis, large (a parts per thousand yen2 cm) LN size was significantly associated with worsened BCSS (HR: 1.169; p = 0.026) and OS (HR: 1.169; p = 0.006) in addition to age, race, grade, PR status, adjuvant radiation, T-stage, and number of positive LNs. Large (a parts per thousand yen2 cm) LNs metastases were associated with lower BCSS and OS after controlling for other known prognostic factors including number of positive LNs. LN size could be useful to risk-stratify patients for adjuvant therapy if these results are validated in future prospective studies. C1 [Rose, Brent S.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Jiang, Wei] Brigham & Womens Hosp, Dept Surg, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Punglia, Rinaa S.] Brigham & Womens Hospital, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Punglia, Rinaa S.] Dana Farber Canc Inst, Ctr Populat Sci, Boston, MA 02115 USA. RP Punglia, RS (reprint author), Harvard Univ, Sch Med, Harvard Radiat Oncol Program, 450 Brookline Ave, Boston, MA 02115 USA. EM rpunglia@lroc.harvard.edu NR 23 TC 3 Z9 3 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2015 VL 152 IS 1 BP 209 EP 216 DI 10.1007/s10549-015-3451-y PG 8 WC Oncology SC Oncology GA CK5FT UT WOS:000356248900022 PM 26041688 ER PT J AU Ogino, S Campbell, PT Nishihara, R Phipps, AI Beck, AH Sherman, ME Chan, AT Troester, MA Bass, AJ Fitzgerald, KC Irizarry, RA Kelsey, KT Nan, H Peters, U Poole, EM Qian, ZR Tamimi, RM Tchetgen, EJT Tworoger, SS Zhang, XH Giovannucci, EL van den Brandt, PA Rosner, BA Wang, ML Chatterjee, N Begg, CB AF Ogino, Shuji Campbell, Peter T. Nishihara, Reiko Phipps, Amanda I. Beck, Andrew H. Sherman, Mark E. Chan, Andrew T. Troester, Melissa A. Bass, Adam J. Fitzgerald, Kathryn C. Irizarry, Rafael A. Kelsey, Karl T. Nan, Hongmei Peters, Ulrike Poole, Elizabeth M. Qian, Zhi Rong Tamimi, Rulla M. Tchetgen, Eric J. Tchetgen Tworoger, Shelley S. Zhang, Xuehong Giovannucci, Edward L. van den Brandt, Piet A. Rosner, Bernard A. Wang, Molin Chatterjee, Nilanjan Begg, Colin B. TI Proceedings of the second international molecular pathological epidemiology (MPE) meeting SO CANCER CAUSES & CONTROL LA English DT Review DE Epidemiologic method; Molecular pathologic epidemiology; Personalized medicine; Systems biology; Translational epidemiology; Unique disease principle ID ISLAND METHYLATOR PHENOTYPE; COLORECTAL-CANCER RISK; LIFE-STYLE FACTORS; MICROSATELLITE INSTABILITY STATUS; DISEASE CLASSIFICATION DATA; EPITHELIAL OVARIAN-CANCER; UNIQUE TUMOR PRINCIPLE; BODY-MASS INDEX; BREAST-CANCER; FAMILY-HISTORY AB Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the Big Data to Knowledge, Genetic Associations and Mechanisms in Oncology, and Precision Medicine Initiative of the US National Institute of Health. The MPE meeting series can help advance transdisciplinary population science and optimize training and education systems for twenty-first century medicine and public health. C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Ogino, Shuji; Nishihara, Reiko; Bass, Adam J.; Qian, Zhi Rong] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02215 USA. [Ogino, Shuji; Nishihara, Reiko; Fitzgerald, Kathryn C.; Tamimi, Rulla M.; Tchetgen, Eric J. Tchetgen; Tworoger, Shelley S.; Giovannucci, Edward L.; Wang, Molin] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Nishihara, Reiko; Irizarry, Rafael A.; Tchetgen, Eric J. Tchetgen; Rosner, Bernard A.; Wang, Molin] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Nishihara, Reiko; Fitzgerald, Kathryn C.; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Phipps, Amanda I.; Peters, Ulrike] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Phipps, Amanda I.; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Beck, Andrew H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Beck, Andrew H.; Bass, Adam J.] Broad Inst, Cambridge, MA USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Sherman, Mark E.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Poole, Elizabeth M.; Tamimi, Rulla M.; Tworoger, Shelley S.; Zhang, Xuehong; Giovannucci, Edward L.; Rosner, Bernard A.; Wang, Molin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02215 USA. [Troester, Melissa A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Irizarry, Rafael A.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Kelsey, Karl T.] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. [Nan, Hongmei] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [van den Brandt, Piet A.] Maastricht Univ, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. [Begg, Colin B.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU US National Institute of Health (NIH) [R01 CA151993, K07 CA190673, R01 CA137178, K24 DK098311, K07 CA172298]; Dana-Farber Cancer Institute FX We thank all of the members of the program committee, the speakers, the discussants, and the other participants of the Second International MPE Meeting on December 4-5, 2014 in Boston, MA, USA. We thank the Dana-Farber Cancer Institute (Edward J. Benz, Jr., President and CEO) for providing the meeting venue and the Department of Pathology, the Brigham and Women's Hospital (Jeffrey A. Golden, Chairperson), and Enzymatics, Inc., for providing meals and refreshments, respectively. We also thank the Department of Pathology, the Brigham and Women's Hospital (Jeffrey A. Golden, Chairperson); the Department of Epidemiology, the Harvard T.H. Chan School of Public Health (Michelle A. Williams, Chairperson); the Dana-Farber Harvard Cancer Center (Giovanni Parmigiani, Meir J. Stampfer, Lorelei A. Mucci, Deborah Schrag, and Charles S. Fuchs; Program Leaders); and the Channing Division of Network Medicine, the Department of Medicine, the Brigham and Women's Hospital (Edwin K. Silverman, Division Chief) for providing morale supports and helping in announcements. This work was supported in part by grants from the US National Institute of Health (NIH) [R01 CA151993 (to SO), K07 CA190673 (to RN), R01 CA137178 (to ATC), K24 DK098311 (to ATC), and K07 CA172298 (to AIP)], and the friends of the Dana-Farber Cancer Institute (to SO). ATC is Damon Runyon Clinical Investigator. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders (including Enzymatics, Inc.) did not have any role in planning the meeting, the decision to submit the manuscript for publication, or the writing of the manuscript. Use of Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC)-approved symbols for genes and gene products: We use symbols approved by HGNC and described at www.genenames.org; those include BRAF, CD274, ERBB2, ESR1, FASN, KRAS, MLH1, PDCD1LG2, PGR, PIK3CA, and VHL. Gene names are italicized, while names of gene products are non-italicized. Non-official names are described in parenthesis where helpful. NR 148 TC 18 Z9 18 U1 9 U2 27 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUL PY 2015 VL 26 IS 7 BP 959 EP 972 DI 10.1007/s10552-015-0596-2 PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CK2DN UT WOS:000356020900001 PM 25956270 ER PT J AU Dey, N Bera, A Das, F Ghosh-Choudhury, N Kasinath, BS Choudhury, GG AF Dey, Nirmalya Bera, Amit Das, Falguni Ghosh-Choudhury, Nandini Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression SO CELLULAR SIGNALLING LA English DT Article DE MicroRNA; Diabetic nephropathy; mTOR; Mesangial cell pathology ID INDUCED COLLAGEN EXPRESSION; MESSENGER-RNA TRANSLATION; TUBULAR EPITHELIAL-CELLS; NF-KAPPA-B; DIABETIC-NEPHROPATHY; PTEN EXPRESSION; TENSIN HOMOLOG; AKT KINASE; TARGETING PHOSPHATASE; DOWN-REGULATION AB High glucose milieu inhibits PTEN expression to activate Akt kinase and induces glomerular mesangial cell hypertrophy and matrix protein expression in diabetic nephropathy. Specific mechanism by which high glucose inhibits PTEN expression is not clear. We found that high glucose increased the expression of the microRNA-26a (miR-26a) in mesangial cells. Using a sensor plasmid with 3'UTR-driven luciferase, we showed PTEN as a target of miR-26a in response to high glucose. Overexpression of miR-26a reduced the PTEN protein levels resulting in increased Akt kinase activity similar to high glucose treatment. In contrast, anti-miR-26a reversed high glucose-induced suppression of PTEN with concomitant inhibition of Akt kinase activity. Akt-mediated phosphorylation of tuberin and PRAS40 regulates mTORC1, which is necessary for mesangial cell hypertrophy and matrix protein expression. Inhibition of high glucose-induced miR-26a blocked phosphorylation of tuberin and PRAS40, which lead to suppression of phosphorylation of S6 kinase and 4EBP-1, two substrates of mTORC1. Furthermore, we show that expression of miR-26a induced mesangial cell hypertrophy and increased fibronectin and collagen I (alpha 2) expression similar to that observed with the cells incubated with high glucose. Anti-miR-26a inhibited these phenomena in response to high glucose. Together our results provide the first evidence for the involvement of miR-26a in high glucose-induced mesangial cell hypertrophy and matrix protein expression. These data indicate the potential therapeutic utility of anti-miR-26a for the complications of diabetic kidney disease. Published by Elsevier Inc. C1 [Dey, Nirmalya; Bera, Amit; Das, Falguni; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, VA Res, San Antonio, TX USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU NIH [RO1 DK50190]; VA Research Service Merit Review [5I01BX000926]; VA Senior Research Career Scientist Award; VA Merit Review grants [5I01BX000150, 5I01BX001340] FX This work was supported by the NIH RO1 DK50190 and VA Research Service Merit Review 5I01BX000926 grants to GGC. GGC is a recipient of VA Senior Research Career Scientist Award. NGC AND BSK are supported by VA Merit Review grants 5I01BX000150 and 5I01BX001340, respectively. NR 55 TC 10 Z9 11 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD JUL PY 2015 VL 27 IS 7 BP 1276 EP 1285 DI 10.1016/j.cellsig.2015.03.007 PG 10 WC Cell Biology SC Cell Biology GA CK0HY UT WOS:000355887500002 PM 25797045 ER PT J AU Bedair, H Goyal, N Dietz, MJ Urish, K Hansen, V Manrique, J Hamilton, W Deirmengian, G AF Bedair, Hany Goyal, Nitin Dietz, Mathew J. Urish, Kenneth Hansen, Viktor Manrique, Jorge Hamilton, William Deirmengian, Greg TI A History of Treated Periprosthetic Joint Infection Increases the Risk of Subsequent Different Site Infection SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TOTAL KNEE ARTHROPLASTY; MORTALITY AB After the successful treatment of periprosthetic joint infection (PJI), patients may present with degenerative joint disease in another joint with symptoms severe enough to warrant arthroplasty. However, it is not known whether patients with a history of treated PJI at one site will have an increased risk of PJI in the second arthroplasty site. The primary objective of this study is to determine if there is a difference in the risk of developing a PJI after a second total hip arthroplasty (THA) or total knee arthroplasty (TKA) in patients who have had a previous PJI at another anatomic site compared with patients who have had no history of PJI. The secondary objective is to determine other potential risk factors that may predict PJI at the site of the second arthroplasty. A retrospective matched cohort study was performed to identify all patients at four academic institutions successfully treated for PJI who subsequently underwent a second primary THA or TKA (n = 90), constituting our study group. Patients were matched (one-to-one) to control subjects who had no history of PJI after their first arthroplasty (n = 90); they were matched based on age, sex, diabetic status, BMI, American Society of Anesthesiologists, institution, joint of interest, and year of surgery (+/- A 2 years). We compared the case and control groups to determine whether a prior infection increased the relative risk of a subsequent PJI at another anatomic site. To identify other potential risk factors for subsequent PJI, a subgroup univariate analysis of our study group (n = 90) was performed. To identify other potential risk factors for subsequent PJI, a subgroup univariate analysis of our study group (n = 90) was performed. Patients with a history of PJI had a greater risk of developing PJI in a subsequent THA or TKA (10 of 90 versus zero of 90 in the control group; relative risk, 21.00; 95% confidence interval [CI], 1.25-353.08; p = 0.035). Excluding PJI, we identified no other factors associated with a second joint infection. In patients with a history of PJI, a second PJI occurred more frequently in female patients (female: nine of 10 [90%] versus female: 40 of 80 [50%]; odds ratio [OR], 8.83; 95% CI, 1.13-403.33; p = 0.02) and in those whose initial infection was a staphylococcal species (subsequent PJI seven of 10 [70%] versus no subsequent PJI 28 of 80 [35%]; OR, 4.26; 95% CI, 0.89-27.50; p = 0.04). A history of PJI predisposes patients to subsequent PJI in primary THA or THA. Patients and surgeons must be aware of the higher risk of this devastating complication before proceeding with a second arthroplasty. Level III, prognostic study. C1 [Bedair, Hany; Hansen, Viktor] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. [Goyal, Nitin; Hamilton, William] Anderson Orthopaed Clin, Alexandria, VA USA. [Dietz, Mathew J.] W Virginia Univ, Dept Orthopaed, Morgantown, WV 26506 USA. [Urish, Kenneth] Univ Pittsburgh, Dept Orthopaed, Pittsburgh, PA USA. [Manrique, Jorge; Deirmengian, Greg] Thomas Jefferson Univ, Dept Orthopaed, Philadelphia, PA 19107 USA. [Manrique, Jorge] Thomas Jefferson Univ, Rothman Inst, Philadelphia, PA 19107 USA. RP Manrique, J (reprint author), Thomas Jefferson Univ, Rothman Inst, 125 S 9th St,Suite 1000, Philadelphia, PA 19107 USA. EM jorgemanriquemd@gmail.com NR 12 TC 3 Z9 3 U1 1 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 JUL PY 2015 VL 473 IS 7 BP 2300 EP 2304 DI 10.1007/s11999-015-4174-4 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CJ8LM UT WOS:000355752200025 PM 25670654 ER PT J AU Janssen, SJ Braun, Y Ready, JE Raskin, KA Ferrone, ML Hornicek, FJ Schwab, JH AF Janssen, Stein J. Braun, Yvonne Ready, John E. Raskin, Kevin A. Ferrone, Marco L. Hornicek, Francis J. Schwab, Joseph H. TI Are Allogeneic Blood Transfusions Associated With Decreased Survival After Surgery for Long-bone Metastatic Fractures? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CHARLSON COMORBIDITY INDEX; CANCER RECURRENCE; SURGICAL-TREATMENT; COLORECTAL-CANCER; DISEASE; RISK; MORBIDITY AB Previous studies have shown that perioperative blood transfusion increases cancer recurrence and decreases patient survival after resection of primary malignancies. The question arises whether this association also exists in patients with already disseminated disease undergoing surgery for metastatic long-bone fractures. We sought to determine whether perioperative allogeneic blood transfusion is associated with decreased survival after operative treatment of long-bone metastatic fractures after accounting for clinical, laboratory, and treatment factors. Secondarily, we aimed to identify potential factors that are associated with decreased survival. We included 789 patients in our retrospective study who underwent surgery at two institutions for a pathologic or impending metastatic long-bone fracture. We used multivariable Cox proportional hazards regression model analysis to assess the relationship of perioperative allogeneic blood transfusion with survival, and accounted for patient age, sex, comorbidities, BMI, tumor type, fracture type and location, presence of other bone and visceral metastases, previous radiotherapy and systemic therapy, preoperative embolization, preoperative hemoglobin level, treatment type, anesthesia time, blood loss, duration of hospital admission, year of surgery, and hospital. Considering transfusion as an "exposure," and comparing patients who received transfusions with those who did not, we found that blood transfusion was not associated with decreased survival after accounting for all explanatory variables (hazard ratio [HR] 1.06; 95% CI, 0.87-1.30; p = 0.57). Evaluating transfusion in terms of dose-response, we found that patients who received more transfusions had lower survival compared with those who had fewer transfusions after accounting for all explanatory variables (HR per unit of blood transfused, 1.07; 95% CI, 1.02-1.12; p = 0.005). We found that age (HR, 1.02; 95% CI, 1.01-1.02; p < 0.001), comorbidity status (HR, 1.06; 95% CI, 1.01-1.10; p = 0.014), duration of hospital stay (HR, 1.02; 95% CI 1.00-1.03; p = 0.021), tumor type (HR, 1.71; 95% CI, 1.44-2.03; p < 0.001), and visceral metastases (HR, 1.59; 95% CI, 1.34-1.88; p < 0.001) were independently associated with survival. We found that exposure to perioperative allogeneic blood transfusion does not decrease survival, with the numbers available. However, our sample size might have been insufficient to reveal a small but potentially relevant effect. Our results do suggest a dose-response relationship; patients who received more transfusions had lower survival compared with those with fewer transfusions. Risk of death increased by 7% per unit of blood transfused. Level III, prognostic study. C1 [Janssen, Stein J.; Braun, Yvonne; Raskin, Kevin A.; Hornicek, Francis J.; Schwab, Joseph H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg,Orthopaed Oncol Serv, Boston, MA 02114 USA. [Ready, John E.; Ferrone, Marco L.] Brigham & Womens Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Janssen, SJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg,Orthopaed Oncol Serv, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM steinjanssen@gmail.com FU Anna Foundation (Oegstgeest, The Netherlands); Michael van Vloten Foundation (Rotterdam, The Netherlands); Stryker (Kalamazoo, MI, USA); Biom'up (Saint-Priest, Lyon, France) FX One of the authors (SJ) received funding, an amount less than USD 10,000, from the Anna Foundation (Oegstgeest, The Netherlands) and an amount less than USD10,000, from the Michael van Vloten Foundation (Rotterdam, The Netherlands). One author (JS) certifies that he or a member of his family has or may receive payments or benefits, an amount less than USD 10,000, from Stryker (Kalamazoo, MI, USA), and an amount less than USD 10,000, from Biom'up (Saint-Priest, Lyon, France). NR 26 TC 2 Z9 2 U1 1 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 JUL PY 2015 VL 473 IS 7 BP 2343 EP 2351 DI 10.1007/s11999-015-4167-3 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CJ8LM UT WOS:000355752200031 PM 25637400 ER PT J AU Teunis, T Thornton, ER Jayakumar, P Ring, D AF Teunis, Teun Thornton, Emily R. Jayakumar, Prakash Ring, David TI Time Seeing a Hand Surgeon Is Not Associated With Patient Satisfaction SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID PRIMARY-CARE; ITEM BANK; OUTCOMES; DEPRESSION; HEALTH; PHYSICIAN; EXTREMITY AB Previous studies, predominantly in the primary care setting, identified time spent with the physician as an important predictor of satisfaction. It is unknown if the same holds true in hand surgery. Is patient satisfaction measured immediately after an office visit associated with the duration of time spent with the hand surgeon? What other factors are associated with satisfaction directly after the visits and 2 weeks after the appointment? We prospectively enrolled 81 patients visiting our hand and upper extremity surgery outpatient clinic. We recorded their demographics and measured physical function, pain behavior, symptoms of depression, time spent in the waiting room, time spent with the physician, and patient satisfaction. Office times were measured using our patient ambulatory tracking system and by a research assistant outside the clinic room. To assess satisfaction we used items from the Consumer Assessment of Healthcare Providers and Systems survey (a federally developed standardized survey instrument) relevant to our study. Two weeks later, 51 (64%) patients were available for telephone followup and the same measures were completed. Mean time spent with the hand surgeon was 8 +/- A 5 minutes and mean in-office wait time to see the hand surgeon was 32 +/- A 18 minutes. A priori power analyses indicated that 77 patients would provide 80% power to detect an effect size f(2) = 0.18 for a regression with five predictors. This means that we would detect time spent with the physician as a significant factor if it accounted for 7% or more of the variability in satisfaction. Time spent with the hand surgeon was not associated with patient satisfaction measured directly after the visit (r = -0.023; p = 0.84). Longer time waiting to see the physician correlated with decreased patient satisfaction (r = -0.30; p = 0.0057). The final multivariable model for increased satisfaction directly after the office visit included shorter waiting time (regression coefficient [beta] -0.0014; partial R-2 0.094; 95% confidence interval [CI], -0.0024 to -0.00042; p = 0.006) and being married/living with a partner (beta 0.057; partial R-2 0.11; 95% CI, 0.021-0.093; p = 0.002 [adjusted R-2 0.18; p < 0.001]). Similarly, multivariable analysis found higher patient satisfaction 2 weeks after the visit to be independently associated with shorter waiting time (beta -0.0037; partial R-2 0.10; 95% CI, -0.0070 to -0.00054; p = 0.023) and being married/living with a partner (beta 0.15; partial R-2 0.12; 95% CI, 0.033-0.26; p = 0.012 [adjusted R-2 0.16; p = 0.0052]). Patient satisfaction among patients undergoing hand surgery may relate more to shorter time in the waiting room and to the quality more than the quantity of time spent with the patient. Level II, prognostic study. C1 [Teunis, Teun; Thornton, Emily R.; Jayakumar, Prakash; Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu FU Wright Medical (Memphis, TN, USA); Skeletal Dynamics (Miami, FL, USA); Biomet (Warsaw, IN, USA); AO North America (Paoli, PA, USA); AO International (Dubendorf, Switzerland) FX One of the authors (DR) certifies that he, or a member of his immediate family, has or may receive payments or benefits, during the study period, from Wright Medical (Memphis, TN, USA) of less than USD 10,000; Skeletal Dynamics (Miami, FL, USA) of less than USD 10,000; Biomet (Warsaw, IN, USA) of less than USD 10,000; AO North America (Paoli, PA, USA) of less than USD 10,000; and AO International (Dubendorf, Switzerland) of less than USD 10,000. NR 30 TC 5 Z9 5 U1 0 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 JUL PY 2015 VL 473 IS 7 BP 2362 EP 2368 DI 10.1007/s11999-014-4090-z PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CJ8LM UT WOS:000355752200034 PM 25475717 ER PT J AU Menendez, ME Ring, D Bateman, BT AF Menendez, Mariano E. Ring, David Bateman, Brian T. TI Preoperative Opioid Misuse is Associated With Increased Morbidity and Mortality After Elective Orthopaedic Surgery SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID NATIONWIDE INPATIENT SAMPLE; QUALITY IMPROVEMENT PROGRAM; ADVERSE DRUG EVENTS; CHRONIC BACK-PAIN; UNITED-STATES; RISK-FACTORS; PRESCRIBED OPIOIDS; IDENTIFY PATIENTS; NARCOTIC USE; ABUSE AB Many patients having discretionary orthopaedic surgery take opioids daily, either with a prescription or illicitly, however little is known regarding the prevalence and effect of high-risk opioid use (eg, abuse, dependence) in the perioperative orthopaedic setting. We sought (1) to determine the prevalence of opioid abuse and dependence in patients undergoing major elective orthopaedic surgery; (2) to characterize the relationship of opioid abuse and dependence with in-hospital postoperative mortality and adverse events, failure to rescue, prolonged length of stay, and nonroutine disposition; and (3) to identify factors associated with high-risk opioid use. We used coding data collected in discharge records from the Nationwide Inpatient Sample (2002-2011). We analyzed changes with time in the prevalence of opioid abuse and dependence on admission. Finally, we used multivariate regression modeling to measure the association of opioid abuse and dependence with in-hospital postoperative mortality, morbidity, and resource utilization, and to identify factors associated with high-risk opioid use. The prevalence of opioid abuse and dependence increased from 0.095% in 2002 to 0.24% in 2011, an increase of 152% (p < 0.001). Opioid abuse and dependence were associated with increased inpatient mortality (odds ratio [OR], 3.7; 95% CI, 2.7-5.1) and aggregate morbidity (OR, 2.3 l; 95% CI, 2.2-2.4), including induced mental disorder (OR, 5.9; 95% CI, 5.4-6.3), respiratory failure (OR, 3.1; 95% CI, 2.7-3.6), surgical site infection (OR, 2.5; 95% CI, 2.0-3.0), mechanical ventilation (OR, 2.3; 95% CI, 2.0-2.5), pneumonia (OR, 2.1; 95% CI, 1.8-2.3), myocardial infarction (OR, 1.9; 95% CI, 1.3-2.6), and postoperative ileus or other gastrointestinal events (OR, 1.4; 95% CI, 1.3-1.6) (p < 0.001 for all listed entities). Abuse and dependence also were associated with increased risk for prolonged hospital length of stay (OR, 2.5; 95% CI, 2.4-2.5), nonroutine discharge (OR, 2.2; 95% CI, 2.2-2.3), and failure to rescue (OR, 2.0; 95% CI, 1.4-2.8). High-risk opioid users were more likely to be younger, male, nonwhite, Medicaid-insured patients with mental health and substance use disorders, and to be undergoing spine surgery. Hospital-related characteristics included urban setting, geographic location in the Northeast or West, and serving as a teaching facility. Opioid abuse and dependence are increasing rapidly among orthopaedic surgical inpatients and are associated with considerable postoperative morbidity and mortality and resource utilization. We recommend that orthopaedic surgeons screen patients carefully for opioid misuse preoperatively, help patients who are using opioids inappropriately to discontinue them before scheduling elective surgery, decline to perform elective surgery in patients who misuse opioids, and closely monitor patients who are habituated to opioids at the time they undergo surgery. Level III, prognostic study. C1 [Menendez, Mariano E.; Ring, David] Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Menendez, Mariano E.; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. RP Menendez, ME (reprint author), Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Suite 2100, Boston, MA 02114 USA. EM marianofurrer@gmail.com NR 57 TC 18 Z9 18 U1 0 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 JUL PY 2015 VL 473 IS 7 BP 2402 EP 2412 DI 10.1007/s11999-015-4173-5 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CJ8LM UT WOS:000355752200039 PM 25694266 ER PT J AU Cahana-Amitay, D Albert, ML AF Cahana-Amitay, Dalia Albert, Martin L. TI Neuroscience of Aphasia Recovery: the Concept of Neural Multifunctionality SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Recovery from aphasia; Neural multifunctionality; Linguistic; Nonlinguistic; Cognition; Aphasia treatment ID SHORT-TERM-MEMORY; POSITRON-EMISSION-TOMOGRAPHY; INFERIOR FRONTAL-CORTEX; COGNITIVE REHABILITATION; POSTSTROKE APHASIA; EXECUTIVE FUNCTION; PREFRONTAL CORTEX; LANGUAGE THERAPY; SEMANTIC CONTROL; INDUCED NEUROPLASTICITY AB Aphasia therapy, while demonstrably successful, has been limited by its primary focus on language, with relatively less attention paid to nonlinguistic factors (cognitive, affective, praxic) that play a major role in recovery from aphasia. Neuroscientific studies of the past 15-20 years have opened a breach in the wall of traditional clinico-anatomical teachings on aphasia. It is not an exaggeration to talk of a paradigm shift. The term "neural multifunctionality" denotes a complex web of neural networks supporting both linguistic and nonlinguistic functions in constant and dynamic interaction, creating language as we know it and contributing to recovery from aphasia following brain damage. This paper reviews scientific underpinnings of neural multifunctionality and suggests ways in which this new approach to understanding the neural basis of language can lead to meaningful, practical steps for improvements in aphasia therapy. C1 [Cahana-Amitay, Dalia; Albert, Martin L.] VA Boston Healthcare Syst, Boston, MA 02114 USA. [Cahana-Amitay, Dalia; Albert, Martin L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Cahana-Amitay, Dalia; Albert, Martin L.] VA Boston Healthcare Syst, Harold Goodglass Aphasia Res Ctr, Boston, MA 02130 USA. [Cahana-Amitay, Dalia; Albert, Martin L.] VA Boston Healthcare Syst, Language Aging Brain Lab, Boston, MA 02130 USA. RP Cahana-Amitay, D (reprint author), VA Boston Healthcare Syst, Boston, MA 02114 USA. EM dcamitay@bu.edu FU National Institutes of Health NIA [R01AG14345]; Boston University, Department of Neurology, Language in the Aging Brain FX We would like to thank Abigail Oveis and Adonai Sebastian for compiling literature and formatting this paper. Support for this research was provided by the National Institutes of Health NIA grant R01AG14345, Boston University, Department of Neurology, Language in the Aging Brain (PIs: Albert and Obler). NR 98 TC 2 Z9 2 U1 6 U2 26 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD JUL PY 2015 VL 15 IS 7 AR 41 DI 10.1007/s11910-015-0568-7 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK5HC UT WOS:000356253200010 PM 26008816 ER PT J AU Ozieh, MN Dismuke, CE Lynch, CP Egede, LE AF Ozieh, Mukoso N. Dismuke, Clara E. Lynch, Cheryl P. Egede, Leonard E. TI Medical care expenditures associated with chronic kidney disease in adults with diabetes: United States 2011 SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Diabetes; Chronic kidney disease; Cost; MEPS ID COMPLICATIONS; MORTALITY; MELLITUS; BURDEN; COSTS AB Objective: Approximately 1 in 3 adults with diabetes have CKD. However, there are no recent national estimates of the association of CKD with medical care expenditures in individuals with diabetes. Our aim is to assess the association of CKD with total medical expenditures in US adults with diabetes using a national sample and novel cost estimation methodology. Research design and methods: Data on 2,053 adults with diabetes in the 2011 Medical Expenditure Panel Survey (MEPS) was analyzed. Individuals with CKD were identified based on self-report. Adjusted mean health services expenditures per person in 2011 were estimated using a two-part model after adjusting for demographic and clinical covariates. Results: Of the 2,053 individuals with diabetes, approximately 9.7% had self-reported CKD. Unadjusted mean expenditures for individuals with CKD were $ 20,726 relative to $ 9,689.49 for no CKD. Adjusted mean expenditures from the 2-part model for individuals with CKD were $ 8473 higher relative to individuals without CKD. Additional significant covariates were Hispanic/other race, uninsured, urban dwellers, CVD, stroke, high cholesterol, arthritis, and asthma. The estimated unadjusted total expenditures for individuals with CKD were estimated to be in excess of $ 43 billion in 2011. Conclusions: We showed that CKD is a significant contributor to the financial burden among individuals with diabetes, and that minorities and the uninsured with CKD may experience barriers in access to care. Our study also provides a baseline national estimate of CKD cost in Diabetes by which future studies can be used for comparison. Published by Elsevier Ireland Ltd. C1 [Ozieh, Mukoso N.] Med Univ S Carolina, Div Nephrol, Charleston, SC 29425 USA. [Ozieh, Mukoso N.; Dismuke, Clara E.; Lynch, Cheryl P.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Div Gen Internal Med, Charleston, SC 29425 USA. [Dismuke, Clara E.; Lynch, Cheryl P.; Egede, Leonard E.] Ralph H Johnson Dept Vet Affairs Med Ctr, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ S Carolina, 135 Rutledge Ave,MSC 593, Charleston, SC 29425 USA. EM egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Disease [K24DK093699] FX This study was supported by Grant K24DK093699 from The National Institute of Diabetes and Digestive and Kidney Disease (PI: Leonard Egede). NR 17 TC 11 Z9 11 U1 3 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD JUL PY 2015 VL 109 IS 1 BP 185 EP 190 DI 10.1016/j.diabres.2015.04.011 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CK4YA UT WOS:000356228100026 PM 25935258 ER PT J AU Wilson, RG Stevens, BW Guo, AY Russell, CN Thornton, A Cohen, MA Sturgeon, HC Giallourakis, C Khalili, H Nguyen, DD Yajnik, V Sauk, J Ananthakrishnan, AN AF Wilson, Robin G. Stevens, Betsy W. Guo, Abra Y. Russell, Caitlin N. Thornton, Anna Cohen, Melissa A. Sturgeon, Holly C. Giallourakis, Cosmas Khalili, Hamed Nguyen, Deanna D. Yajnik, Vijay Sauk, Jenny Ananthakrishnan, Ashwin N. TI High C-Reactive Protein Is Associated with Poor Sleep Quality Independent of Nocturnal Symptoms in Patients with Inflammatory Bowel Disease SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Sleep; Inflammatory bowel disease; C-reactive protein; Inflammation ID CROHNS-DISEASE; ULCERATIVE-COLITIS; OF-LIFE; DURATION; DISTURBANCES; DEPRIVATION; DISORDERS; RISK; INTERLEUKIN-6; METAANALYSIS AB Sleep disruption is common in inflammatory bowel diseases (IBD). However, studies demonstrating a similar prevalence in irritable bowel syndrome suggest that nighttime disruption due to diarrhea and abdominal pain may be key drivers of poor sleep quality. Whether inflammation is associated with poor sleep independently has not been examined previously. This single-center study included subjects with IBD recruited to an ongoing prospective registry who completed a questionnaire assessing sleep quality and mood. Inflammatory marker levels [C-reactive protein (CRP), erythrocyte sedimentation rate] and clinical disease activity including nighttime disruption on the day of enrollment were obtained from the medical record. Logistic regression models were used to identify predictors of sleep quality. The study included 131 subjects (72 women) with a median age of IBD diagnosis of 25 years. Twenty-three subjects (19 %) had a high C-reactive protein level (a parts per thousand yen8 mg/dL). Poor sleep was more common in those with high CRP levels than with normal values (70 vs. 39 %, p = 0.009). This association remained significant on multivariate analysis [Odds ratio (OR) 4.12, 95 % confidence interval (CI) 1.38-12.29]. Adjusting for the presence of nighttime disruption did not significant alter this association (OR 3.16, 95 % CI 1.01-9.90). High CRP correlated with poor sleep even in patients not experiencing nocturnal symptoms (n = 101, OR 4.89, 95 % CI 1.24-19.36). High CRP is associated with poor sleep quality in IBD independent of the presence of nighttime disruptions, suggesting that a relationship exists between circulating inflammatory markers and sleep. C1 [Wilson, Robin G.; Stevens, Betsy W.; Guo, Abra Y.; Russell, Caitlin N.; Thornton, Anna; Cohen, Melissa A.; Sturgeon, Holly C.; Giallourakis, Cosmas; Khalili, Hamed; Nguyen, Deanna D.; Yajnik, Vijay; Sauk, Jenny; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Giallourakis, Cosmas; Khalili, Hamed; Nguyen, Deanna D.; Yajnik, Vijay; Sauk, Jenny; Ananthakrishnan, Ashwin N.] Harvard Univ, Sch Med, Boston, MA USA. [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org FU National Institutes of Health (NIH) [P30 DK043351]; National Institutes of Health [K23 DK097142] FX We acknowledge the valuable contributions of the participants and the research staff of our registry. This work was presented as a poster at the American College of Gastroenterology Annual Meeting 2014, Philadelphia, PA. This work is supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). NR 47 TC 3 Z9 4 U1 2 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUL PY 2015 VL 60 IS 7 BP 2136 EP 2143 DI 10.1007/s10620-015-3580-5 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CK2DT UT WOS:000356021500035 PM 25701321 ER PT J AU Sharaiha, RZ Sethi, A Weaver, KR Gonda, TA Shah, RJ Fukami, N Kedia, P Kumta, NA Clavo, CMR Saunders, MD Cerecedo-Rodriguez, J Barojas, PF Widmer, JL Gaidhane, M Brugge, WR Kahaleh, M AF Sharaiha, Reem Z. Sethi, Amrita Weaver, Kristen R. Gonda, Tamas A. Shah, Raj J. Fukami, Norio Kedia, Prashant Kumta, Nikhil A. Clavo, Carlos M. Rondon Saunders, Michael D. Cerecedo-Rodriguez, Jorge Barojas, Paola Figueroa Widmer, Jessica L. Gaidhane, Monica Brugge, William R. Kahaleh, Michel TI Impact of Radiofrequency Ablation on Malignant Biliary Strictures: Results of a Collaborative Registry SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Radiofrequency ablation; Biliary obstruction; Stent patency; Survival; Cholangiocarcinoma; Pancreatic cancer ID BILE-DUCT CARCINOMA; RANDOMIZED-TRIAL; METAL STENTS; INTRALUMINAL BRACHYTHERAPY; PHOTODYNAMIC THERAPY; HILAR CHOLANGIOCARCINOMA; ENDOSCOPIC PALLIATION; OBSTRUCTIVE-JAUNDICE; PLASTIC STENTS; EXTERNAL-BEAM AB Radiofrequency ablation of malignant biliary strictures has been offered for the last 3 years, but only limited data have been published. To assess the safety, efficacy, and survival outcomes of patients receiving endoscopic radiofrequency ablation. Between April 2010 and December 2013, 69 patients with unresectable neoplastic lesions and malignant biliary obstruction underwent 98 radiofrequency ablation sessions with stenting. A total of 69 patients (22 male, aged 66.1 +/- A 13.3) were included in the registry. The etiology of malignant biliary stricture included unresectable cholangiocarcinoma (n = 45), pancreatic cancer (n = 19), gallbladder cancer (n = 2), gastric cancer (n = 1), and liver metastasis from colon cancer (n = 3). Seventy-eight percentage of patients had prior chemotherapy. All strictures were stented post-radiofrequency ablation with either plastic stents or metal stents. The mean stricture length treated was 14.3 mm. There was a statistically significant improvement in stricture diameter post-ablation (p < 0.0001). The likelihood of stricture improvement was significantly greater in pancreatic cancer-associated strictures [RR 1.8 (95 % 1.03-5.38)]. Seven patients (10 %) had adverse events, not linked directly to radiofrequency ablation. Median survival was 11.46 months (6.2-25 months). Radiofrequency ablation is effective and safe in malignant biliary obstruction and seems to be associated with improved survival. C1 [Sharaiha, Reem Z.; Weaver, Kristen R.; Kedia, Prashant; Kumta, Nikhil A.; Clavo, Carlos M. Rondon; Cerecedo-Rodriguez, Jorge; Barojas, Paola Figueroa; Widmer, Jessica L.; Gaidhane, Monica; Kahaleh, Michel] Weill Cornell Med Coll, Div Gastroenterol & Hepatol, New York, NY 10021 USA. [Sethi, Amrita; Gonda, Tamas A.] Columbia Univ, Med Ctr, Gastroenterol, New York, NY USA. [Shah, Raj J.; Fukami, Norio] Univ Colorado, Gastroenterol, Denver, CO 80202 USA. [Saunders, Michael D.] Univ Washington, Gastroenterol, Seattle, WA 98195 USA. [Brugge, William R.] Massachusetts Gen Hosp, Gastroenterol, Boston, MA 02114 USA. RP Kahaleh, M (reprint author), Weill Cornell Med Coll, Div Gastroenterol & Hepatol, 1305 York Ave,4th Floor, New York, NY 10021 USA. EM mkahaleh@gmail.com RI Gaidhane, Monica/B-9414-2009 OI Gaidhane, Monica/0000-0001-6773-7080 FU Boston Scientific; Fujinon; EMcison; Xlumena Inc.; W.L. Gore; MaunaKea; Apollo Endosurgery; Cook Endoscopy; ASPIRE Bariatrics; GI Dynamics; MI Tech FX Michel Kahaleh MD has received grant support from Boston Scientific, Fujinon, EMcison, Xlumena Inc., W.L. Gore, MaunaKea, Apollo Endosurgery, Cook Endoscopy, ASPIRE Bariatrics, GI Dynamics, and MI Tech. He is a consultant for Boston Scientific and Xlumena Inc.; Amrita Sethi MD is a consultant for Boston Scientific. All other authors have no conflicts of interest to report. NR 45 TC 7 Z9 8 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUL PY 2015 VL 60 IS 7 BP 2164 EP 2169 DI 10.1007/s10620-015-3558-3 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CK2DT UT WOS:000356021500039 PM 25701319 ER PT J AU Johnson, KB Mueller, JL Simon, TG Zheng, H King, LY Makar, RS Gervais, DA Chung, RT AF Johnson, Kara B. Mueller, Jessica L. Simon, Tracey G. Zheng, Hui King, Lindsay Y. Makar, Robert S. Gervais, Debra A. Chung, Raymond T. TI Reduced Albumin Dosing During Large-Volume Paracentesis Is Not Associated with Adverse Clinical Outcomes SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Paracentesis; Albumin; Cirrhosis; Renal disease ID INDUCED CIRCULATORY DYSFUNCTION; CIRRHOSIS; PREVENTION; ASCITES; MIDODRINE AB LVP is used to manage diuretic-resistant ascites in cirrhotic patients. Albumin administration prevents complications including acute kidney injury and paracentesis-induced circulatory dysfunction, but the optimal dose is unclear. We sought to assess adherence to guidelines enacted in July 2011 at our center for reducing the albumin dose administered at large-volume paracentesis (LVP) and evaluate the cost and rate of complications of LVPs before and after guideline enactment. All LVPs performed on cirrhotic patients in our center's Department of Radiology between July 2009 and January 2014 were studied. Outcomes included adherence to guidelines, LVP complications, and administered albumin cost. Groups were compared using Student's t tests for continuous data and Chi-square or Fisher's exact tests for categorical data. A repeated measurements model accounted for patients with multiple LVPs. Of the 935 LVPs, 288 occurred before guideline implementation (group 1) and 647 occurred after (group 2). The mean dose of albumin administered was 13.7 g/L of ascites removed in group 1 versus 10.3 g/L in group 2 (p < 0.0001). Of the group 2 LVPs, 235 (36.3 %) adhered to guidelines. There were no significant differences in LVP complications. Guidelines were followed in one-third of LVPs. Despite this limited adherence, a reduction in albumin administration and associated cost savings was still observed. There was no increase in LVP-related complications after guideline implementation or in the adherent group, suggesting that albumin dose can be safely reduced. Future efforts should be directed at enhancing guideline adherence and potentially further reducing albumin dosing. C1 [Johnson, Kara B.; Mueller, Jessica L.; King, Lindsay Y.; Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Johnson, Kara B.; Mueller, Jessica L.; King, Lindsay Y.; Chung, Raymond T.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Boston, MA 02114 USA. [Simon, Tracey G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Makar, Robert S.] Massachusetts Gen Hosp, Dept Pathol, Blood Transfus Serv, Boston, MA 02114 USA. [Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM KARA.B.JOHNSON@GMAIL.COM; JMUELLER2@PARTNERS.ORG; TGSIMON@PARTNERS.ORG; HZHENG1@PARTNERS.ORG; LYKING@PARTNERS.ORG; RMAKAR@PARTNERS.ORG; DGERVAIS@PARTNERS.ORG; RTCHUNG@PARTNERS.ORG FU NIH [K24 DK078772, T32 DK007191] FX All of the authors had access to the study data and reviewed and approved the manuscript. The authors would like to gratefully acknowledge the assistance of Kent Eliason. The following authors would like to acknowledge NIH grants; these grants were not connected specifically to this project but contributed to the work. Raymond T. Chung MD: NIH K24 DK078772, Kara B. Johnson MD: NIH T32 DK007191, Jessica L. Mueller BA: NIH T32 DK007191, Lindsay Y. King MD, MPH: NIH T32 DK007191. NR 10 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUL PY 2015 VL 60 IS 7 BP 2190 EP 2195 DI 10.1007/s10620-015-3578-z PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CK2DT UT WOS:000356021500043 PM 25724164 ER PT J AU Iezzoni, LI Wint, AJ Smeltzer, SC Ecker, JL AF Iezzoni, Lisa I. Wint, Amy J. Smeltzer, Suzanne C. Ecker, Jeffrey L. TI "How did that happen?" Public responses to women with mobility disability during pregnancy SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Pregnancy; Public; Societal attitudes; Qualitative research ID CHRONIC PHYSICAL-DISABILITIES; US WOMEN; BREAST-CANCER; HEALTH-CARE; EXPERIENCES; PREVALENCE; DIAGNOSIS; BARRIERS AB Background: Little is known about current societal attitudes toward women with significant mobility disability who are visibly pregnant. Objective: To use qualitative descriptive analysis methods to examine perceptions of women with significant mobility disability about how strangers reacted to their visible pregnancies. Methods: In late 2013, we conducted 2-h telephone interviews with 22 women with significant mobility difficulties who had delivered babies within the prior 10 years. The semi-structured, open-ended interview protocol addressed wide-ranging pregnancy-related topics, including statements from strangers. Most participants were recruited through social networks, coming from 17 states nationwide. We used NVivo to sort the texts for content analysis. Results: The women's mean (standard deviation) age was 34.8 (5.3) years; most were white, well-educated, and higher income, although half had Medicaid during their pregnancies; and 18 used wheeled mobility aids. Eighteen women described memorable interactions with strangers relating to their pregnancies or newborn babies. Strangers' statements fell into six categories: (1) curious; (2) intrusively and persistently curious; (3) hostile, including concerns that taxpayers would end up supporting the mother and child; (4) questioning woman's competence as a potential parent; (5) oblivious, not recognizing visible pregnancy or motherhood; and (6) positive. Many women reported strangers asking how their pregnancy had happened. The women doubted that visibly pregnant women without disabilities evoke the same reactions from strangers. Conclusions: Women with mobility disability who are visibly pregnant may perceive reactions from strangers that appear intrusive. Planning ahead for handling such encounters could reduce the stresses of these interactions. (C) 2015 Elsevier Inc. All rights reserved. C1 [Iezzoni, Lisa I.; Wint, Amy J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Ecker, Jeffrey L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Ecker, Jeffrey L.] Harvard Univ, Sch Med, Dept Obstet & Gynecol, Cambridge, MA 02138 USA. [Smeltzer, Suzanne C.] Villanova Univ, Coll Nursing, Ctr Nursing Res, Villanova, PA 19085 USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@mgh.harvard.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [1R21HD068756-02] FX The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded this study (Grant No. 1R21HD068756-02). NR 26 TC 4 Z9 4 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD JUL PY 2015 VL 8 IS 3 BP 380 EP 387 DI 10.1016/j.dhjo.2015.02.002 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA CJ8QM UT WOS:000355768600011 PM 25944504 ER PT J AU Puzanov, I Amaravadi, RK McArthur, GA Flaherty, KT Chapman, PB Sosman, JA Ribas, A Shackleton, M Hwu, P Chmielowski, B Nolop, KB Lin, PS Kim, KB AF Puzanov, Igor Amaravadi, Ravi K. McArthur, Grant A. Flaherty, Keith T. Chapman, Paul B. Sosman, Jeffrey A. Ribas, Antoni Shackleton, Mark Hwu, Patrick Chmielowski, Bartosz Nolop, Keith B. Lin, Paul S. Kim, Kevin B. TI Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Vemurafenib; BRAF inhibitor; Metastatic melanoma ID METASTATIC MELANOMA; B-RAF; ACQUIRED-RESISTANCE; RESPONSE CRITERIA; BRAF INHIBITION; MEK INHIBITION; PLX4032; MUTATIONS; SURVIVAL; KINASE AB Introduction: Vemurafenib induces tumour regression in most patients with BRAF(V600E) - mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported. Methods: Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Results: Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (>= 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Conclusions: Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Puzanov, Igor; Sosman, Jeffrey A.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Amaravadi, Ravi K.] Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Amaravadi, Ravi K.] Univ Penn, Philadelphia, PA 19104 USA. [McArthur, Grant A.; Shackleton, Mark] Peter MacCallum Canc Ctr, East Melbourne, Vic 3002, Australia. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Chapman, Paul B.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Ribas, Antoni; Chmielowski, Bartosz] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Hwu, Patrick; Kim, Kevin B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Nolop, Keith B.; Lin, Paul S.] Plexxikon Inc, Berkeley, CA 94710 USA. RP Kim, KB (reprint author), Calif Pacific Med Ctr, Melanoma Clin Res Program, 2333 Buchanan St, San Francisco, CA 94115 USA. EM igor.puzanov@vanderbilt.edu; Ravi.Amaravadi@uphs.upenn.edu; grant.mcarthur@petermac.org; kflaherty@partners.org; chapmanp@mskcc.org; jeff.sosman@vanderbilt.edu; aribas@mednet.ucla.edu; Mark.Shackleton@petermac.org; phwu@mdanderson.org; BChmielowski@mednet.ucla.edu; easybreathe@msn.com; plin@plexxikon.com; KimKB@sutterhealth.org OI Chmielowski, Bartosz/0000-0002-2374-3320 FU F. Hoffmann-La Roche Ltd. FX This study was funded by F. Hoffmann-La Roche Ltd. NR 29 TC 17 Z9 19 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2015 VL 51 IS 11 BP 1435 EP 1443 DI 10.1016/j.ejca.2015.04.010 PG 9 WC Oncology SC Oncology GA CJ8HR UT WOS:000355741300010 PM 25980594 ER PT J AU Treister, R O'Neil, K Downs, HM Oaklander, AL AF Treister, R. O'Neil, K. Downs, H. M. Oaklander, A. L. TI Validation of the composite autonomic symptom scale 31 (COMPASS-31) in patients with and without small fiber polyneuropathy SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE autonomic function testing; autonomic nervous system; dysautonomia; neurodiagnostic skin biopsies; pain ID PRACTICE PARAMETER; SKIN BIOPSY; RECOMMENDATIONS AB Background and purposeThe recently developed composite autonomic symptom score 31 (COMPASS-31) is a questionnaire that assess symptoms of dysautonomia. It was distilled from the well-established Autonomic Symptom Profile questionnaire. COMPASS-31 has not yet been externally validated. To do so, its psychometric properties and convergent validity in patients with and without objective diagnosis of small fiber polyneuropathy (SFPN) were assessed. MethodsInternal validity and reliability of COMPASS-31 were assessed in participants with or without SFPN spanning the full range of severity of autonomic symptoms. Convergent validity was assessed by comparing results of the COMPASS-31 with the gold standard autonomic function testing that measures cardiovagal, adrenergic and sudomotor functions. Additionally, relationships between COMPASS-31 and the Short Form McGill Pain Questionnaire, Short Form Health Survey and 0-10 numeric pain scale were measured. COMPASS-31 and all other questionnaire results were compared between patients with or without evidence of SFPN, objectively confirmed by distal-leg PGP9.5-immunolabeled skin biopsy. ResultsAmongst 66 participants (28 SFPN+, 38 SFPN-), COMPASS-31 total scores had excellent internal validity (Cronbach's =0.919), test-retest reliability (r(s)=0.886; P<0.001) and good convergent validity (r(s)=0.474; P<0.001). COMPASS-31 scores differed between subjects with or without SFPN (Z=-3.296, P<0.001) and demonstrated fair diagnostic accuracy. Area under the Receiver Operating Characteristic curve was 0.749 (P=0.01, 95% confidence interval 0.627-0.871). ConclusionsCOMPASS-31 has good psychometric properties in the population of patients being evaluated for SFPN and thus it might be useful as an initial screening tool for the more expensive SFPN objective tests. C1 [Treister, R.; O'Neil, K.; Downs, H. M.; Oaklander, A. L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Treister, R.; O'Neil, K.; Downs, H. M.; Oaklander, A. L.] Harvard Univ, Sch Med, Boston, MA USA. [Oaklander, A. L.] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. RP Treister, R (reprint author), Massachusetts Gen Hosp, 275 Charles St Warren Bldg 310, Boston, MA 02114 USA. EM treister.roi@gmail.com FU US Department of Defense [GW093049]; Public Health Service [NINDS K24NS59892] FX Financial support was received from the US Department of Defense (GW093049) and the Public Health Service (NINDS K24NS59892). NR 16 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD JUL PY 2015 VL 22 IS 7 BP 1124 EP 1130 DI 10.1111/ene.12717 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK3BP UT WOS:000356090800015 PM 25907824 ER PT J AU Goldman, SM Umbach, DM Kamel, F Tanner, CM AF Goldman, S. M. Umbach, D. M. Kamel, F. Tanner, C. M. TI Head injury, alpha-synuclein Rep1 and Parkinson's disease: a meta-analytic view of gene-environment interaction SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Letter DE alpha-synuclein; epidemiology; gene-environment interaction; genetic association study; Parkinson's disease; traumatic brain injury C1 [Goldman, S. M.; Tanner, C. M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Goldman, S. M.; Tanner, C. M.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Umbach, D. M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Kamel, F.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Goldman, SM (reprint author), San Francisco VA Med Ctr, 4150 Clement St,Box 127-P, San Francisco, CA 94121 USA. EM samuel.goldman@ucsf.edu OI Kamel, Freya/0000-0001-5052-6615 NR 3 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD JUL PY 2015 VL 22 IS 7 BP E75 EP E75 DI 10.1111/ene.12694 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK3BP UT WOS:000356090800002 PM 26060929 ER PT J AU Sammon, JD Abdollah, F Reznor, G Pucheril, D Choueiri, TK Hu, JC Kim, SP Schmid, M Sood, A Sun, M Kibel, AS Nguyen, PL Menon, M Trinh, QD AF Sammon, Jesse D. Abdollah, Firas Reznor, Gally Pucheril, Daniel Choueiri, Toni K. Hu, Jim C. Kim, Simon P. Schmid, Marianne Sood, Akshay Sun, Maxine Kibel, Adam S. Nguyen, Paul L. Menon, Mani Quoc-Dien Trinh TI Patterns of Declining Use and the Adverse Effect of Primary Androgen Deprivation on All-cause Mortality in Elderly Men with Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Medicare; Androgen deprivation; SEER ID RADICAL PROSTATECTOMY; RADIATION-THERAPY; HORMONE-THERAPY; RADIOTHERAPY; DISEASE; LIFE; SUPPRESSION; IMMEDIATE; CARCINOMA; SURVIVAL AB Background: Primary androgen deprivation therapy (pADT) is commonly used to treat elderly men diagnosed with localized prostate cancer (CaP), despite the lack of evidence supporting its use. Objective: To examine the effect of pADT on mortality and to assess contemporary trends of pADT use in elderly men with CaP. Design, setting, and participants: Men older than 65 yr residing in Surveillance, Epidemiology, and End Results (SEER) registry areas diagnosed with localized or locally advanced CaP between 1992 and 2009 and not receiving definitive therapy. Outcome measurements and statistical analysis: Propensity score (PS)-weighted Cox proportional hazards models were used to estimate the effect of pADT use on overall survival among patients receiving pADT. The interaction between comorbidity-adjusted life expectancy (LE) and pADT use was assessed within the Cox and PS-weighted models. Contemporary (2004-2009) trends for pADT use were analyzed by linear regression. Results and limitations: The primary cohort included 46 376 men, of whom 17 873 received pADT (39%). Patients with >10 yr LE had lower pADT utilization rates than patients with short LE. Between 2004 and 2009, the use of pADT in men with localized CaP decreased by 14% (from 36% to 22%). Relative to observation, pADT was associated with a survival disadvantage, with a hazard ratio for all-cause mortality of 1.37 (95% confidence interval 1.20-1.56). Limitations included biases not accounted for by the PS-weighted model, changes in CaP staging over the study period, the absence of prostate-specific antigen (PSA) data prior to 2004, and the limits of retrospective analysis to demonstrate causality. Conclusions: The use of pADT in elderly men with localized CaP has decreased over time. For men forgoing primary definitive therapy, the use of pADT is not associated with a survival benefit compared to observation, and denies men an opportunity for cure with definitive therapy. The deleterious effect of pADT is most pronounced in men with prolonged LE. Patient summary: In this report, we assessed the effect of primary androgen deprivation (pADT) on prostate cancer mortality and determined current trends in the use of pADT. We showed that use of pADT in men aged >65 yr with localized prostate cancer has decreased over time. We also found that pADT is detrimental to men with localized prostate cancer, and particularly men with longer life expectancy. Therefore, we conclude that ADT should not be used as a primary treatment for men with prostate cancer that has not spread beyond the prostate. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Sammon, Jesse D.; Abdollah, Firas; Pucheril, Daniel; Sood, Akshay; Menon, Mani] Henry Ford Hlth Syst, VUI Ctr Outcomes Res Analyt & Evaluat, Detroit, MI USA. [Reznor, Gally; Schmid, Marianne; Kibel, Adam S.; Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Urol Surg,Brigham & Womens Hosp, Boston, MA 02115 USA. [Reznor, Gally; Schmid, Marianne; Kibel, Adam S.; Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Surg & Publ Hlth,Brigham & Womens Hosp, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Brigham & Womens Hosp, Boston, MA 02115 USA. [Hu, Jim C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Kim, Simon P.] Yale Univ, Dept Urol, New Haven, CT USA. [Sun, Maxine] Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, Montreal, PQ, Canada. [Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp, Boston, MA 02115 USA. RP Trinh, QD (reprint author), Ctr Surg & Publ Hlth, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. EM qtrinh@partners.org FU Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital FX Quoc-Dien Trinh is supported by the Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital. NR 29 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD JUL PY 2015 VL 68 IS 1 BP 32 EP 39 DI 10.1016/j.eururo.2014.10.018 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CK0YO UT WOS:000355932000014 PM 25457017 ER PT J AU Fizazi, K Massard, C Smith, M Rader, M Brown, J Milecki, P Shore, N Oudard, S Karsh, L Carducci, M Damiao, R Wang, H Ying, W Goessl, C AF Fizazi, Karim Massard, Christophe Smith, Matthew Rader, Michael Brown, Janet Milecki, Piotr Shore, Neal Oudard, Stephane Karsh, Lawrence Carducci, Michael Damiao, Ronaldo Wang, Huei Ying, Wendy Goessl, Carsten TI Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Castration-resistant prostate cancer; Bone metastases; Survival; Prognostic factors; Nomogram ID CHEMOTHERAPY; MARKERS; MODEL AB Background: Previous studies have reported on prognostic factors for castration-resistant prostate cancer (CRPC); however, most of these studies were conducted before docetaxel chemotherapy was approved for CRPC. Objective: To evaluate the prognostic value of multiple parameters in men with bone metastases due to CRPC using a contemporary dataset. Design, setting, and participants: The analysis included 1901 patients with metastatic CRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial conducted between May 2006 and October 2009. Outcome measures and statistical analysis: We developed multivariate validated Cox proportional hazards models and nomograms to estimate 12-mo and 24-mo survival probabilities and median survival time. Results and limitations: The median (95% confidence interval) overall survival was 20 (18, 21) mo. The final model included 12 of the 15 potential prognostic variables evaluated (concordance index 0.72). Seven bone-related variables were associated with longer survival in the final model: alkaline phosphatase <= 143 U/l (p < 0.0001); bone-specific alkaline phosphatase (BSAP) < 146 U/l (p < 0.0001); corrected urinary N-telopeptide (uNTx) <= 50 nmol/mmol (p = 0.0008); mild or no pain (Brief Pain Inventory-Short Form [BPI-SF] score <= 4) (p < 0.0001); no previous skeletal-related event (SRE; p = 0.0002); longer time from initial diagnosis to first bone metastasis (p < 0.0001); and longer time from first bone metastasis to randomization (p < 0.0001). Other significant predictors of improved survival included prostate-specific antigen (PSA) level < 10 ng/ml (p < 0.0001), hemoglobin >128 g/l (p < 0.0001), absence of visceral metastases (p < 0.0001), Eastern Co-operative Oncology Group (ECOG) score <= 1 (p = 0.017), and younger age (p = 0.008). Nomograms were generated based on the parameters included in the final validated models (with/without uNTx and BSAP). One limitation was that lactate dehydrogenase (LDH) levels, a known prognostic factor, were not available in this study. Conclusions: Bone-related parameters are strong prognostic variables for overall survival in patients with bone metastases from CRPC. Patient summary: Survival time is variable in patients with bone metastases from prostate cancer. We found that factors related to bone help to predict how long a patient will live. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Fizazi, Karim; Massard, Christophe] Univ Paris 11, Inst Gustave Roussy, F-94800 Villejuif, France. [Smith, Matthew] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Rader, Michael] Nyack Hosp, Nyack, NY USA. [Brown, Janet] Canc Res UK Expt Canc Med Ctr, Leeds, W Yorkshire, England. [Brown, Janet] Canc Res UK Expt Canc Med Ctr, Sheffield, S Yorkshire, England. [Milecki, Piotr] Med Univ, Dept Radiotherapy, Greater Poland Canc Ctr, Poznan, Poland. [Milecki, Piotr] Med Univ, Dept Electroradiol, Poznan, Poland. [Shore, Neal] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Oudard, Stephane] Hop Europeen Georges Pompidou, Paris, France. [Karsh, Lawrence] Urol Ctr Colorado, Denver, CO USA. [Carducci, Michael] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Damiao, Ronaldo] Univ Pedro Ernesto, Rio De Janeiro, Brazil. [Wang, Huei; Ying, Wendy; Goessl, Carsten] Amgen Inc, Thousand Oaks, CA 91320 USA. RP Fizazi, K (reprint author), Univ Paris 11, Inst Gustave Roussy, Dept Canc Med, 39 Rue Camille Desmoulins, F-94800 Villejuif, France. EM karim.fizazi@igr.fr FU Amgen Inc. (Thousand Oaks, CA, USA) FX Amgen Inc. (Thousand Oaks, CA, USA) sponsored this study/analysis and was involved in the design and conduct of the study; management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. NR 27 TC 19 Z9 19 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD JUL PY 2015 VL 68 IS 1 BP 42 EP 50 DI 10.1016/j.eururo.2014.10.001 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CK0YO UT WOS:000355932000016 PM 25449207 ER PT J AU Volpe, A Blute, ML Ficarra, V Gill, IS Kutikov, A Porpiglia, F Rogers, C Touijer, KA Van Poppel, H Thompson, RH AF Volpe, Alessandro Blute, Michael L. Ficarra, Vincenzo Gill, Inderbir S. Kutikov, Alexander Porpiglia, Francesco Rogers, Craig Touijer, Karim A. Van Poppel, Hendrik Thompson, R. Houston TI Renal Ischemia and Function After Partial Nephrectomy: A Collaborative Review of the Literature SO EUROPEAN UROLOGY LA English DT Review DE Ischemia; Nephron-sparing surgery; Partial nephrectomy; Renal cell carcinoma; Renal function ID LAPAROSCOPIC PARTIAL NEPHRECTOMY; NEPHRON-SPARING SURGERY; ROBOTIC PARTIAL NEPHRECTOMY; PARENCHYMAL VOLUME PRESERVATION; ASSISTED PARTIAL NEPHRECTOMY; GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; WARM ISCHEMIA; LONG-TERM; SERUM CREATININE AB Context: Partial nephrectomy (PN) is the current gold standard treatment for small localized renal tumors.; however, the impact of duration and type of intraoperative ischemia on renal function (RF) after PN is a subject of significant debate. Objective: To review the current evidence on the relationship of intraoperative ischemia and RF after PN. Evidence acquisition: A review of English-language publications on renal ischemia and RF after PN was performed from 2005 to 2014 using the Medline, Embase, and Web of Science databases. Ninety-one articles were selected with the consensus of all authors and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Evidence synthesis: The vast majority of reviewed studies were retrospective, nonrandomized observations. Based on the current literature, RF recovery after PN is strongly associated with preoperative RF and the amount of healthy kidney parenchyma preserved. Warm ischemia time (WIT) is modifiable and prolonged warm ischemia is significantly associated with adverse postoperative RF. Available data suggest a benefit of keeping WIT <25 min, although the level of evidence to support this threshold is limited. Cold ischemia safely facilitates longer durations of ischemia. Surgical techniques that minimize or avoid global ischemia may be associated with improved RF outcomes. Conclusions: Although RF recovery after PN is strongly associated with quality and quantity of preserved kidney, efforts should be made to limit prolonged WIT. Cold ischemia should be preferred when longer ischemia is expected, especially in presence of imperative indications for PN. Additional research with higher levels of evidence is needed to clarify the optimal use of renal ischemia during PN. Patient summary: In this review of the literature, we looked at predictors of renal function after surgical resection of renal tumors. There is a strong association between the quality and quantity of renal tissue that is preserved after surgery and long-term renal function. The time of interruption of renal blood flow during surgery is an important, modifiable predictor of postoperative renal function. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Volpe, Alessandro] Univ Piemonte Orientale, Div Urol, Maggiore Carita Hosp, Dept Translat Med, I-28100 Novara, Italy. [Blute, Michael L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. [Ficarra, Vincenzo] Univ Udine, Div Urol, Dept Expt & Clin Med Sci, I-33100 Udine, Italy. [Gill, Inderbir S.] Univ So Calif, Keck Sch Med, Catherine & Joseph Aresty Dept Urol, USC Inst Urol, Los Angeles, CA 90033 USA. [Kutikov, Alexander] Fox Chase Canc Ctr, Dept Surg Oncol, Div Urol Oncol, Philadelphia, PA 19111 USA. [Porpiglia, Francesco] Univ Turin, Dept Oncol, Div Urol, San Luigi Hosp, Turin, Italy. [Rogers, Craig] Henry Ford Hosp, Vattikuti Urol Inst, Detroit, MI 48202 USA. [Touijer, Karim A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Van Poppel, Hendrik] Univ Ziekenhuis Gasthuisberg, Leuven Canc Inst, Dept Urol, Leuven, Belgium. [Thompson, R. Houston] Mayo Clin, Dept Urol, Rochester, MN USA. RP Volpe, A (reprint author), Univ Piemonte Orientale, Div Urol, Maggiore Carita Hosp, Corso Mazzini 18, I-28100 Novara, Italy. EM alessandro.volpe@med.unipmn.it OI PORPIGLIA, Francesco/0000-0002-0752-4857 NR 94 TC 40 Z9 41 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD JUL PY 2015 VL 68 IS 1 BP 61 EP 74 DI 10.1016/j.eururo.2015.01.025 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA CK0YO UT WOS:000355932000020 PM 25703575 ER PT J AU Mashmoushi, AK Oates, JC AF Mashmoushi, Ahmad K. Oates, Jim C. TI Lipopolysaccharide induces inducible nitric oxide synthase-dependent podocyte dysfunction via a hypoxia-inducible factor 1 alpha and cell division control protein 42 and Ras-related C3 botulinum toxin substrate 1 pathway SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Podocyte; Toll-like receptor 4; Nitric oxide; Superoxide; Lipopolysaccharide; Hypoxia-inducible factor 1 alpha; Cell division control protein 42; Ras-related C3 botulinum toxin substrate 1; Inducible nitric oxide synthase; Lupus nephritis; Peroxynitrite Free radicals ID TOLL-LIKE RECEPTORS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; IN-VIVO; AUTOIMMUNE-DISEASE; NEPHROTIC SYNDROME; MRL/LPR MICE; EXPRESSION; KIDNEY; NEPHRITIS; INJURY AB Urine protein loss in immune complex-mediated diseases such as lupus nephritis is associated with podocyte foot process effacement (podocytopathy) but is not always dependent on glomerular immune complex deposition. Several murine and human studies have associated lupus nephritis with inducible nitric oxide synthase (iNOS) expression in what appear to be podocytes. This study was conducted to determine mechanisms of immune-complex-independent and iNOS-dependent podocyte dysfunction. Conditionally immortalized podocytes were Cultured with lipopolysaccharide (LPS) and nitric oxide (NO), superoxide (SO), or peroxynitrite donors in the presence or absence of inhibitors of iNOS, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase or monocyte chemotactic protein 1 (MCP-1), or with sepiapterin to increase coupling of iNOS homodimers. Podocyte NO, SO, and MCP-1 production and nitrotyrosine modifications were determined. The podocytopathy phenotype was determined by measuring cell Motility and membrane permeability to albumin. This study determined that NO produced by iNOS is sufficient and necessary to induce podocytopathy. NO probably induces this phenotype via hypoxia-inducible factor, its and cell division control protein 42 and Ras-related C3 botulinum toxin substrate 1 pathways. With LPS stimulation, neither SO nor peroxynitrite produced by uncoupled iNOS or NADPH oxidase nor MCP-1 was sufficient to induce the full phenotype. This study supports the notion that iNOS may induce autocrine podocyte dysfunction. Thus, targeting iNOS or the pathways of its induction may have therapeutic benefit. Published by Elsevier Inc. C1 [Mashmoushi, Ahmad K.; Oates, Jim C.] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Oates, Jim C.] Ralph H Johnson VA Med Ctr, Rheumatol Sect, Med Serv, Charleston, SC 29401 USA. RP Oates, JC (reprint author), Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. EM oatesjc@musc.edu FU Veterans Affairs Administration [5I01CX000218]; National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR045476] FX We give special thanks to Dr. Jeffery Kopp at the National Institute of Diabetes, Digestive, and Kidney Diseases in Bethesda, Maryland, for generously providing the conditionally immortalized podocytes. Thanks go to Dr. Julie Chao for technical assistance with the lucigenin assay protocol and Ms. May Amria for assistance with the transepithelial resistance assay. This work was funded by grants from the Veterans Affairs Administration (VA Merit Project 5I01CX000218) and the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR045476). None of these funding agencies played a role in the design, conduct, or reporting of this study. NR 57 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2015 VL 84 BP 185 EP 195 DI 10.1016/j.freeradbiomed.2015.02.031 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CK0LK UT WOS:000355896500017 PM 25765888 ER PT J AU Hung, J Capoulade, R AF Hung, Judy Capoulade, Romain TI Therapy for secondary mitral regurgitation: time to 'cut the chord'? SO HEART LA English DT Editorial Material C1 [Hung, Judy; Capoulade, Romain] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Hung, J (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Blake 256,55 Fruit St, Boston, MA 02114 USA. EM JHUNG@mgh.harvard.edu FU NHLBI NIH HHS [5 U01 HL088942, R01 HL092101] NR 9 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD JUL 1 PY 2015 VL 101 IS 13 BP 996 EP 997 DI 10.1136/heartjnl-2015-307473 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK4FM UT WOS:000356177600002 PM 25810156 ER PT J AU Harinstein, ME Butler, J Greene, SJ Fonarow, GC Stockbridge, NL O'Connor, CM Pfeffer, MA Mehra, MR Solomon, SD Yancy, CW Fiuzat, M Mentz, RJ Collins, SP McMurray, JJV Vaduganathan, M Dunnmon, PM Rosano, GMC Dinh, W Misselwitz, F Bonow, RO Gheorghiade, M AF Harinstein, Matthew E. Butler, Javed Greene, Stephen J. Fonarow, Gregg C. Stockbridge, Norman L. O'Connor, Christopher M. Pfeffer, Marc A. Mehra, Mandeep R. Solomon, Scott D. Yancy, Clyde W. Fiuzat, Mona Mentz, Robert J. Collins, Sean P. McMurray, John J. V. Vaduganathan, Muthiah Dunnmon, Preston M. Rosano, Giuseppe M. C. Dinh, Wilfried Misselwitz, Frank Bonow, Robert O. Gheorghiade, Mihai TI Site selection for heart failure clinical trials in the USA SO HEART FAILURE REVIEWS LA English DT Article DE Clinical trials; Site selection; Heart failure; United States; Outcomes ID PRESERVED EJECTION FRACTION; VASOPRESSIN ANTAGONISM; MYOCARDIAL-INFARCTION; THROMBUS ASPIRATION; EVEREST EFFICACY; UNITED-STATES; OUTCOMES; TOLVAPTAN; REGISTRY; PROGRAM AB There are more than 1 million primary hospitalizations for heart failure (HF) annually in the USA alone, and post-discharge outcomes remain persistently poor despite available therapies and quality improvement initiatives. Recent international randomized clinical trials in hospitalized HF have repeatedly failed to improve this post-discharge event rate. A potential reason for this persistent lack of clinical trial success that has not previously received significant attention relates to site selection and the generally low level of patient enrollment from the USA. Only similar to 5 % of US hospitals participate in clinical trials, and in four recent randomized trials of hospitalized HF, only one-third of patients were enrolled in North America. This poor participation among US centers has necessitated disproportionate enrollment from non-US sites. Regional variations in HF patient characteristics and clinical outcomes are well documented, and a lack of US patient representation in clinical trials limits the generalizability of results and presents obstacles for US regulatory agency approval. There are multiple impediments to successful US enrollment including a lack of incentive for investigators and institutions, the relative value unit-based compensation system, poor institutional framework for identification of appropriate patients, and increasing liability to conduct trials. In this manuscript, we specifically identify barriers to successful hospitalized HF clinical trial participation in the USA and suggest possible solutions. C1 [Harinstein, Matthew E.] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Butler, Javed] SUNY Stony Brook, Sch Med, Div Cardiol, Stony Brook, NY 11794 USA. [Greene, Stephen J.; Bonow, Robert O.; Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Chicago, IL 60611 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Stockbridge, Norman L.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [O'Connor, Christopher M.; Fiuzat, Mona; Mentz, Robert J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Pfeffer, Marc A.; Mehra, Mandeep R.; Solomon, Scott D.] Brigham & Womens Hosp, Heart & Vasc Ctr, Boston, MA 02115 USA. [Pfeffer, Marc A.; Mehra, Mandeep R.; Solomon, Scott D.] Harvard Univ, Sch Med, Boston, MA USA. [Yancy, Clyde W.] Northwestern Univ, Div Cardiol, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Collins, Sean P.] Vanderbilt Univ, Sch Med, Dept Emergency Med, Nashville, TN 37212 USA. [McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Vaduganathan, Muthiah] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dunnmon, Preston M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Rosano, Giuseppe M. C.] IRCC San Raffaele, Div Cardiol, Rome, Italy. [Dinh, Wilfried; Misselwitz, Frank] Bayer Pharma AG, Global Drug Discovery, Clin Sci, Expt Med, Berlin, Germany. [Dinh, Wilfried] Univ Witten Herdecke, Dept Cardiol, Witten, Germany. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 201 East Huron St,Galter 3-150, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu OI Mehra, Mandeep/0000-0001-8683-7044; mcmurray, john/0000-0002-6317-3975 FU National Institutes of Health; European Union; Health Resource Services Administration; Food and Drug Administration; Amgen; Celladon; Novartis; Sanofi-Aventis; AstraZeneca; Bristol-Myers Squibb; GlaxoSmithKline; Gilead; Otsuka; ResMed; NIH/NHLBI; Medtronic; Cardiorentis; Abbott Point-of-Care; Medicines Company; Astellas; Bayer Schering Pharma AG; DebioPharm S.A.; Novartis Pharma AG; Otsuka Pharmaceuticals; Sigma Tau; Solvay Pharmaceuticals; Sticares InterACT; Takeda Pharmaceuticals North America, Inc. FX JB.: Research support: National Institutes of Health, European Union, Health Resource Services Administration, Food and Drug Administration, Consultant: Amgen, Bayer, Celladon, Gambro, GE Healthcare, Janssen, Medtronic, Novartis, Ono, Relypsa, Trevena, Stock options: Stemedica; G. C. F.: Research AHRQ significant, NHLBI significant, Consultant: Novartis significant, Medtronic modest, Bayer modest, Gambro modest, Janssen modest; C. M. O.: none; M.A.P.: Research Support: Amgen, Celladon, Novartis, Sanofi-Aventis, Consultant: Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Fibrogen, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Roche, Servier, Teva, University of Oxford; M. R. M.: Consultant: Boston Scientific, St. Jude's, Medtronic, Johnson and Johnson, ABIM, NIH/NHLBI, Baxter, Abbott Vascular, Thoratec; R. J. M. receives research support from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, Otsuka, and ResMed; honoraria from Thoratec; and has served on an advisory board for Luitpold Pharmaceuticals, Inc; S. P. C.: Research support: NIH/NHLBI, Medtronic, Cardiorentis, Abbott Point-of-Care, Novartis, The Medicines Company, Astellas, Consultant: Trevena, Novartis, Otsuka, Radiometer, The Medicines Company, Medtronic, BRAHMS, Insys; J. J. V. M.: none; W. D. is a full time employee of Bayer Pharma; F. M. is a full time employee of Bayer Pharma; M. G.: Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S. A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson and Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT,Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT and Takeda Pharmaceuticals North America, Inc. All others authors report no conflicts of interest. NR 43 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 EI 1573-7322 J9 HEART FAIL REV JI Heart Fail. Rev. PD JUL PY 2015 VL 20 IS 4 BP 375 EP 383 DI 10.1007/s10741-015-9473-z PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK2KK UT WOS:000356039000001 PM 25649127 ER PT J AU Vaduganathan, M Butler, J Roessig, L Fonarow, GC Greene, SJ Metra, M Cotter, G Kupfer, S Zalewski, A Sato, N Filippatos, G Gheorghiade, M AF Vaduganathan, Muthiah Butler, Javed Roessig, Lothar Fonarow, Gregg C. Greene, Stephen J. Metra, Marco Cotter, Gadi Kupfer, Stuart Zalewski, Andrew Sato, Naoki Filippatos, Gerasimos Gheorghiade, Mihai TI Clinical trials in hospitalized heart failure patients: targeting interventions to optimal phenotypic subpopulations SO HEART FAILURE REVIEWS LA English DT Article DE Clinical trials; Heart failure; Outcomes; Patient selection ID RELAX-AHF; EJECTION FRACTION; DRUG DEVELOPMENT; END-POINTS; STRATEGIES; GUIDELINES; REGISTRIES; SERELAXIN; TOLVAPTAN; ADMISSION AB With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?. C1 [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Butler, Javed] Emory Univ Hosp, Div Cardiol, Atlanta, GA 30322 USA. [Roessig, Lothar] Novartis Pharmaceut, E Hanover, NJ USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Greene, Stephen J.; Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Chicago, IL 60611 USA. [Metra, Marco] Univ Brescia, Div Cardiol, Brescia, Italy. [Cotter, Gadi] Momentum Res Inc, Durham, NC USA. [Kupfer, Stuart] Takeda Global Res & Dev Ctr Inc, Deerfield, IL USA. [Zalewski, Andrew] Bayer Pharma AG, Berlin, Germany. [Sato, Naoki] Musashi Kosugi Hosp, Dept Internal Med & Cardiol, Nippon Med Sch, Kawasaki, Kanagawa, Japan. [Filippatos, Gerasimos] Attikon Univ Hosp, Athens, Greece. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 201 East Huron St,Galter 3-150, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu OI Metra, Marco/0000-0001-6691-8568 FU National Institutes of Health; European Union; Health Resource Services Administration; Food and Drug Administration; Agency for Healthcare Research and Quality FX Javed Butler: Research Support: National Institutes of Health, European Union, Health Resource Services Administration, Food and Drug Administration; Consultant: Amgen, Bayer, Celladon, Gambro, GE Healthcare, Janssen, Medtronic, Novartis, Ono, Relypsa, Trevena; Stock Options: Stemedica. Lothar Roessig: Employee of Bayer Pharma AG. Gregg C Fonarow: Research support: Agency for Healthcare Research and Quality (significant), Consultant: Medtronic (modest), Gambro (significant), and Novartis (significant). Marco Metra: Received honoraria from Bayer, Corthera, Novartis, and Servier for speeches or participation in advisory boards/steering committees. Gadi Cotter: Employee of Momentum-Research, Inc. Stuart Kupfer: Employee of Takeda Global Research and Development Center, Inc. Andrew Zalewski: Employee of Novartis Pharmaceutical Corporation. Naoki Sato: Consultant to Chugai Pharmaceutical Company and honoraria from Daiichi-Sankyo, Otsuka, Philips Respironics, Astellas, Ono, Eisai, Chugai, Mitsubishi-Tanabe, Sanofi-Aventis, and Novartis pharmaceuticals. Mihai Gheorghiade: Consultant for Abbott Laboratories, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera, Cytokinetics, DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceutical and Trevena Therapeutics. Muthiah Vaduganathan, Stephen J Greene, and Gerasimos Filippatos have no conflicts of interest or financial ties to disclose. NR 32 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 EI 1573-7322 J9 HEART FAIL REV JI Heart Fail. Rev. PD JUL PY 2015 VL 20 IS 4 BP 393 EP 400 DI 10.1007/s10741-015-9485-8 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK2KK UT WOS:000356039000003 PM 25894076 ER PT J AU Yoong, SL Hall, A Williams, CM Skelton, E Oldmeadow, C Wiggers, J Karimkhani, C Boyers, LN Dellavalle, RP Hilton, J Wolfenden, L AF Yoong, Sze Lin Hall, Alix Williams, Christopher M. Skelton, Eliza Oldmeadow, Christopher Wiggers, John Karimkhani, Chante Boyers, Lindsay N. Dellavalle, Robert P. Hilton, John Wolfenden, Luke TI Alignment of systematic reviews published in the Cochrane Database of Systematic Reviews and the Database of Abstracts and Reviews of Effectiveness with global burden-of-disease data: a bibliographic analysis SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Review ID HEALTH-CARE; ASSOCIATION AB Background Systematic reviews of high-quality evidence are used to inform policy and practice. To improve community health, the production of such reviews should align with burden of disease. This study aims to assess if the volume of research output from systematic reviews proportionally aligns with burden of disease assessed using percentages of mortality and disability-adjusted life years (DALYs). Methods A cross-sectional audit of reviews published between January 2012 and August 2013 in the Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE) was undertaken. Percentages of mortality and DALYs were obtained from the 2010 Global Burden of Disease study. Standardised residual differences (SRD) based on percentages of mortality and DALYs were calculated, where conditions with SRD of more than or less than three were considered overstudied or understudied, respectively. Results 1029 reviews from CDSR and 1928 reviews from DARE were examined. There was a significant correlation between percentage DALYs and systematic reviews published in CDSR and DARE databases (CDSR: r=0.68, p=0.001; DARE: r=0.60, p<0.001). There was no significant correlation between percentage mortality and number of systematic reviews published in either database (CDSR: r=0.34, p=0.14; DARE: r=0.22, p=0.34). Relative to percentage of mortality, mental and behavioural disorders, musculoskeletal conditions and other non-communicable diseases were overstudied. Maternal disorders were overstudied relative to percentages of mortality and DALYs in CDSR. Conclusions The focus of systematic reviews is moderately correlated with DALYs. A number of conditions may be overstudied relative to percentage of mortality particularly in the context of health and medical reviews. C1 [Yoong, Sze Lin; Williams, Christopher M.; Wiggers, John; Wolfenden, Luke] Hunter New England Populat Hlth, Wallsend, NSW 2287, Australia. [Yoong, Sze Lin; Hall, Alix; Williams, Christopher M.; Skelton, Eliza; Oldmeadow, Christopher; Wiggers, John; Wolfenden, Luke] Univ Newcastle, Sch Med & Publ Hlth, Callaghan, NSW 2308, Australia. [Yoong, Sze Lin; Hall, Alix; Williams, Christopher M.; Oldmeadow, Christopher; Wiggers, John; Wolfenden, Luke] Hunter Med Res Inst, New Lambton, NSW, Australia. [Oldmeadow, Christopher] George Inst Global Hlth, Sydney, NSW, Australia. [Karimkhani, Chante] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Boyers, Lindsay N.] Georgetown Univ, Sch Med, Washington, DC USA. [Dellavalle, Robert P.] Dermatol Serv, US Dept Vet Affairs, Eastern Colorado Hlth Care Syst, Denver, CO USA. [Dellavalle, Robert P.] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Hilton, John] Cochrane Collaborat, Cochrane Editorial Unit, London, England. RP Yoong, SL (reprint author), Hunter New England Populat Hlth, Locked Bag 10, Wallsend, NSW 2287, Australia. EM Serene.Yoong@hnehealth.nsw.gov.au OI Hilton, John/0000-0002-1607-3250; Wolfenden, Luke/0000-0002-6178-3868 FU Australian National and Medical Research Council Career Development Fellowship [APP1041867]; US Department of Veterans Affairs; Centers for Disease Control and Prevention [CDC 3U48DP001938-0451]; National Institutes of Health [NCI R21 CA173654] FX This work was supported by the Hunter Medical Research Institute and Hunter New England Population Health through providing infrastructure support. LW is supported by an Australian National and Medical Research Council Career Development Fellowship APP1041867. RPD is supported by a salary from the US Department of Veterans Affairs and grants from the Centers for Disease Control and Prevention (CDC 3U48DP001938-0451 (PI:Crane), and the National Institutes of Health (NCI R21 CA173654 (PI:Walkocz). JH is an employee of The Cochrane Collaboration which produces the Cochrane Database of Systematic Reviews. NR 32 TC 1 Z9 1 U1 2 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD JUL PY 2015 VL 69 IS 7 BP 708 EP 714 DI 10.1136/jech-2014-205389 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK4BS UT WOS:000356164200017 PM 25888595 ER PT J AU Paithankar, DY Sakamoto, FH Farinelli, WA Kositratna, G Blomgren, RD Meyer, TJ Faupel, LJ Kauvar, ANB Lloyd, JR Cheung, WL Owczarek, WD Suwalska, AM Kochanska, KB Nawrocka, AK Paluchowska, EB Podolec, KM Pirowska, MM Wojas-Pelc, AB Anderson, RR AF Paithankar, Dilip Y. Sakamoto, Fernanda H. Farinelli, William A. Kositratna, Garuna Blomgren, Richard D. Meyer, Todd J. Faupel, Linda J. Kauvar, Arielle N. B. Lloyd, Jenifer R. Cheung, Wang L. Owczarek, Witold D. Suwalska, Anna M. Kochanska, Katarzyna B. Nawrocka, Agnieszka K. Paluchowska, Elwira B. Podolec, Katarzyna M. Pirowska, Magdalena M. Wojas-Pelc, Anna B. Anderson, R. Rox TI Acne Treatment Based on Selective Photothermolysis of Sebaceous Follicles with Topically Delivered Light-Absorbing Gold Microparticles SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID FREE-ELECTRON LASER; 13-CIS-RETINOIC ACID; PHOTODYNAMIC THERAPY; AMINOLEVULINIC ACID; HAIR-FOLLICLES; DRUG-DELIVERY; SKIN; VULGARIS; NANOPARTICLES; MICROSPHERES AB The pathophysiology of acne vulgaris depends on active sebaceous glands, implying that selective destruction of sebaceous glands could be an effective treatment. We hypothesized that light-absorbing microparticles could be delivered into sebaceous glands, enabling local injury by optical pulses. A suspension of topically applied gold-coated silica microparticles exhibiting plasmon resonance with strong absorption at 800 nm was delivered into human pre-auricular and swine sebaceous glands in vivo, using mechanical vibration. After exposure to 1050 J cm(-2), 30 milliseconds, 800 nm diode laser pulses, microscopy revealed preferential thermal injury to sebaceous follicles and glands, consistent with predictions from a computational model. Inflammation was mild; gold particles were not retained in swine skin 1 month after treatment, and uptake in other organs was negligible. Two independent prospective randomized controlled clinical trials were performed for treatment of moderate-to-severe facial acne, using unblinded and blinded assessments of disease severity. Each trial showed clinically and statistically significant improvement of inflammatory acne following three treatments given 1-2 weeks apart. In Trial 2, inflammatory lesions were significantly reduced at 12 weeks (P = 0.015) and 16 weeks (P = 0.04) compared with sham treatments. Optical microparticles enable selective photothermolysis of sebaceous glands. This appears to be a well-tolerated, effective treatment for acne vulgaris. C1 [Paithankar, Dilip Y.; Blomgren, Richard D.; Meyer, Todd J.; Faupel, Linda J.] Sebacia, Duluth, GA USA. [Sakamoto, Fernanda H.; Farinelli, William A.; Kositratna, Garuna; Anderson, R. Rox] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Sakamoto, Fernanda H.; Farinelli, William A.; Kositratna, Garuna; Anderson, R. Rox] Harvard Univ, Sch Med, Boston, MA USA. [Kauvar, Arielle N. B.] New York Laser & Skin Care, New York, NY USA. [Lloyd, Jenifer R.] Lloyd Dermatol & Laser Ctr, Youngstown, OH USA. [Cheung, Wang L.] Univ Arkansas, Dept Pathol, Little Rock, AR 72204 USA. [Owczarek, Witold D.; Suwalska, Anna M.; Kochanska, Katarzyna B.; Nawrocka, Agnieszka K.; Paluchowska, Elwira B.] Mil Inst Med, Dept Dermatol, Warsaw, Poland. [Podolec, Katarzyna M.; Pirowska, Magdalena M.; Wojas-Pelc, Anna B.] Jagiellonian Univ, Dept Dermatol, Krakow, Poland. RP Paithankar, DY (reprint author), Sebacia Inc, 2905 Premiere Pkwy,Suite 150, Duluth, GA 30097 USA. EM dilip@sebacia.com FU Sebacia, Duluth, GA FX This research was sponsored by Sebacia, Duluth, GA. We acknowledge Apostolos G. Doukas, Stephanie Beall, and Anthony Lando for help with various stages of the project. NR 30 TC 9 Z9 10 U1 4 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2015 VL 135 IS 7 BP 1727 EP 1734 DI 10.1038/jid.2015.89 PG 8 WC Dermatology SC Dermatology GA CK4GB UT WOS:000356180100011 PM 25748556 ER PT J AU Lauss, M Haq, R Cirenajwis, H Phung, B Harbst, K Staaf, J Rosengren, F Holm, K Aine, M Jirstrom, K Borg, A Busch, C Geisler, J Lonning, PE Ringner, M Howlin, J Fisher, DE Jonsson, G AF Lauss, Martin Haq, Rizwan Cirenajwis, Helena Phung, Bengt Harbst, Katja Staaf, Johan Rosengren, Frida Holm, Karolina Aine, Mattias Jirstrom, Karin Borg, Ake Busch, Christian Geisler, Jurgen Lonning, Per E. Ringner, Markus Howlin, Jillian Fisher, David E. Jonsson, Goran TI Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID MICROPHTHALMIA TRANSCRIPTION FACTOR; MAPK PATHWAY INHIBITORS; MALIGNANT-MELANOMA; GENE; CANCER; MUTATIONS; PROFILES; SURVIVAL; HYPERMETHYLATION; MELANOCYTES AB The microphthalmia-associated transcription factor (MITF) is a key regulator of melanocyte development and a lineage-specific oncogene in melanoma; a highly lethal cancer known for its unpredictable clinical course. MITF is regulated by multiple intracellular signaling pathways, although the exact mechanisms that determine MITF expression and activity remain incompletely understood. In this study, we obtained genome-wide DNA methylation profiles from 50 stage IV melanomas, normal melanocytes, keratinocytes, and dermal fibroblasts and utilized The Cancer Genome Atlas data for experimental validation. By integrating DNA methylation and gene expression data, we found that hypermethylation of MITF and its co-regulated differentiation pathway genes corresponded to decreased gene expression levels. In cell lines with a hypermethylated MITF-pathway, overexpression of MITF did not alter the expression level or methylation status of the MITF pathway genes. In contrast, however, demethylation treatment of these cell lines induced MITF-pathway activity, confirming that gene regulation was controlled via methylation. The discovery that the activity of the master regulator of pigmentation, MITF, and its downstream targets may be regulated by hypermethylation has significant implications for understanding the development and evolvement of melanoma. C1 [Lauss, Martin; Cirenajwis, Helena; Phung, Bengt; Harbst, Katja; Staaf, Johan; Rosengren, Frida; Holm, Karolina; Aine, Mattias; Jirstrom, Karin; Borg, Ake; Ringner, Markus; Howlin, Jillian; Jonsson, Goran] Lund Univ, Div Oncol & Pathol, Dept Clin Sci, S-22381 Lund, Sweden. [Lauss, Martin; Cirenajwis, Helena; Harbst, Katja; Staaf, Johan; Holm, Karolina; Borg, Ake; Ringner, Markus; Jonsson, Goran] Lund Univ, CREATE Hlth Strateg Ctr Translat Canc Res, Lund, Sweden. [Haq, Rizwan; Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Haq, Rizwan; Fisher, David E.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Jirstrom, Karin] Skane Univ Hosp, Dept Clin Pathol, Lund, Sweden. [Busch, Christian; Lonning, Per E.] Univ Bergen, Inst Med, Sect Oncol, Bergen, Norway. [Geisler, Jurgen] Akershus Univ Hosp, Dept Clin Mol Biol & Lab Sci, Lorenskog, Norway. [Geisler, Jurgen] Univ Oslo, Inst Clin Med, Oslo, Norway. RP Jonsson, G (reprint author), Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Scheelevagen 2, S-22381 Lund, Sweden. EM Goran_B.Jonsson@med.lu.se RI Ringner, Markus/G-3641-2011; OI Ringner, Markus/0000-0001-5469-8940; Aine, Mattias/0000-0002-0851-5952 FU Swedish Cancer Society; Swedish Research Council; BioCARE; Berta Kamprad Foundation; Gunnar Nilsson Cancer Foundation; Gustav Vth Jubilee Foundation; Governmental Support for Medical Research FX The work was supported by the Swedish Cancer Society, The Swedish Research Council, BioCARE, Berta Kamprad Foundation, The Gunnar Nilsson Cancer Foundation, The Gustav Vth Jubilee Foundation, and Governmental Support for Medical Research. We thank Lars Ronnstrand for providing us with PLX4032. NR 43 TC 7 Z9 7 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2015 VL 135 IS 7 BP 1820 EP 1828 DI 10.1038/jid.2015.61 PG 9 WC Dermatology SC Dermatology GA CK4GB UT WOS:000356180100021 PM 25705847 ER PT J AU Ji, ZY Chen, YE Kumar, R Taylor, M Njauw, CNJ Miao, BC Frederick, DT Wargo, JA Flaherty, KT Jonsson, G Tsao, H AF Ji, Zhenyu Chen, Yiyin Erin Kumar, Raj Taylor, Michael Njauw, Ching-Ni Jenny Miao, Benchun Frederick, Dennie T. Wargo, Jennifer A. Flaherty, Keith T. Jonsson, Goran Tsao, Hensin TI MITF Modulates Therapeutic Resistance through EGFR Signaling SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID RAF INHIBITOR RESISTANCE; BRAF(V600E) INHIBITION; MAPK PATHWAY; MELANOMA; REACTIVATION; MEK; VEMURAFENIB; SENSITIVITY; GROWTH; CANCER AB Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF (V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs), although the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR-induced vemurafenib resistance is ligand dependent. We employed whole-genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor (MITF), along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance, and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition. C1 [Ji, Zhenyu; Chen, Yiyin Erin; Kumar, Raj; Taylor, Michael; Njauw, Ching-Ni Jenny; Miao, Benchun; Tsao, Hensin] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Frederick, Dennie T.; Flaherty, Keith T.; Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Surg Oncol & Genom Med, Houston, TX 77030 USA. [Jonsson, Goran] Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Edwards 211,55 Fruit St, Boston, MA 02114 USA. EM htsao@mgh.harvard.edu FU National Institutes of Health [K24 CA149202, P01CA163222, 5T32CA071345, 5T32AR007098]; American Skin Association; Swedish Cancer Society; Swedish Research Council; Berta Kamprad Foundation; Gunnar Nilsson Cancer Foundation; Gustav Vth Jubilee Foundation FX This work was supported in part by the National Institutes of Health (K24 CA149202, P01CA163222, 5T32CA071345, and 5T32AR007098), the American Skin Association, and the generous donors to the MGH Millennium Melanoma Fund. The work was further supported by the Swedish Cancer Society, Swedish Research Council, Berta Kamprad Foundation, Gunnar Nilsson Cancer Foundation, and Gustav Vth Jubilee Foundation. NR 24 TC 9 Z9 9 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2015 VL 135 IS 7 BP 1863 EP 1872 DI 10.1038/jid.2015.105 PG 10 WC Dermatology SC Dermatology GA CK4GB UT WOS:000356180100025 PM 25789707 ER PT J AU Ratushny, V Smith, GP AF Ratushny, Vladimir Smith, Gideon P. TI Geographical and Temporal Correlations in the Incidence of Lyme Disease, RMSF, Ehrlichiosis, and Coccidioidomycosis with Search Data SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID GOOGLE FLU TRENDS; VECTOR IXODES-SCAPULARIS; CLIMATE-CHANGE; BIG DATA; INFLUENZA C1 [Ratushny, Vladimir; Smith, Gideon P.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Ratushny, V (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. EM vratushny@partners.org NR 15 TC 0 Z9 0 U1 5 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2015 VL 135 IS 7 BP 1903 EP 1905 DI 10.1038/jid.2015.93 PG 3 WC Dermatology SC Dermatology GA CK4GB UT WOS:000356180100029 PM 25756797 ER PT J AU Wright, N Mazori, D Patel, M Lin, J Merola, J Femia, A Vleugels, R AF Wright, N. Mazori, D. Patel, M. Lin, J. Merola, J. Femia, A. Vleugels, R. TI Epidemiology and treatment of eosinophilic fasciitis: A retrospective analysis from three tertiary care centers SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Medical-Dermatology-Society CY MAR 19, 2015 CL San Francisco, CA SP Med Dermatol Soc C1 [Wright, N.; Mazori, D.; Patel, M.; Merola, J.; Vleugels, R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Femia, A.] New York Univ Langone Medical Center, New York, NY USA. [Lin, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2015 VL 135 IS 7 MA 2 BP 1926 EP 1926 PG 1 WC Dermatology SC Dermatology GA CK4GB UT WOS:000356180100039 ER PT J AU Sforza, C Frigerio, A Mapelli, A Tarabbia, F Annoni, I Colombo, V Latiff, M Ferreira, CLP Rabbiosi, D Sidequersky, FV Zago, M Biglioli, F AF Sforza, Chiarella Frigerio, Alice Mapelli, Andrea Tarabbia, Filippo Annoni, Isabella Colombo, Valeria Latiff, Mahfuz Ferreira, Claudia L. Pimenta Rabbiosi, Dimitri Sidequersky, Fernanda V. Zago, Matteo Biglioli, Federico TI Double-powered free gracilis muscle transfer for smile reanimation: A longitudinal optoelectronic study SO JOURNAL OF PLASTIC RECONSTRUCTIVE AND AESTHETIC SURGERY LA English DT Article DE Facial nerve paresis; 3D; Motion analysis; Mimetics; Asymmetry ID CLIMA EVALUATING SYSTEM; MASSETER MOTOR-NERVE; FACIAL REANIMATION; PARALYSIS; QUANTIFICATION; RECONSTRUCTION; INNERVATION; EXCURSION; MIMICRY; QUALITY AB The choice of the motor donor nerve is a crucial point in free flap transfer algorithms. In the case of unilateral facial paralysis, the contralateral healthy facial nerve can provide coordinated smile animation and spontaneous emotional expression, but with unpredictable axonal ingrowth into the recipient muscle. Otherwise, the masseteric nerve ipsilateral to the paralysis can provide a powerful neural input, without a spontaneous trigger of the smile. Harvesting a bulky muscular free flap may enhance the quantity of contraction but esthetic results are unpleasant. Therefore, the logical solution for obtaining high amplitude of smiling combined with spontaneity of movement is to couple the neural input: the contralateral facial nerve plus the ipsilateral masseteric nerve. Thirteen patients with unilateral dense facial paralysis underwent a one-stage facial reanimation with a gracilis flap powered by a double donor neural input, provided by both the ipsilateral masseteric nerve (coaptation by an end-to-end neurorrhaphy with the obturator nerve) and the contralateral facial nerve (coaptation through a cross-face nerve graft: end-to-end neurorrhaphy on the healthy side and end-to-side neurorrhaphy on the obturator nerve, distal to the masseteric/obturator neurorrhaphy). Their facial movements were evaluated with an optoelectronic motion analyzer. Before surgery, on average, the paretic side exhibited a smaller total three-dimensional mobility than the healthy side, with a 52% activation ratio and >30% of asymmetry. After surgery, the differences significantly decreased (analysis of variance (ANOVA), p < 0.05), with an activation ratio between 75% (maximum smile) and 91% (maximum smile with teeth clenching), and <20% of asymmetry. Similar modifications were seen for the performance of spontaneous smiles. The significant presurgical asymmetry of labial movements reduced after surgery. The use of a double donor neural input permitted both movements that were similar in force to that of the healthy side, and spontaneous movements elicited by emotional triggering. (C) 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. C1 [Sforza, Chiarella; Mapelli, Andrea; Annoni, Isabella; Ferreira, Claudia L. Pimenta; Sidequersky, Fernanda V.; Zago, Matteo] Univ Milan, Fac Med & Chirurg, FARC, Dipartimento Sci Biomed Salute,LAFAL,LAFAS, I-20133 Milan, Italy. [Frigerio, Alice] Univ Milan, Fac Med & Chirurg, Dept Pathophysiol & Transplantat, Human Physiol Sect, I-20133 Milan, Italy. [Frigerio, Alice] Harvard Univ, Sch Med,Div Facial Plast & Reconstruct Surg, Massachusetts Eye & Ear Infirm,Dept Otol & Laryng, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, Boston, MA USA. [Mapelli, Andrea; Ferreira, Claudia L. Pimenta; Sidequersky, Fernanda V.] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Ophthalmol Otorhinolaryngol & Head & Neck Su, Sao Paulo, Brazil. [Tarabbia, Filippo; Colombo, Valeria; Latiff, Mahfuz; Rabbiosi, Dimitri; Biglioli, Federico] Univ Milan, San Paolo Hosp, Fac Med & Chirurg, Surg Unit Maxillofacial Surg, Milan, Italy. RP Sforza, C (reprint author), Dipartimento Sci Biomed Salute, Via Mangiagalli 31, I-20133 Milan, Italy. EM chiarella.sforza@unimi.it RI Zago, Matteo/B-1481-2015; Sidequersky, Fernanda/A-6032-2017; OI Zago, Matteo/0000-0002-0649-3665; mapelli, andrea/0000-0003-0476-836X; Sidequersky, Fernanda/0000-0001-9966-2386; Sforza, Chiarella/0000-0001-6532-6464; Rabbiosi, Dimitri/0000-0001-5207-2055; Frigerio, Alice/0000-0001-9202-9553 FU Ministerio da Ciencia e Tecnologia, MCT Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, CNP; University of Milan; CNPq, Brazil FX A. Mapelli is currently a recipient of a grant (Atracao de Jovens Talentos, Pesquisador Colaborador no Brasil, BJT, Programa Ciencia sem Fronteiras) from the Ministerio da Ciencia e Tecnologia, MCT Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, CNP; C.L. Pimenta Ferreira is a fellow of Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, CNPq (National Council for Scientific and Technological Development e CNPq, Brazil); F. Sidequersky received a scholarship from the University of Milan, and currently she has a scholarship from CNPq, Brazil (Bolsa Jovens Talentos). For the remaining authors, no conflicts of interest were declared. NR 18 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1748-6815 EI 1878-0539 J9 J PLAST RECONSTR AES JI J. Plast. Reconstr. Aesthet. Surg. PD JUL PY 2015 VL 68 IS 7 BP 930 EP 939 DI 10.1016/j.bjps.2015.03.029 PG 10 WC Surgery SC Surgery GA CK4ZO UT WOS:000356232100009 PM 26026222 ER PT J AU Bird, ER Gilmore, AK George, WH Lewis, MA AF Bird, E. R. Gilmore, A. K. George, W. H. Lewis, M. A. TI A CYCLE OF RISK? THE ROLE OF SOCIAL DRINKING FACTORS IN THE RELATIONSHIP BETWEEN INCAPACITATED SEXUAL ASSAULT AND DRINKING BEFORE SEX SO JOURNAL OF SEXUAL MEDICINE LA English DT Meeting Abstract C1 [Bird, E. R.; George, W. H.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Gilmore, A. K.] VA Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA 98101 USA. [Lewis, M. A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD JUL PY 2015 VL 12 SU 4 SI SI MA 038 BP 285 EP 285 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA CK2VJ UT WOS:000356071800034 ER PT J AU Ring, D AF Ring, David TI Regarding "Distal peripheral neuropathy after open and arthroscopic shoulder surgery: an under-recognized complication'' SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Yawkey 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Ring, David/0000-0002-6506-4879 NR 3 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD JUL PY 2015 VL 24 IS 7 BP E200 EP E200 DI 10.1016/j.jse.2015.03.020 PG 1 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA CK2OZ UT WOS:000356051700005 PM 25957109 ER PT J AU Strazzula, L Cotliar, J Fox, LP Hughey, L Shinkai, K Gee, SN Kroshinsky, D AF Strazzula, Lauren Cotliar, Jonathan Fox, Lindy P. Hughey, Lauren Shinkai, Kanade Gee, Sarah N. Kroshinsky, Daniela TI Inpatient dermatology consultation aids diagnosis of cellulitis among hospitalized patients: A multi-institutional analysis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE antibiotics; cellulitis; contact dermatitis; internal medicine; medical dermatology; skin and soft-tissue infections; stasis dermatitis ID ERYSIPELAS; CARE AB Background: Given its nonspecific physical examination findings, accurately distinguishing cellulitis from a cellulitis mimicker (pseudocellulitis) is challenging. Objective: We sought to investigate the national incidence of cellulitis misdiagnosis among inpatients. Methods: We conducted a retrospective review of inpatient dermatology consultations at Massachusetts General Hospital, University of Alabama at Birmingham Medical Center, University of California Los Angeles Medical Center, and University of California San Francisco Medical Center in 2008. All consults requested for the evaluation of cellulitis were included. The primary outcomes were determining the incidence of cellulitis misdiagnosis, evaluating the prevalence of associated risk factors, and identifying common pseudocellulitides. Results: Of the 1430 inpatient dermatology consultations conducted in 2008, 74 (5.17%) were requested for the evaluation of cellulitis. In all, 55 (74.32%) patients evaluated for cellulitis were given a diagnosis of pseudocellulitis. There was no statistically significant difference in the rate of misdiagnosis across institutions (P = .12). Patient demographics and associated risk factor prevalence did not statistically vary in patients given a diagnosis of cellulitis versus those with pseudocellulitis (P > .05). Limitations: This study was unable to evaluate all patients admitted with cellulitis and was conducted at tertiary care centers, which may affect the generalizability of the results. Conclusions: Cellulitis is commonly misdiagnosed in the inpatient setting. Involving dermatologists may improve diagnostic accuracy and decrease unnecessary antibiotic use. C1 [Strazzula, Lauren; Kroshinsky, Daniela] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cotliar, Jonathan] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Fox, Lindy P.; Shinkai, Kanade] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Hughey, Lauren] Univ Alabama Birmingham, Birmingham, AL USA. [Gee, Sarah N.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, 50 Staniford St, Boston, MA 02114 USA. EM dkroshinsky@mgh.harvard.edu NR 18 TC 12 Z9 12 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2015 VL 73 IS 1 BP 70 EP 75 DI 10.1016/j.jaad.2014.11.012 PG 6 WC Dermatology SC Dermatology GA CK6BZ UT WOS:000356314100026 PM 26089048 ER PT J AU Linos, E Berger, T Chren, MM AF Linos, Eleni Berger, Timothy Chren, Mary-Margaret TI Point: Care of potential low-risk basal cell carcinomas (BCCs) at the end of life The key role of the dermatologist SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material DE basal cell carcinoma; elders; end of life; skin cancer; squamous cell carcinoma ID SKIN-CANCER C1 [Linos, Eleni; Berger, Timothy; Chren, Mary-Margaret] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Berger, Timothy; Chren, Mary-Margaret] San Francisco VA Med Ctr, Dermatol Serv, San Francisco, CA USA. RP Linos, E (reprint author), Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St,Room N421,Mail Code Box 0808, San Francisco, CA 94143 USA. EM linose@derm.ucsf.edu OI Linos, Eleni/0000-0002-5856-6301; , Eleni/0000-0003-2538-0700 FU NCATS NIH HHS [KL2TR000143]; NIA NIH HHS [P30AG044281]; NIAMS NIH HHS [5K24AR052667-09] NR 9 TC 6 Z9 6 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2015 VL 73 IS 1 BP 158 EP 161 DI 10.1016/j.jaad.2015.02.005 PG 4 WC Dermatology SC Dermatology GA CK6BZ UT WOS:000356314100038 PM 26089051 ER PT J AU Tsao, CK Gray, KP Nakabayashi, M Evan, C Kantoff, PW Huang, JT Galsky, MD Pomerantz, M Oh, WK AF Tsao, Che-kai Gray, Kathryn P. Nakabayashi, Mari Evan, Carolyn Kantoff, Philip W. Huang, Jiaoti Galsky, Matthew D. Pomerantz, Mark Oh, William K. TI Patients with Biopsy Gleason 9 and 10 Prostate Cancer Have Significantly Worse Outcomes Compared to Patients with Gleason 8 Disease SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; biopsy; neoplasm grading; prognosis; mortality ID RADICAL PROSTATECTOMY; ANDROGEN SUPPRESSION; RADIATION-THERAPY; PATTERN 5; RADIOTHERAPY; PROGRESSION; CARCINOMA AB Purpose: We examined differences in outcome in patients with biopsy Gleason score 8 vs 9-10 who received definitive local therapy. Materials and Methods: Using an institutional database we identified a cohort of 847 patients with biopsy Gleason 8-10 disease who received definitive local therapy with radiation therapy or radical prostatectomy between January 2001 and December 2011. Multivariable Cox modeling was used to assess the association of Gleason score 8 vs 9-10 with time to biochemical recurrence, metastasis and overall survival, and evaluate treatment by Gleason score interaction. Median followup in the cohort was 5.3 years. Results: Baseline patient characteristics were similar for biopsy Gleason 8 vs 9-10. Gleason 9-10 disease was associated with higher prostate specific antigen at diagnosis. As local treatment such patients were also more likely to have received radiation therapy (58% vs 46%, p = 0.001) and neoadjuvant/adjuvant androgen deprivation therapy (64% vs 49%, p < 0.001). Those with higher grade disease were at increased risk for metastasis (HR 1.41, 95% CI 1.11-1.79). There was a trend toward an increased risk of death in Gleason 9-10 vs 8 cases (HR 1.28, 95% CI 0.98-1.66). The increased risk of death for Gleason 9-10 was mainly observed in patients treated with radical prostatectomy with or without additional radiation therapy (HR 1.74, 95% CI 1.15-2.65). Conclusions: Patients with localized biopsy Gleason 9-10 disease treated with definitive local therapy had worse outcomes than those diagnosed with biopsy Gleason 8 disease. Clinical trials are urgently needed that incorporate newer approaches to Gleason 9-10 cancer. C1 [Tsao, Che-kai; Galsky, Matthew D.; Oh, William K.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY 10029 USA. [Gray, Kathryn P.; Nakabayashi, Mari; Evan, Carolyn; Kantoff, Philip W.; Pomerantz, Mark] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Huang, Jiaoti] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. RP Tsao, CK (reprint author), Icahn Sch Med Mt Sinai, Tisch Canc Inst, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM Che-kai.tsao@mssm.edu NR 15 TC 13 Z9 14 U1 0 U2 1 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 JUL PY 2015 VL 194 IS 1 BP 91 EP 97 DI 10.1016/j.juro.2015.01.078 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CK2AQ UT WOS:000356012100024 PM 25623747 ER PT J AU Yu, MK Katon, W Young, BA AF Yu, Margaret K. Katon, Wayne Young, Bessie A. TI Associations between sex and incident chronic kidney disease in a prospective diabetic cohort SO NEPHROLOGY LA English DT Article DE chronic renal insufficiency; diabetes mellitus; health disparity; vulnerable population; women's health ID GLOMERULAR-FILTRATION-RATE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; SELF-CARE; DEPRESSION; CKD; NEPHROPATHY; DISPARITIES; MELLITUS; MDRD AB AimWomen with diabetes have a higher prevalence of chronic kidney disease (CKD) risk factors compared with men, but whether they are at higher risk for incident CKD remains uncertain. MethodsThis was a prospective, observational cohort study of 1464 patients with diabetes and normal renal function, recruited from primary care clinics at a vertically integrated healthcare system in Seattle, WA, USA. The primary predictor was sex. Incident CKD was defined by an estimated glomerular filtration rate (eGFR)<60mL/min per 1.73m(2) by Chronic Kidney Disease-Epidemiology equations or sex-specific microalbuminuria (urine albumin/creatinine ratio 25mg/g for women or 17mg/g for men). ResultsOf the 1464 patients (52.0% women), CKD incidence rates were 154.0 and 144.3 cases per 1000 patient-years for women and men, respectively. In the competing risks regression, women had an increased risk of incident CKD (sub-hazard ratio 1.37, 95% confidence interval (CI) 1.17, 1.60) compared with men after adjustment for demographics, baseline eGFR and duration of diabetes, which persisted after additional adjustment for CKD risk factors, depressive symptoms and diabetes self-care (sub-hazard ratio 1.35, 95% CI 1.15, 1.59). Sex differences in incident CKD were consistent across age groups and appeared to be driven by differences in the development of low eGFR rather than microalbuminuria. ConclusionWomen with diabetes had a higher risk of incident CKD compared with men, which could not be entirely explained by differences in biologic CKD risk factors, depression or diabetes self-care. Additional work is needed determine if these sex differences contribute to worse outcomes in women with diabetes. Summary at a Glance The authors have evaluated associations between sex and chronic kidney disease (CKD) incidence in a primary care population with diabetes using Chronic Kidney Disease-Epidemiology equations for estimating glomerular filtration rate (GFR) and sex-specific definitions of microalbuminuria. They found that women had an increased risk of incident CKD compared with men. They also found that this difference in incident CKD was primarily driven by differences in incident eGFR<60mL/min per 1.73m(2). C1 [Yu, Margaret K.; Young, Bessie A.] VA Puget Sound Hlth Care Syst, Ctr Innovat, VA Hlth Serv Res & Dev, Seattle, WA 98101 USA. [Yu, Margaret K.; Young, Bessie A.] Univ Washington, Sch Med, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Katon, Wayne] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Young, Bessie A.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Yu, Margaret K.; Young, Bessie A.] Kidney Res Inst, Seattle, WA USA. RP Yu, MK (reprint author), VA Puget Sound Hlth Care Syst, 1100 Olive Way Suite 1400, Seattle, WA 98101 USA. EM mkyu@uw.edu FU National Institutes of Health National Institute of Diabetes, Digestive, and Kidney Diseases [DK079745]; National Institute of Mental Health [MH41739, MH01643]; American Kidney Fund; VA Advanced Fellowship Program in Health Services Research and Development; American Kidney Fund's Clinical Scientist in Nephrology Program; VA Puget Sound Health Care System FX This work was supported by research grants by the National Institutes of Health National Institute of Diabetes, Digestive, and Kidney Diseases (DK079745) and National Institute of Mental Health (MH41739, MH01643) and the American Kidney Fund. Dr. Yu was supported by the VA Advanced Fellowship Program in Health Services Research and Development and the American Kidney Fund's Clinical Scientist in Nephrology Program. Dr. Young was supported by the VA Puget Sound Health Care System. The study sponsor had no role in study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. NR 32 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1320-5358 EI 1440-1797 J9 NEPHROLOGY JI Nephrology PD JUL PY 2015 VL 20 IS 7 BP 451 EP 458 DI 10.1111/nep.12468 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CK2ZK UT WOS:000356084100003 PM 25807970 ER PT J AU Dumas, O Varraso, R Zock, JP Henneberger, PK Speizer, FE Wiley, AS Le Moual, N Camargo, CA AF Dumas, Orianne Varraso, Raphaelle Zock, Jan Paul Henneberger, Paul K. Speizer, Frank E. Wiley, Aleta S. Le Moual, Nicole Camargo, Carlos A., Jr. TI Asthma history, job type and job changes among US nurses SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID WORK-RELATED ASTHMA; HEALTH-CARE PROFESSIONALS; IN-HOSPITAL WORKERS; ADULT-ONSET ASTHMA; OCCUPATIONAL EXPOSURES; RESPIRATORY SYMPTOMS; CLEANING PRODUCTS; SURVEILLANCE DATA; YOUNG-ADULTS; NEW-JERSEY AB Objectives Nurses are at increased risk of occupational asthma, an observation that may be related to disinfectants exposure. Whether asthma history influences job type or job changes among nurses is unknown. We investigated this issue in a large cohort of nurses. Methods The Nurses' Health Study II is a prospective study of US female nurses enrolled in 1989 (ages 2444 years). Job status and asthma were assessed in biennial (1989-2011) and asthma-specific questionnaires (1998, 2003). Associations between asthma history at baseline (diagnosis before 1989, n=5311) and job type at baseline were evaluated by multinomial logistic regression. The relations of asthma history and severity during follow-up to subsequent job changes were evaluated by Cox models. Results The analytic cohort included 98 048 nurses. Compared with nurses in education/administration (likely low disinfectant exposure jobs), women with asthma history at baseline were less often employed in jobs with likely high disinfectant exposure, such as operating rooms (odds ratio 0.73 (95% CI 0.63 to 0.86)) and emergency room/inpatient units (0.89 (0.82 to 0.97)). During a 22-year follow-up, nurses with a baseline history of asthma were more likely to move to jobs with lower exposure to disinfectants (HR 1.13 (1.07 to 1.18)), especially among those with more severe asthma (HR for mild persistent: 1.13; moderate persistent 1.26; severe persistent: 1.50, compared with intermittent asthma, p trend: 0.004). Conclusions Asthma history was associated with baseline job type and subsequent job changes among nurses. This may partly reflect avoidance of tasks involving disinfectant use, and may introduce bias in cross-sectional studies on disinfectant exposure and asthma in nurses. C1 [Dumas, Orianne; Speizer, Frank E.; Wiley, Aleta S.; Camargo, Carlos A., Jr.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Dumas, Orianne; Speizer, Frank E.; Wiley, Aleta S.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Dumas, Orianne; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Varraso, Raphaelle; Le Moual, Nicole] INSERM, VIMA Aging & Chron Dis Epidemiol & Publ Hlth Appr, U1168, F-94807 Villejuif, France. [Varraso, Raphaelle; Le Moual, Nicole] Univ Versailles St Quentin En Yvelines, UMR S 1168, UVSQ, St Quentin En Yveline, France. [Zock, Jan Paul] Netherlands Inst Hlth Serv Res NIVEL, Utrecht, Netherlands. [Henneberger, Paul K.] NIOSH, Div Resp Dis Studies, Morgantown, WV 26505 USA. RP Dumas, O (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM orianne.dumas@channing.harvard.edu RI Varraso, Raphaelle/R-8740-2016; LeMoual, Nicole/R-8976-2016 OI Varraso, Raphaelle/0000-0002-3338-7825; LeMoual, Nicole/0000-0002-2723-5569 FU Centers for Disease Control and Prevention [R01 OH-10359]; National Institutes of Health [UM1 CA176726]; Fondation pour la Recherche Medicale [SPE20130326585]; Fond de dotation Recherche en Sante Respiratoire FX Centers for Disease Control and Prevention R01 OH-10359; National Institutes of Health UM1 CA176726; Fondation pour la Recherche Medicale SPE20130326585 and Fond de dotation Recherche en Sante Respiratoire 2013. NR 41 TC 5 Z9 5 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JUL PY 2015 VL 72 IS 7 BP 482 EP 488 DI 10.1136/oemed-2014-102547 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK5WR UT WOS:000356298200005 PM 25713153 ER PT J AU Fisichella, PM Jalilvand, A Lebenthal, A AF Fisichella, P. Marco Jalilvand, Anahita Lebenthal, Abraham TI Diagnostic Evaluation of Achalasia: From the Whalebone to the Chicago Classification SO WORLD JOURNAL OF SURGERY LA English DT Article ID ESOPHAGEAL PRESSURE TOPOGRAPHY; HIGH-RESOLUTION MANOMETRY; MOTILITY DISORDERS; CRITERIA; MYOTOMY; HELLER AB From the earliest description of dysphagia relieved by dilatation with a whalebone in 1674 we have witnessed the evolution of esophageal function testing from the conventional manometry to the high-resolution manometry (HRM) and esophageal topography pressure plotting that have led to the revised Chicago classification for esophageal motility disorders in 2014. The goals of this paper are, therefore, (1) to highlight the historical milestones that have led to the diagnostic definition of achalasia, as we know it today; (2) to describe the evaluation process of patients with suspected achalasia; (3) to describe the diagnostic value of the HRM and the usefulness of the Chicago classification in predicting treatment outcomes. The value of Chicago classification is linked to the ability of the clinician to perform a thorough clinical evaluation to identify and correlate specific clinical phenotypes to specific manometric subtypes and predict treatment outcomes. Chicago classification, however, cannot predict which treatment, pneumatic dilatation, or Heller myotomy, should be selected for those with a specific subtype of achalasia. C1 [Fisichella, P. Marco; Lebenthal, Abraham] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. [Fisichella, P. Marco; Lebenthal, Abraham] Boston VA Healthcare Syst, Dept Surg, West Roxbury, MA 02132 USA. [Jalilvand, Anahita] Ohio State Univ, Dept Surg, Cleveland, OH USA. RP Fisichella, PM (reprint author), Boston VA Healthcare Syst, Dept Surg, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM marco6370@yahoo.com NR 18 TC 1 Z9 1 U1 0 U2 1 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 JUL PY 2015 VL 39 IS 7 BP 1593 EP 1597 DI 10.1007/s00268-014-2939-7 PG 5 WC Surgery SC Surgery GA CJ7SH UT WOS:000355698900002 PM 25575460 ER PT J AU Fisichella, PM Jalilvand, A Dobrowolsky, A AF Fisichella, P. Marco Jalilvand, Anahita Dobrowolsky, Adrian TI Achalasia and Epiphrenic Diverticulum SO WORLD JOURNAL OF SURGERY LA English DT Article ID ESOPHAGEAL DIVERTICULA; SURGICAL-TREATMENT; HELLER MYOTOMY; FUNDOPLICATION; OUTCOMES; SURGERY AB Epiphrenic diverticula are a rare disease almost always associated with an underlying motility disorder of the esophagus, such as achalasia. Treatment of any underlying motility disorder must be included in the management of epiphrenic diverticula to prevent postoperative complications and recurrences. Therefore, the goal of this paper is to describe the pathophysiology, clinical presentation, and proper methods of diagnosis and treatment of patients with epiphrenic diverticula. In addition, we aim to provide an overview of the surgical management and discuss the indications for surgery and choice of surgical approach. In general, surgical intervention is favored for symptomatic patients and the optimal surgical approach depends on the size and location of the diverticulum. Surgery is not without seemingly high rates of morbidity when a myotomy is not performed together with the diverticulectomy, even in those with normal manometry. The risk of carcinoma is exceedingly rare and it is usually discovered at later stages; therefore, no surveillance programs have been established in asymptomatic patients with unresected diverticula. C1 [Fisichella, P. Marco] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. [Fisichella, P. Marco] Harvard Univ, Boston VA Healthcare Syst, Sch Med, Boston, MA 02115 USA. [Jalilvand, Anahita] Ohio State Univ, Dept Surg, Cleveland, OH USA. [Dobrowolsky, Adrian] Loyola Univ Chicago, Dept Surg, Maywood, IL USA. RP Fisichella, PM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. EM piero.fisichella@va.gov NR 24 TC 3 Z9 3 U1 0 U2 0 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 JUL PY 2015 VL 39 IS 7 BP 1614 EP 1619 DI 10.1007/s00268-015-2950-7 PG 6 WC Surgery SC Surgery GA CJ7SH UT WOS:000355698900006 PM 25609118 ER PT J AU Young, AMH Karri, SK Helmy, A Budohoski, KP Kirolloski, RW Bulters, DO Kirkpatrick, PJ Ogilvy, CS Trivedi, RA AF Young, Adam M. H. Karri, Surya K. Helmy, Adel Budohoski, Karol P. Kirolloski, Ramez W. Bulters, Diederik O. Kirkpatrick, Peter J. Ogilvy, Christopher S. Trivedi, Rikin A. TI Pharmacologic Management of Subarachnoid Hemorrhage SO WORLD NEUROSURGERY LA English DT Article DE Mortality; Outcome; Subarachnoid hemorrhage; Therapy ID CEREBRAL-BLOOD-FLOW; ENDOTHELIN RECEPTOR ANTAGONIST; HIGH-DOSE METHYLPREDNISOLONE; RANDOMIZED CONTROLLED-TRIAL; VEHICLE-CONTROLLED TRIAL; DOUBLE-BLIND; TIRILAZAD MESYLATE; ANTIFIBRINOLYTIC THERAPY; MAGNESIUM-SULFATE; INTRACRANIAL ANEURYSMS AB Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed. C1 [Young, Adam M. H.; Helmy, Adel; Budohoski, Karol P.; Kirolloski, Ramez W.; Bulters, Diederik O.; Kirkpatrick, Peter J.; Trivedi, Rikin A.] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Div Neurosurg, Cambridge CB2 2QQ, England. [Young, Adam M. H.; Karri, Surya K.; Ogilvy, Christopher S.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Sch Med, Boston, MA USA. RP Young, AMH (reprint author), Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Div Neurosurg, Cambridge CB2 2QQ, England. EM ay276@cam.ac.uk NR 74 TC 1 Z9 1 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL PY 2015 VL 84 IS 1 BP 28 EP 35 DI 10.1016/j.wneu.2015.02.004 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CK5DK UT WOS:000356242200012 PM 25701766 ER PT J AU Sayer, NA Orazem, RJ Noorbaloochi, S Gravely, A Frazier, P Carlson, KF Schnurr, PP Oleson, H AF Sayer, Nina A. Orazem, Robert J. Noorbaloochi, Siamak Gravely, Amy Frazier, Patricia Carlson, Kathleen F. Schnurr, Paula P. Oleson, Heather TI Iraq and Afghanistan War Veterans with Reintegration Problems: Differences by Veterans Affairs Healthcare User Status SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Veterans; Healthcare service needs; Mental health; Posttraumatic stress disorder; Traumatic brain injury; Department of Veterans Affairs Healthcare ID TRAUMATIC BRAIN-INJURY; FREEDOM VETERANS; BINGE DRINKING; MEDICAL-CARE; DEPLOYMENT; MILITARY; SOLDIERS; DIAGNOSES; SERVICES; RISK AB We studied 1,292 Iraq and Afghanistan War veterans who participated in a clinical trial of expressive writing to estimate the prevalence of perceived reintegration difficulty and compare Veterans Affairs (VA) healthcare users to nonusers in terms of demographic and clinical characteristics. About half of participants perceived reintegration difficulty. VA users and nonusers differed in age and military background. Levels of mental and physical problems were higher in VA users. In multivariate analysis, military service variables and probable traumatic brain injury independently predicted VA use. Findings demonstrate the importance of research comparing VA users to nonusers to understand veteran healthcare needs. C1 [Sayer, Nina A.; Orazem, Robert J.; Noorbaloochi, Siamak; Gravely, Amy; Oleson, Heather] Minneapolis VA Healthcare Syst, Ctr Chron Dis Outcomes Res, Minneapolis, MN 55417 USA. [Sayer, Nina A.; Noorbaloochi, Siamak] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Sayer, Nina A.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Frazier, Patricia] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Carlson, Kathleen F.] Portland VA Med Ctr, Ctr Improve Vet Involvement Care, Portland, OR USA. [Carlson, Kathleen F.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Schnurr, Paula P.] Natl Ctr PTSD, White River Jct, VT USA. [Schnurr, Paula P.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Sayer, NA (reprint author), Minneapolis VA Healthcare Syst, Ctr Chron Dis Outcomes Res, One Vet Dr, Minneapolis, MN 55417 USA. EM nina.sayer@va.gov RI Sayer, Nina/E-3249-2016 FU Department of Veterans Affairs (VA); Health Services Research and Development (HSRD) Service [DHI-07-150]; Department of Defense (DoD) [08-2-0045] FX This research was supported by the Department of Veterans Affairs (VA), Health Services Research and Development (HSR&D) Service (Grant No. DHI-07-150) and the Department of Defense (DoD) (Grant No. 08-2-0045). The sponsors were not involved in any aspect of the study's design and conduct; data collection, management, analysis, or interpretation of data; or in the preparation, review or approval of the manuscript. The findings and conclusions presented in this manuscript are those of the authors and do not necessarily represent the views of the VA, HSR&D, or DoD. NR 39 TC 5 Z9 5 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD JUL PY 2015 VL 42 IS 4 BP 493 EP 503 DI 10.1007/s10488-014-0564-2 PG 11 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CJ7EC UT WOS:000355656100012 PM 24913102 ER PT J AU Zorbas, KA Economopoulos, KP Vlahos, NF AF Zorbas, Konstantinos A. Economopoulos, Konstantinos P. Vlahos, Nikos F. TI Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review SO ARCHIVES OF GYNECOLOGY AND OBSTETRICS LA English DT Review DE Endometriosis; Continuous; Cyclic; Oral contraceptives; Pelvic pain; Dysmenorrhea ID LAPAROSCOPIC EXCISION; OVARIAN ENDOMETRIOMAS; CONSERVATIVE SURGERY; TRIAL; WOMEN; PAIN; RECURRENCE; QUALITY; PLACEBO; TISSUE AB Purpose Recurrence of endometriosis after conservative surgery has been observed in 40-50 % of patients within the first 5 years. A variety of regimens such as combined oral contraceptives, GnRH agonists, danazol, and progestins have been used postoperatively to reduce recurrence rates. Oral contraceptives (oCP) have been used either in a cyclic or in a continuous (no pill-free interval) fashion. The purpose of this article was to summarize the existing evidence on the efficacy and patient compliance for the use of oCP in a continuous versus cyclic fashion following conservative surgery for endometriosis. Methods A systematic search of Medline identified four eligible studies. Studies were considered eligible, if they have evaluated oCP therapy, either in a cyclic or continuous regimen, after conservative surgery for endometriosis. Specifically, studies (1) reporting on women with endometriosis who were treated postoperatively with both continuous oCP and cyclic oCP, (2) written in English, (3) with minimum 6 months duration of medical treatment, and (4) with minimum 12 months duration of follow-up were considered eligible for our systematic review. Outcome measures of these eligible studies were tabulated and then analyzed cumulatively. A purely descriptive approach was adopted concerning all variables. Results Postoperative use of continuous oCP was associated with a reduction in the recurrence rate of dysmenorrhea, delay in the presentation of dysmenorrhea, reduction in nonspecific pelvic pain, and reduction in the recurrence rate for endometrioma. Conclusions Use of oCP in a continuous fashion following conservative surgery for endometriosis is more beneficial to cyclic use. C1 [Zorbas, Konstantinos A.] Gen Hosp Veria, Dept Obstet & Gynecol, Veria, Greece. [Zorbas, Konstantinos A.; Economopoulos, Konstantinos P.] Soc Jr Doctors, Athens, Greece. [Economopoulos, Konstantinos P.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vlahos, Nikos F.] Univ Athens, Sch Med, Dept Obstet & Gynecol 2, Aretaie Hosp, GR-11527 Athens, Greece. RP Economopoulos, KP (reprint author), Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, 101 Merrimack St, Boston, MA 02114 USA. EM keconomopoulos@mgh.harvard.edu OI Economopoulos, Konstantinos/0000-0003-4856-0405 NR 29 TC 17 Z9 17 U1 5 U2 12 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0932-0067 EI 1432-0711 J9 ARCH GYNECOL OBSTET JI Arch. Gynecol. Obstet. PD JUL PY 2015 VL 292 IS 1 BP 37 EP 43 DI 10.1007/s00404-015-3641-1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CJ7ES UT WOS:000355657800006 PM 25644508 ER PT J AU Derringer, J Corley, RP Haberstick, BC Young, SE Demmitt, BA Howrigan, DP Kirkpatrick, RM Iacono, WG McGue, M Keller, MC Brown, S Tapert, S Hopfer, CJ Stallings, MC Crowley, TJ Rhee, SH Krauter, K Hewitt, JK McQueen, MB AF Derringer, Jaime Corley, Robin P. Haberstick, Brett C. Young, Susan E. Demmitt, Brittany A. Howrigan, Daniel P. Kirkpatrick, Robert M. Iacono, William G. McGue, Matt Keller, Matthew C. Brown, Sandra Tapert, Susan Hopfer, Christian J. Stallings, Michael C. Crowley, Thomas J. Rhee, Soo Hyun Krauter, Ken Hewitt, John K. McQueen, Matthew B. TI Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample SO BEHAVIOR GENETICS LA English DT Article DE Behavioral disinhibition; GWAS; Pathway analysis; Heritability ID QUANTITATIVE TRAIT LOCI; ALCOHOL DEPENDENCE; SUBSTANCE DEPENDENCE; NICOTINE DEPENDENCE; GENETIC INFLUENCE; SMOKING-BEHAVIOR; RISK LOCI; METAANALYSIS; VARIANTS; IDENTIFY AB Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p a parts per thousand currency sign 2.0 x 10(-6)). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD. C1 [Derringer, Jaime] Univ Illinois, Dept Psychol, Champaign, IL 61820 USA. [Corley, Robin P.; Haberstick, Brett C.; Young, Susan E.; Demmitt, Brittany A.; Keller, Matthew C.; Stallings, Michael C.; Rhee, Soo Hyun; Krauter, Ken; Hewitt, John K.; McQueen, Matthew B.] Univ Colorado, Boulder, CO 80309 USA. [Howrigan, Daniel P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kirkpatrick, Robert M.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Iacono, William G.; McGue, Matt] Univ Minnesota, Minneapolis, MN USA. [Brown, Sandra; Tapert, Susan] Univ Calif San Diego, La Jolla, CA 92093 USA. [Hopfer, Christian J.; Crowley, Thomas J.] Univ Colorado, Denver, CO 80202 USA. RP Derringer, J (reprint author), Univ Illinois, Dept Psychol, Champaign, IL 61820 USA. EM jderr@illinois.edu OI Derringer, Jaime/0000-0002-7352-9859 FU National Institute on Drug Abuse [P60 DA011015, R01 DA012845, R01 DA021913, R01 DA021905, DA05147, DA13240, DA024417]; USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism [AA09367, AA11886]; National Institute of Mental Health [MH066140, T32 MH016880]; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]; Gene Environment Association Studies (GENEVA) under GEI; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; NIH [HHSN268200782096C] FX The Center on Antisocial Drug Dependence (CADD) data reported here were funded by grants from the National Institute on Drug Abuse (P60 DA011015, R01 DA012845, R01 DA021913, R01 DA021905). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886), the National Institute on Drug Abuse (DA05147, DA13240, and DA024417), and the National Institute of Mental Health (MH066140). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease'' (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs0 00092.v1.p1 through dbGaP accession number phs000092.v1.p. Jaime Derringer was supported by the National Institute of Mental Health (T32 MH016880). NR 46 TC 8 Z9 8 U1 6 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD JUL PY 2015 VL 45 IS 4 BP 375 EP 381 DI 10.1007/s10519-015-9705-y PG 7 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA CJ8KJ UT WOS:000355748700001 PM 25637581 ER PT J AU Papesh, MA Billings, CJ Baltzell, LS AF Papesh, Melissa A. Billings, Curtis J. Baltzell, Lucas S. TI Background noise can enhance cortical auditory evoked potentials under certain conditions SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Electroencephalography; Event related potential; Hearing; Human; Presentation rate; Speech ID STOCHASTIC RESONANCE; BINAURAL INTERACTION; NEUROMAGNETIC FIELDS; MIDDLE-LATENCY; COCHLEAR-NERVE; HEARING-LOSS; BRAIN-STEM; SPEECH; RESPONSES; STIMULATION AB Objective: To use cortical auditory evoked potentials (CAEPs) to understand neural encoding in background noise and the conditions under which noise enhances CAEP responses. Methods: CAEPs from 16 normal-hearing listeners were recorded using the speech syllable/ba/presented in quiet and speech-shaped noise at signal-to-noise ratios of 10 and 30 dB. The syllable was presented binaurally and monaurally at two presentation rates. Results: The amplitudes of N1 and N2 peaks were often significantly enhanced in the presence of low-level background noise relative to quiet conditions, while P1 and P2 amplitudes were consistently reduced in noise. P1 and P2 amplitudes were significantly larger during binaural compared to monaural presentations, while N1 and N2 peaks were similar between binaural and monaural conditions. Conclusions: Methodological choices impact CAEP peaks in very different ways. Negative peaks can be enhanced by background noise in certain conditions, while positive peaks are generally enhanced by binaural presentations. Significance: Methodological choices significantly impact CAEPs acquired in quiet and in noise. If CAEPs are to be used as a tool to explore signal encoding in noise, scientists must be cognizant of how differences in acquisition and processing protocols selectively shape CAEP responses. Published by Elsevier Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 [Papesh, Melissa A.; Billings, Curtis J.; Baltzell, Lucas S.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR 97207 USA. [Billings, Curtis J.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. RP Papesh, MA (reprint author), Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. EM Melissa.Papesh@va.gov FU NIH-NIDCD [R03DC010914]; VA-RRD [CoE C4844C] FX This work was supported by NIH-NIDCD (R03DC010914) and VA-RR&D (CoE C4844C). These funding sources had no role in the design, interpretation, or publishing of this work. NR 43 TC 2 Z9 2 U1 3 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 2015 VL 126 IS 7 BP 1319 EP 1330 DI 10.1016/j.clinph.2014.10.017 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CJ9QF UT WOS:000355836600008 PM 25453611 ER PT J AU Mehndiratta, A Rabinov, JD Grasruck, M Liao, EC Crandell, D Gupta, R AF Mehndiratta, Amit Rabinov, James D. Grasruck, Michael Liao, Eric C. Crandell, David Gupta, Rajiv TI High-resolution dynamic angiography using flat-panel volume CT: feasibility demonstration for neuro and lower limb vascular applications SO EUROPEAN RADIOLOGY LA English DT Article DE Dynamic imaging; CT angiography; Intracranial aneurysm; Limb ischaemia; Digital flat panel detectors ID BREAST RECONSTRUCTION; PERFUSION AB This paper evaluates a prototype flat-panel volume CT (fpVCT) for dynamic in vivo imaging in a variety of neurovascular and lower limb applications. Dynamic CTA was performed on 12 patients (neuro = 8, lower limb = 4) using an fpVCT with 120 kVp, 50 mA, rotation time varying from 8 to 19 s, and field of view of 25 x 25 x 18 cm(3). Four-dimensional data sets (i.e. 3D images over time) were reconstructed and reviewed. Dynamic CTA demonstrated sufficient spatio-temporal resolution to elucidate first-pass and recirculation dynamics of contrast bolus through neurovasclaur pathologies and phasic blood flow though lower-limb vasculature and grafts. The high spatial resolution of fpVCT resulted in reduced partial volume and metal beam-hardening artefacts. This facilitated assessment of vascular lumen in the presence of calcified plaque and evaluation of fractures, especially in the presence of fixation hardware. Evaluation of arteriovenous malformation using dynamic fpVCT angiography was of limited utility. Dynamic CTA using fpVCT can visualize time-varying phenomena in neuro and lower limb vascular applications and has suffcient diagnostic imaging quality to evaluate a number of pathologies affecting these regions. aEuro cent CTA using fpVCT has sufficient spatial and temporal resolution to study phasic blood flow. aEuro cent CTA using fpVCT reveals recurrence of aneurysms even after clipping/coiling. aEuro cent fpVCT has reduced partial volume and metal beam-hardening artefacts. aEuro cent fpVCT can show vessel lumen in the presence of calcified plaque. aEuro cent CTA using fpVCT can demonstrate vascular supply to transplanted grafts. C1 [Mehndiratta, Amit; Gupta, Rajiv] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mehndiratta, Amit] Univ Oxford, Inst Biomed Engn, Oxford, England. [Mehndiratta, Amit] Univ Oxford Keble Coll, Oxford OX1 3PG, England. [Mehndiratta, Amit] Indian Inst Technol Delhi, Ctr Biomed Engn, New Delhi, India. [Mehndiratta, Amit] All India Inst Med Sci, New Delhi, India. [Rabinov, James D.] Harvard Univ, Sch Med, Intervent Neuroradiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Grasruck, Michael] Siemens Med Solut, Forchheim, Germany. [Liao, Eric C.] Harvard Univ, Sch Med, Dept Plast & Reconstruct Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Liao, Eric C.] Harvard Univ, Sch Med, Ctr Regenerat Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Crandell, David] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Charlestown, MA USA. RP Mehndiratta, A (reprint author), Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 55 Fruit St,GRB 273A, Boston, MA 02114 USA. EM amit.mehndiratta@keble.oxon.org FU Siemens Healthcare [MGH-2010-CT-35702]; Defense Advanced Research Projects Agency [N66001-11-1-4204]; US Army Medical Research Acquisitions [W81XWH-09-2-0001] FX The scientific guarantor of this publication is Dr. Rajiv Gupta, Radiology, MGH, Boston. R. Gupta's research was partially supported by a research grant from Siemens Healthcare (MGH-2010-CT-35702), Defense Advanced Research Projects Agency (N66001-11-1-4204), and US Army Medical Research Acquisitions (W81XWH-09-2-0001). Michael Grasruck is an employee at Siemens Healthcare, Forchheim, Germany. Amit Mehndiratta, James D. Rabinov, Eric C. Liao, and David Crandell declare no relationships with any companies whose products or services may be related to the subject matter of the article. The authors state that this work has not received any funding. No complex statistical methods were necessary for this paper. Institutional review board approval was obtained. Written informed consent was obtained from all subjects (patients) in this study. Methodology: prospective, diagnostic or prognostic study, performed at one institution. NR 22 TC 0 Z9 0 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD JUL PY 2015 VL 25 IS 7 BP 1901 EP 1910 DI 10.1007/s00330-015-3612-8 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ8MJ UT WOS:000355755300008 PM 25716938 ER PT J AU Engel, CC Litz, B Magruder, KM Harper, E Gore, K Stein, N Yeager, D Liu, X Coe, TR AF Engel, Charles C. Litz, Brett Magruder, Kathryn M. Harper, Elizabeth Gore, Kristie Stein, Nathan Yeager, Derik Liu, Xian Coe, T. Ray TI Delivery of self training and education for stressful situations (DESTRESS-PC): a randomized trial of nurse assisted online self-management for PTSD in primary care SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Posttraumatic Stress Disorder; Depression; Military mental health; Primary care; Telehealth ID COMORBIDITY SURVEY REPLICATION; MENTAL-HEALTH PROBLEMS; POSTTRAUMATIC-STRESS; DISORDER; DEPRESSION; PREVALENCE; SEVERITY; INTERNET; IRAQ; AFGHANISTAN AB Objective: This randomized controlled trial examined the effectiveness of a nurse assisted online cognitive-behavioral self-management intervention forwar-related posttraumatic stress disorder (PTSD), compared to optimized usual primary care PTSD Treatment (OUC) to reduce PTSD symptoms. Method: Participants were 80 veterans of recent military conflicts with PTSD as assessed by the PTSD Checklist (PCL) seeking primary care treatment at one of three Veterans Affairs (VA) and four Army clinics. DESTRESS-PC consisted of logins to a secure website three times per week for 6 weeks with monitoring by a study nurse. All participants received nurse care management in the form of phone check-ins every two weeks and feedback to their primary care providers. Blinded raters assessed outcomes 6, 12, and 18 weeks post-randomization. Results: DESTRESS-PC was associated with a significantly greater decrease in PTSD symptoms compared to OUC (F(3, 186)=3.72, p=.012). The effect was largest at the 12-week assessment (Delta PCL=12.6 +/- 16.6 versus 5.7 +/- 12.5, p<0.05) with the treatment effect disappearing by the 18-week follow-up. Notably, there was a dose effect; number of logins correlated significantly with PTSD outcomes, with more logins associated with greater PTSD symptom improvement. None of the secondary outcomes (depression, anxiety, somatic symptoms, and functional status) showed statistically significant improvement; however, the treatment effect on depression approached significance (F(3, 186)=2.17, p=.093). Conclusions: DESTRESS-PC shows promise as a means of delivering effective, early PTSD treatment in primary care. Larger trials are needed. (C) 2015 Elsevier Inc. All rights reserved. C1 [Engel, Charles C.; Liu, Xian] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. [Litz, Brett; Stein, Nathan] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Jamaica Plain, MA USA. [Litz, Brett; Stein, Nathan] Boston Univ, Dept Psychiat, Boston, MA 02215 USA. [Magruder, Kathryn M.; Yeager, Derik] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Magruder, Kathryn M.; Yeager, Derik] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Harper, Elizabeth; Gore, Kristie; Liu, Xian] Walter Reed Natl Mil Med Ctr, Deployment Hlth Clin Ctr, Bethesda, MD USA. [Liu, Xian] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Coe, T. Ray] Womack Army Med Ctr, Ft Bragg, NC USA. RP Engel, CC (reprint author), RAND Corp, 1200 South Hayes St, Arlington, VA 22202 USA. EM cengel@rand.org FU NIMH NIH HHS [R34 MH078874] NR 32 TC 3 Z9 3 U1 5 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2015 VL 37 IS 4 BP 323 EP 328 DI 10.1016/j.genhosppsych.2015.04.007 PG 6 WC Psychiatry SC Psychiatry GA CJ5UG UT WOS:000355555800010 PM 25929985 ER PT J AU Baldini, EH Wang, D Haas, RLM Catton, CN Indelicato, DJ Kirsch, DG Roberge, D Salerno, K Deville, C Guadagnolo, BA O'Sullivan, B Petersen, IA Le Pechoux, C Abrams, RA DeLaney, TF AF Baldini, Elizabeth H. Wang, Dian Haas, Rick L. M. Catton, Charles N. Indelicato, Daniel J. Kirsch, David G. Roberge, David Salerno, Kilian Deville, Curtiland Guadagnolo, B. Ashleigh O'Sullivan, Brian Petersen, Ivy A. Le Pechoux, Cecile Abrams, Ross A. DeLaney, Thomas F. TI Treatment Guidelines for Preoperative Radiation Therapy for Retroperitoneal Sarcoma: Preliminary Consensus of an International Expert Panel SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review ID SOFT-TISSUE SARCOMA; ELECTRON-BEAM RADIOTHERAPY; RESECTION PREDICT PATTERN; PROGNOSTIC-FACTORS; LOCOREGIONAL RECURRENCE; SURGICAL-MANAGEMENT; HISTOLOGIC SUBTYPE; RANDOMIZED-TRIAL; DOSE-ESCALATION; TARGET VOLUME AB Purpose: Evidence for external beam radiation therapy (RT) as part of treatment for retroperitoneal sarcoma (RPS) is limited. Preoperative RT is the subject of a current randomized trial, but the results will not be available for many years. In the meantime, many practitioners use preoperative RT for RPS, and although this approach is used in practice, there are no radiation treatment guidelines. An international expert panel was convened to develop consensus treatment guidelines for preoperative RT for RPS. Methods and Materials: An expert panel of 15 academic radiation oncologists who specialize in the treatment of sarcoma was assembled. A systematic review of reports related to RT for RPS, RT for extremity sarcoma, and RT-related toxicities for organs at risk was performed. Due to the paucity of high-quality published data on the subject of RT for RPS, consensus recommendations were based largely on expert opinion derived from clinical experience and extrapolation of relevant published reports. It is intended that these clinical practice guidelines be updated as pertinent data become available. Results: Treatment guidelines for preoperative RT for RPS are presented. Conclusions: An international panel of radiation oncologists who specialize in sarcoma reached consensus guidelines for preoperative RT for RPS. Many of the recommendations are based on expert opinion because of the absence of higher level evidence and, thus, are best regarded as preliminary. We emphasize that the role of preoperative RT for RPS has not been proven, and we await data from the European Organization for Research and Treatment of Cancer (EORTC) study of preoperative radiotherapy plus surgery versus surgery alone for patients with RPS. Further data are also anticipated pertaining to normal tissue dose constraints, particularly for bowel tolerance. Nonetheless, as we await these data, the guidelines herein can be used to establish treatment uniformity to aid future assessments of efficacy and toxicity. (C) 2015 Elsevier Inc. All rights reserved. C1 [Baldini, Elizabeth H.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Baldini, Elizabeth H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wang, Dian; Abrams, Ross A.] Rush Univ, Med Ctr, Dept Radiat Oncol, Chicago, IL USA. [Haas, Rick L. M.] Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Radiotherapy, Amsterdam, Netherlands. [Catton, Charles N.; O'Sullivan, Brian] Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Indelicato, Daniel J.] Univ Florida, Med Ctr, Dept Radiat Oncol, Jacksonville, FL 32209 USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. [Roberge, David] Univ Montreal, Ctr Hosp, Dept Radiat Oncol, Montreal, PQ, Canada. [Salerno, Kilian] Roswell Pk Canc Inst, Dept Radiat Oncol, Buffalo, NY 14263 USA. [Deville, Curtiland] Johns Hopkins Sidney Kimmel Canc Ctr, Dept Radiat Oncol & Mol Radiat Sci, Washington, DC USA. [Guadagnolo, B. Ashleigh] Univ Texas Houston, MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Petersen, Ivy A.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Le Pechoux, Cecile] Inst Gustave Roussy, Dept Radiotherapy, Villejuif, France. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Baldini, EH (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, L2,75 Francis St, Boston, MA 02115 USA. EM ebaldini@partners.org RI Deville, Curtiland/B-2819-2013 OI Deville, Curtiland/0000-0003-4846-6486 FU US National Cancer Institute/National Institutes of Health [U10CA21661, U10CA180868, U10CA180822, U10 CA37422, U24CA180803] FX This project was supported by US National Cancer Institute/National Institutes of Health grants U10CA21661, U10CA180868, U10CA180822, U10 CA37422, and U24CA180803. NR 80 TC 16 Z9 17 U1 0 U2 3 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 JUL 1 PY 2015 VL 92 IS 3 BP 602 EP 612 DI 10.1016/j.ijrobp.2015.02.013 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CJ6WV UT WOS:000355636800022 PM 26068493 ER PT J AU Hall, DE Hanusa, BH Fine, MJ Arnold, RM AF Hall, Daniel E. Hanusa, Barbara H. Fine, Michael J. Arnold, Robert M. TI Do surgeons and patients discuss what they document on consent forms? SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Informed consent; Shared decision making; Ethics; Cholecystectomy; Herniorrhaphy ID INFORMED DECISION-MAKING; GENERAL-PRACTICE; HAWTHORNE; CONSULTATIONS; QUALITY; DOCTORS; BACK; TIME AB Background: Previous studies of surgeon behavior report that surgeons rarely meet basic standards of informed consent, raising concerns that current practice requires urgent remediation. We wondered if the Veterans Affairs Healthcare System's recent implementation of standardized, procedure-specific consent forms might produce a better practice of informed consent than has been reported previously. Our goal was to determine how the discussions shared between surgeons and patients correspond to the VA's standardized consent forms. Methods: We enrolled a prospective cohort of patients presenting for possible cholecystectomy or inguinal herniorrhaphy and the surgical providers for those patients. Audio recordings captured the clinical encounter(s) culminating in a decision to have surgery. Each patient's informed consent was documented using a standardized, computer-generated form. We abstracted and compared the information documented with the information discussed. Results: Of 75 consecutively enrolled patients, 37 eventually decided to have surgery and signed the standardized consent form. Patients and providers discussed 37% (95% confidence interval, 0.07-0.67) and 33% (95% confidence interval, 0.21-0.43) of the information found on the cholecystectomy and herniorrhaphy consent forms, respectively. However, the patienteprovider discussions frequently included relevant details nowhere documented on the standardized forms, culminating in discussions that included a median 27.5 information items for cholecystectomy and 20 items for herniorrhaphy. Fully, 80% of cholecystectomy discussions and 76% of herniorrhaphy discussions mentioned at least one risk, benefit or alternative, indication for, and description of the procedure. Conclusions: The patients and providers observed here collaborated in a detailed process of informed consent that challenges the initial reports suggesting the need to remediate surgeon's practice of informed consent. However, because the discrepancy between the information documented and discussed exposes legal and ethical liability, there is an opportunity to improve the iMed system so that it better reflects what surgeons discuss and more frequently includes all the information patients need. Published by Elsevier Inc. C1 [Hall, Daniel E.; Fine, Michael J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Hall, Daniel E.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Hanusa, Barbara H.] VA Pittsburgh Healthcare Syst, MIRECC, Pittsburgh, PA 15240 USA. [Arnold, Robert M.] Univ Pittsburgh, UPMC Montefiore Hosp, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. RP Hall, DE (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Bldg 30,Univ Dr 151C, Pittsburgh, PA 15240 USA. EM hallde@upmc.edu OI Hall, Daniel/0000-0001-6382-0522 FU US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development [CDA 08-281]; VISN4 CPPF [XVA 72-057]; VA Center for Health Equity Research and Promotion [LIP 72-043] FX This research was supported by supported by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development (CDA 08-281). It was also supported by the VISN4 CPPF (XVA 72-057) and the VA Center for Health Equity Research and Promotion (LIP 72-043). NR 26 TC 1 Z9 1 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD JUL PY 2015 VL 197 IS 1 BP 67 EP 77 DI 10.1016/j.jss.2015.03.058 PG 11 WC Surgery SC Surgery GA CJ5UA UT WOS:000355554900012 PM 25891679 ER PT J AU Zhu, CL Xiao, F Hong, J Wang, K Liu, X Cai, DC Fusco, DN Zhao, L Jeong, SW Brisac, C Chusri, P Schaefer, EA Zhao, H Peng, LF Lin, W Chung, RT AF Zhu, Chuanlong Xiao, Fei Hong, Jian Wang, Kun Liu, Xiao Cai, Dachuan Fusco, Dahlene N. Zhao, Lei Jeong, Soung Won Brisac, Cynthia Chusri, Pattranuch Schaefer, Esperance A. Zhao, Hong Peng, Lee F. Lin, Wenyu Chung, Raymond T. TI EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway SO JOURNAL OF VIROLOGY LA English DT Article ID INTERFERON-STIMULATED GENES; JAK-STAT PATHWAY; I-LIKE RECEPTORS; RIG-I; RNA VIRUSES; RECOGNITION; EXPRESSION; PROTEIN; ACTIVATION; INDUCTION AB The elongation factor Tu GTP binding domain-containing protein 2 (EFTUD2) was identified as an anti-hepatitis C virus (HCV) host factor in our recent genome-wide small interfering RNA (siRNA) screen. In this study, we sought to further determine EFTUD2's role in HCV infection and investigate the interaction between EFTUD2 and other regulators involved in HCV innate immune (RIG-I, MDA5, TBK1, and IRF3) and JAK-STAT1 pathways. We found that HCV infection decreased the expression of EFTUD2 and the viral RNA sensors RIG-I and MDA5 in HCV-infected Huh7 and Huh7.5.1 cells and in liver tissue from in HCV-infected patients, suggesting that HCV infection downregulated EFTUD2 expression to circumvent the innate immune response. EFTUD2 inhibited HCV infection by inducing expression of the interferon (IFN)-stimulated genes (ISGs) in Huh7 cells. However, its impact on HCV infection was absent in both RIG-I knockdown Huh7 cells and RIG-I-defective Huh7.5.1 cells, indicating that the antiviral effect of EFTUD2 is dependent on RIG-I. Furthermore, EFTUD2 upregulated the expression of the RIG-I-like receptors (RLRs) RIG-I and MDA5 to enhance the innate immune response by gene splicing. Functional experiments revealed that EFTUD2-induced expression of ISGs was mediated through interaction of the EFTUD2 downstream regulators RIG-I, MDA5, TBK1, and IRF3. Interestingly, the EFTUD2-induced antiviral effect was independent of the classical IFN-induced JAK-STAT pathway. Our data demonstrate that EFTUD2 restricts HCV infection mainly through an RIG-I/MDA5-mediated, JAK-STAT-independent pathway, thereby revealing the participation of EFTUD2 as a novel innate immune regulator and suggesting a potentially targetable antiviral pathway. IMPORTANCE Innate immunity is the first line defense against HCV and determines the outcome of HCV infection. Based on a recent highthroughput whole-genome siRNA library screen revealing a network of host factors mediating antiviral effects against HCV, we identified EFTUD2 as a novel innate immune regulator against HCV in the infectious HCV cell culture model and confirmed that its expression in HCV-infected liver tissue is inversely related to HCV infection. Furthermore, we determined that EFTUD2 exerts its antiviral activity mainly through governing its downstream regulators RIG-I and MDA5 by gene splicing to activate IRF3 and induce classical ISG expression independent of the JAT-STAT signaling pathway. This study broadens our understanding of the HCV innate immune response and provides a possible new antiviral strategy targeting this novel regulator of the innate response. C1 [Zhu, Chuanlong; Xiao, Fei; Wang, Kun] Anhui Med Univ, Anhui Prov Hosp, Dept Infect Dis, Hefei, Anhui, Peoples R China. [Zhu, Chuanlong; Hong, Jian; Liu, Xiao; Cai, Dachuan; Fusco, Dahlene N.; Zhao, Lei; Jeong, Soung Won; Brisac, Cynthia; Chusri, Pattranuch; Schaefer, Esperance A.; Zhao, Hong; Peng, Lee F.; Lin, Wenyu; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Liver Ctr & Gastrointestinal Div,Dept Med, Boston, MA 02115 USA. [Zhu, Chuanlong] Nanjing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Nanjing, Jiangsu, Peoples R China. [Xiao, Fei] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Infect Dis, Wuhan, Hubei, Peoples R China. [Zhao, Hong] Peking Univ, Hosp 1, Dept Infect Dis, Beijing 100871, Peoples R China. RP Lin, W (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Liver Ctr & Gastrointestinal Div,Dept Med, Boston, MA 02115 USA. EM wlin1@mgh.harvard.edu; Chung.Raymond@mgh.harvard.edu FU National Natural Science Foundation of China [81271713, 81170386]; NIH-MGH Center for Human Immunology Pilot/Feasibility Study grant; NIH [DA033541, DK098079, AI082630] FX This work was supported by National Natural Science Foundation of China grant 81271713 (C.Z.), National Natural Science Foundation of China grant 81170386 (H.Z.), an NIH-MGH Center for Human Immunology Pilot/Feasibility Study grant (W.L.), and NIH grants DA033541 (R.T.C.), DK098079 (R.T.C.), and AI082630 (R.T.C.). NR 47 TC 6 Z9 6 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2015 VL 89 IS 13 BP 6608 EP 6618 DI 10.1128/JVI.00364-15 PG 11 WC Virology SC Virology GA CJ6GW UT WOS:000355593000009 PM 25878102 ER PT J AU Hwang, JH Fernando, ATP Faure, N Andrabi, S Adelmant, G Hahn, WC Marto, JA Schaffhausen, BS Roberts, TM AF Hwang, Justin H. Fernando, Arun T. Pores Faure, Nathalie Andrabi, Shaida Adelmant, Guillaume Hahn, William C. Marto, Jarrod A. Schaffhausen, Brian S. Roberts, Thomas M. TI Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation (vol 88, pg 12055, 2014) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Hwang, Justin H.; Faure, Nathalie; Schaffhausen, Brian S.] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. [Hwang, Justin H.; Schaffhausen, Brian S.] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Fernando, Arun T. Pores; Andrabi, Shaida; Adelmant, Guillaume; Marto, Jarrod A.; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fernando, Arun T. Pores; Adelmant, Guillaume; Marto, Jarrod A.; Roberts, Thomas M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Andrabi, Shaida] Univ Kashmir, Dept Biochem, Kashmir, India. [Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hahn, William C.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. RP Hwang, JH (reprint author), Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2015 VL 89 IS 13 BP 6971 EP 6971 DI 10.1128/JVI.00952-15 PG 1 WC Virology SC Virology GA CJ6GW UT WOS:000355593000043 PM 26041839 ER PT J AU Winn, K Ozanne, E Sepucha, K AF Winn, Karen Ozanne, Elissa Sepucha, Karen TI Measuring patient-centered care: An updated systematic review of how studies define and report concordance between patients' preferences and medical treatments SO PATIENT EDUCATION AND COUNSELING LA English DT Review DE Quality; Decisions; Decision making; Measurement; Patient-centered; Value concordance ID RANDOMIZED CONTROLLED-TRIAL; DECISION AID; PROSTATE-CANCER; INFORMED CHOICE; PLANNED BEHAVIOR; BREAST-CANCER; WOMEN; SUPPORT; RISK; COMMUNICATION AB Objective: The purpose was to examine recent advances in measuring value concordance and to highlight best practices. Methods: The paper updates a prior systematic review. A systematic review of the literature from 2008 to 2012 identified articles that reported a relationship between patients' preferences concerning health outcomes and/or medical treatments, and treatment (intended or actual). Relevant articles were independently abstracted by two reviewers. Results: The search identified 3635 unique citations, the full text of 187 articles was examined, and 63 articles covering 61 studies were included, nearly a third more articles than identified in the original review. There were 72 different value concordance calculations, the majority of which were clearly reported with significance. More studies assessed knowledge, reported on the association between value concordance and knowledge, and included a decision aid compared to those in the original review. Conclusion: There is increased reporting of value concordance in the literature. However, large differences exist in the way that the measure is defined and calculated. The variability makes it difficult to draw conclusions about the quality of care across studies. Practice implications: Value concordance is a critical component of patient-centered care, and further attention is needed to establish standards for measurement and reporting. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Winn, Karen] MGH Inst Hlth Profess, Boston, MA 02129 USA. [Ozanne, Elissa] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Sepucha, Karen] Harvard Univ, Sch Med, Boston, MA USA. [Sepucha, Karen] Massachusetts Gen Hosp, Div Gen Internal Med, Hlth Decis Sci Ctr, Boston, MA 02114 USA. RP Winn, K (reprint author), MGH Inst Hlth Profess, 36 1st Ave, Boston, MA 02129 USA. EM kwinn@mghihp.edu NR 79 TC 8 Z9 8 U1 4 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JUL PY 2015 VL 98 IS 7 BP 811 EP 821 DI 10.1016/j.pec.2015.03.012 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA CJ7VP UT WOS:000355708800001 PM 25846191 ER PT J AU August, DA Cote, CJ AF August, David A. Cote, Charles J. TI Response to the letter of Dr. B Haydar SO PEDIATRIC ANESTHESIA LA English DT Letter ID EPINEPHRINE C1 [August, David A.; Cote, Charles J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Pediat Anesthesia, Boston, MA 02114 USA. RP August, DA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Pediat Anesthesia, Boston, MA 02114 USA. EM daugust@mgh.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 EI 1460-9592 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD JUL PY 2015 VL 25 IS 7 BP 753 EP 754 DI 10.1111/pan.12661 PG 2 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA CK0FP UT WOS:000355881200016 PM 26053771 ER PT J AU Dunn, EC Masyn, KE Jones, SM Subramanian, SV Koenen, KC AF Dunn, Erin C. Masyn, Katherine E. Jones, Stephanie M. Subramanian, S. V. Koenen, Karestan C. TI Measuring Psychosocial Environments Using Individual Responses: an Application of Multilevel Factor Analysis to Examining Students in Schools SO PREVENTION SCIENCE LA English DT Article DE Multilevel; Factor analysis; School environment; School climate; Latent variable; Ecological ID CONFIRMATORY FACTOR-ANALYSIS; CLIMATE; MODELS AB Interest in understanding how psychosocial environments shape youth outcomes has grown considerably. School environments are of particular interest to prevention scientists as many prevention interventions are school-based. Therefore, effective conceptualization and operationalization of the school environment is critical. This paper presents an illustration of an emerging analytic method called multilevel factor analysis (MLFA) that provides an alternative strategy to conceptualize, measure, and model environments. MLFA decomposes the total sample variance-covariance matrix for variables measured at the individual level into within-cluster (e.g., student level) and between-cluster (e.g., school level) matrices and simultaneously models potentially distinct latent factor structures at each level. Using data from 79,362 students from 126 schools in the National Longitudinal Study of Adolescent to Adult Health (formerly known as the National Longitudinal Study of Adolescent Health), we use MLFA to show how 20 items capturing student self-reported behaviors and emotions provide information about both students (within level) and their school environment (between level). We identified four latent factors at the within level: (1) school adjustment, (2) externalizing problems, (3) internalizing problems, and (4) self-esteem. Three factors were identified at the between level: (1) collective school adjustment, (2) psychosocial environment, and (3) collective self-esteem. The finding of different and substantively distinct latent factor structures at each level emphasizes the need for prevention theory and practice to separately consider and measure constructs at each level of analysis. The MLFA method can be applied to other nested relationships, such as youth in neighborhoods, and extended to a multilevel structural equation model to better understand associations between environments and individual outcomes and therefore how to best implement preventive interventions. C1 [Dunn, Erin C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Dunn, Erin C.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Dunn, Erin C.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Masyn, Katherine E.] Georgia State Univ, Div Epidemiol & Biostat, Sch Publ Hlth, Atlanta, GA 30303 USA. [Jones, Stephanie M.] Harvard Univ, Harvard Grad Sch Educ, Cambridge, MA 02138 USA. [Subramanian, S. V.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Dunn, EC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. EM edunn2@mgh.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01-HD31921]; National Institute of Mental Health [F31 MH088074] FX This research uses data from Add Health, a program project directed by Kathleen Mullan Harris and designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill, and funded by grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website (http://www.cpc.unc.edu/addhealth). No direct support was received from grant P01-HD31921 for this analysis. Visit Add Health online: https://www.cpc.unc.edu/projects/addhealth. Research reported in this publication was supported by the National Institute of Mental Health under Award Number F31 MH088074 to Erin C. Dunn, ScD, MPH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 35 TC 3 Z9 3 U1 2 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD JUL PY 2015 VL 16 IS 5 BP 718 EP 733 DI 10.1007/s11121-014-0523-x PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CJ6WC UT WOS:000355634900009 PM 25421872 ER PT J AU Ventura, J Ered, A Gretchen-Doorly, D Subotnik, KL Horan, WP Hellemann, GS Nuechterlein, KH AF Ventura, J. Ered, A. Gretchen-Doorly, D. Subotnik, K. L. Horan, W. P. Hellemann, G. S. Nuechterlein, K. H. TI Theory of mind in the early course of schizophrenia: stability, symptom and neurocognitive correlates, and relationship with functioning SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Disorganization; early-course schizophrenia; functioning; neurocognition; theory of mind ID SOCIAL COGNITION; 1ST EPISODE; 1ST-EPISODE SCHIZOPHRENIA; INTENTIONAL MOVEMENT; ASPERGER-SYNDROME; ANIMATED SHAPES; MENTAL STATES; RATING-SCALE; METAANALYSIS; ATTRIBUTION AB Background. Numerous studies have reported links between theory of mind (ToM) deficits, neurocognition and negative symptoms with functional outcome in chronic schizophrenia patients. Although the ToM deficit has been observed in first-episode patients, fewer studies have addressed ToM as a possible trait marker, neurocognitive and symptom correlations longitudinally, and associations with later functioning. Method. Recent-onset schizophrenia patients (n = 77) were assessed at baseline after reaching medication stabilization, and again at 6 months (n = 48). Healthy controls (n = 21) were screened, and demographically comparable with the patients. ToM was assessed with a Social Animations Task (SAT), in which the participants' descriptions of scenes depicting abstract visual stimuli 'interacting' in three conditions (ToM, goal directed and random) were rated for degree of intentionality attributed to the figures and for appropriateness. Neurocognition, symptoms and role functioning were also assessed. Results. On the SAT, patients had lower scores than controls for both intentionality (p < 0.01) and appropriateness (p < 0.01) during the ToM condition, at baseline and 6 months. The ToM deficit was stable and present even in remitted patients. Analyses at baseline and 6 months indicated that for patients, ToM intentionality and appropriateness were significantly correlated with neurocognition, negative symptoms and role functioning. The relationship between ToM and role functioning was mediated by negative symptoms. Conclusions. The ToM deficit was found in recent-onset schizophrenia patients and appears to be moderately trait-like. ToM is also moderately correlated with neurocognition, negative and positive symptoms, and role functioning. ToM appears to influence negative symptoms which in turn makes an impact on role functioning. C1 [Ventura, J.; Ered, A.; Gretchen-Doorly, D.; Subotnik, K. L.; Horan, W. P.; Hellemann, G. S.; Nuechterlein, K. H.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Horan, W. P.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Nuechterlein, K. H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Ventura, J (reprint author), Univ Calif Los Angeles, Dept Psychiat, 300 Med Plaza,Room 2243, Los Angeles, CA 90095 USA. EM jventura@ucla.edu FU National Institute of Mental Health [MH37705, P50 MH066286]; Janssen Scientific Affairs, LLC. FX This research was supported in part by National Institute of Mental Health grants MH37705 (principal investigator K.H.N.) and P50 MH066286 (principal investigator K.H.N.), and supplemental support from an investigator-initiated grant from Janssen Scientific Affairs, LLC. The authors would like to thank the following research associates who worked on data collection: Sarah Wilson, Robin Kite, Rachel Wood, Sharon Birman, Jackie Hayata and Lilian Medina. NR 54 TC 8 Z9 8 U1 2 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2015 VL 45 IS 10 BP 2031 EP 2043 DI 10.1017/S0033291714003171 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CJ8MW UT WOS:000355757500003 PM 25647289 ER PT J AU Logue, MW Smith, AK Baldwin, C Wolf, EJ Guffanti, G Ratanatharathorn, A Stone, A Schichman, SA Humphries, D Binder, EB Arloth, J Menke, A Uddin, M Wildman, D Galea, S Aiello, AE Koenen, KC Miller, MW AF Logue, Mark W. Smith, Alicia K. Baldwin, Clinton Wolf, Erika J. Guffanti, Guia Ratanatharathorn, Andrew Stone, Annjanette Schichman, Steven A. Humphries, Donald Binder, Elisabeth B. Arloth, Janine Menke, Andreas Uddin, Monica Wildman, Derek Galea, Sandro Aiello, Allison E. Koenen, Karestan C. Miller, Mark W. TI An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE PTSD; Gene expression; Whole blood; DSCAM; ATP6AP1L; Glucocortitoid responsive ID GENOME-WIDE ASSOCIATION; NEUROTROPHIC FACTOR; PERIPHERAL-BLOOD; CHILDHOOD MALTREATMENT; OXIDATIVE STRESS; IMPRINTED GENES; NERVOUS-SYSTEM; DISORDER; BRAIN; METHYLATION AB We examined the association between posttraumatic stress disorder (PTSD) and gene expression using whole blood samples from a cohort of trauma-exposed white non-Hispanic male veterans (115 cases and 28 controls). 10,264 probes of genes and gene transcripts were analyzed. We found 41 that were differentially expressed in PTSD cases versus controls (multiple-testing corrected p <0.05). The most significant was DSCAM, a neurological gene expressed widely in the developing brain and in the annygdala and hippocampus of the adult brain. We then examined the 41 differentially expressed genes in a meta-analysis using two replication cohorts and found significant associations with PTSD for 7 of the 41 (p <0.05), one of which (ATP6AP1L) survived multiple-testing correction. There was also broad evidence of overlap across the discovery and replication samples for the entire set of genes implicated in the discovery data based on the direction of effect and an enrichment of p <0.05 significant probes beyond what would be expected under the null. Finally, we found that the set of differentially expressed genes from the discovery sample was enriched for genes responsive to glucocorticoid signaling with most showing reduced expression in PTSD cases compared to controls. Published by Elsevier Ltd. C1 [Logue, Mark W.] VA Boston Healthcare Syst, Res Serv, Boston, MA 02130 USA. [Logue, Mark W.; Baldwin, Clinton] Boston Univ, Sch Med, Biomed Genet, Boston, MA 02118 USA. [Logue, Mark W.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Smith, Alicia K.; Binder, Elisabeth B.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Wolf, Erika J.; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Wolf, Erika J.; Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Guffanti, Guia] Columbia Univ NYSPI, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY USA. [Ratanatharathorn, Andrew; Galea, Sandro; Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Stone, Annjanette; Schichman, Steven A.] Cent Arkansas Vet Healthcare Syst, Pharmacogen Anal Lab, Res Serv, Little Rock, AR USA. [Humphries, Donald] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA 02130 USA. [Binder, Elisabeth B.; Arloth, Janine; Menke, Andreas] Max Planck Inst Psychiat, Dept Translat Res Psychiat, D-80804 Munich, Germany. [Uddin, Monica; Wildman, Derek] Univ Illinois, Inst Genom Biol, Champaign, IL USA. [Uddin, Monica] Univ Illinois, Dept Psychol, Champaign, IL USA. [Wildman, Derek] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Aiello, Allison E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Logue, MW (reprint author), VA Boston Healthcare Syst, Mail Stop 151C,150 South Huntington Ave, Boston, MA 02130 USA. EM mark.logue@va.gov OI Wolf, Erika/0000-0003-2666-2435 FU U.S. Department of Veterans Affairs VA CSRD grant; U.S. Department of Veterans Affairs VA BLRD grant; NIH [R21MH102834]; United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program; ERC [GSE46743, GxEmolmech-281338] FX This research was supported by U.S. Department of Veterans Affairs VA CSR&D and BLR&D grants and NIH grant R21MH102834 to MWM. This work was also supported by a Career Development Award to EJW from the United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program. Data collection and analysis of GSE46743 was supported within the 7th framework programme by an ERC starting grant to EB, GxEmolmech-281338. NR 54 TC 9 Z9 9 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUL PY 2015 VL 57 BP 1 EP 13 DI 10.1016/j.psyneuen.2015.03.016 PG 13 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA CJ7UY UT WOS:000355707000001 PM 25867994 ER PT J AU Godoy, MCB Marom, EM Carter, BW Sorensen, J Truong, MT Abbott, GF AF Godoy, Myrna C. B. Marom, Edith M. Carter, Brett W. Sorensen, James Truong, Mylene T. Abbott, Gerald F. TI Computed Tomography Imaging of Lung Infection in the Oncologic Setting: Typical Features and Potential Pitfalls SO SEMINARS IN ROENTGENOLOGY LA English DT Article ID REVERSED HALO SIGN; STEM-CELL TRANSPLANTATION; HIGH-RESOLUTION CT; INVASIVE PULMONARY ASPERGILLOSIS; FUNGAL-INFECTIONS; IMMUNOCOMPROMISED PATIENTS; BRONCHIOLITIS OBLITERANS; ORGANIZING PNEUMONIA; COMPLICATIONS; CANCER C1 [Godoy, Myrna C. B.; Marom, Edith M.; Carter, Brett W.; Sorensen, James; Truong, Mylene T.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Abbott, Gerald F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Godoy, MCB (reprint author), Univ Texas MD Anderson Canc Ctr, DI Dept Diagnost Radiol, 1515 Holcombe Blvd,Unit 371, Houston, TX 77030 USA. EM mgodoy@mdanderson.org NR 19 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-198X EI 1558-4658 J9 SEMIN ROENTGENOL JI Semin. Roentgenology PD JUL PY 2015 VL 50 IS 3 BP 192 EP 196 DI 10.1053/j.ro.2015.01.009 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ6BA UT WOS:000355576800006 PM 26002239 ER PT J AU de Groot, PM Carter, BW Abbott, GF Wu, CC AF de Groot, Patricia M. Carter, Brett W. Abbott, Gerald F. Wu, Carol C. TI Pitfalls in Chest Radiographic Interpretation: Blind Spots SO SEMINARS IN ROENTGENOLOGY LA English DT Article ID MISSED LUNG-CANCER; PULMONARY NODULES; NEVER SMOKERS; RADIOLOGY; ERRORS; PERFORMANCE; IMPROVEMENT; RETROSPECT; DIAGNOSIS; ACCURACY C1 [de Groot, Patricia M.; Carter, Brett W.; Wu, Carol C.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Abbott, Gerald F.] Massachusetts Gen Hosp, Dept Radiol, Div Thorac Imaging & Intervent, Boston, MA 02114 USA. RP de Groot, PM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Sect Thorac Imaging, 1515 Holcombe Blvd,Unit 1478, Houston, TX 77030 USA. EM pdegroot@mdanderson.org NR 34 TC 0 Z9 0 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-198X EI 1558-4658 J9 SEMIN ROENTGENOL JI Semin. Roentgenology PD JUL PY 2015 VL 50 IS 3 BP 197 EP 209 DI 10.1053/j.ro.2015.01.008 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ6BA UT WOS:000355576800007 PM 26002240 ER PT J AU Lichtenberger, JP Carter, BW Abbott, GF AF Lichtenberger, John P., III Carter, Brett W. Abbott, Gerald F. TI Pitfalls in Imaging of the Chest Wall SO SEMINARS IN ROENTGENOLOGY LA English DT Article ID RADIOLOGIC FINDINGS; PECTUS EXCAVATUM; PATHOLOGICAL CORRELATION; TUMORS; SPECTRUM C1 [Lichtenberger, John P., III] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. [Carter, Brett W.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Abbott, Gerald F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Lichtenberger, JP (reprint author), Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM John.lichtenberger@usuhs.edu NR 24 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-198X EI 1558-4658 J9 SEMIN ROENTGENOL JI Semin. Roentgenology PD JUL PY 2015 VL 50 IS 3 BP 251 EP 257 DI 10.1053/j.ro.2015.01.006 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ6BA UT WOS:000355576800014 PM 26002247 ER PT J AU Kidia, K Machando, D Bere, T Macpherson, K Nyamayaro, P Potter, L Makadzange, T Munjoma, R Marufu, M Araya, R Safren, S O'Cleirigh, C Chibanda, D Abas, M AF Kidia, Khameer Machando, Debra Bere, Tarisai Macpherson, Kirsty Nyamayaro, Primrose Potter, Lucy Makadzange, Tariro Munjoma, Ronald Marufu, Marshall Araya, Ricardo Safren, Steven O'Cleirigh, Conall Chibanda, Dixon Abas, Melanie TI 'I was thinking too much': experiences of HIV-positive adults with common mental disorders and poor adherence to antiretroviral therapy in Zimbabwe SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE HIV/AIDS; depression; mental health; adherence; antiretroviral therapy; barriers ID QUALITY-OF-LIFE; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; MIDDLE-INCOME COUNTRIES; DEPRESSION CBT-AD; SOCIAL SUPPORT; TREATMENT NONADHERENCE; EXPLANATORY MODELS; HIV/AIDS TREATMENT; INFECTED PERSONS AB OBJECTIVE To document the lived experiences of people with both poor mental health and suboptimal adherence to antiretroviral therapy in high HIV prevalence settings. METHODS In-depth qualitative interviews were conducted with 47 (female = 31) HIV-positive adults who scored above the cut-point on a locally validated scale for common mental disorders (CMDs). Purposive sampling was used to recruit participants with evidence of poor adherence. Six additional key informant interviews (female = 6) were conducted with healthcare workers. Data were collected and analysed inductively by an interdisciplinary coding team. RESULTS The major challenges faced by participants were stressors (poverty, stigma, marital problems) and symptoms of CMDs ('thinking too much', changes to appetite and sleep, 'burdened heart' and low energy levels). Thinking too much, which appears closely related to rumination, was the symptom with the greatest negative impact on adherence to antiretroviral therapy among HIV-positive adults with CMDs. In turn, thinking too much was commonly triggered by the stressors faced by people living with HIV/AIDS, especially poverty. Finally, participants desired private counselling, access to income-generating activities and family engagement in mental health care. CONCLUSIONS Better understanding of the local expression of mental disorders and of underlying stressors can inform the development of culturally sensitive interventions to reduce CMDs and poor adherence to antiretroviral therapy. C1 [Kidia, Khameer] Icahn Sch Med Mt Sinai, Arnhold Global Hlth Inst, New York, NY 10029 USA. [Kidia, Khameer; Machando, Debra; Bere, Tarisai; Nyamayaro, Primrose; Makadzange, Tariro; Munjoma, Ronald; Marufu, Marshall; Chibanda, Dixon; Abas, Melanie] Univ Zimbabwe, Coll Hlth Sci, Harare, Zimbabwe. [Machando, Debra] Womens Univ Africa, Harare, Zimbabwe. [Macpherson, Kirsty; Potter, Lucy; Abas, Melanie] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Makadzange, Tariro] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Araya, Ricardo] London Sch Hyg & Trop Med, Dept Populat Hlth, London WC1, England. [Safren, Steven; O'Cleirigh, Conall] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Kidia, K (reprint author), Icahn Sch Med Mt Sinai, Arnhold Global Hlth Inst, 1 Gustave Levy Pl, New York, NY 10029 USA. EM kkidia@gmail.com FU NIH - National Institute of Mental Health [1R21MH094156-01] FX This study was supported by NIH Research Grant 1R21MH094156-01 funded by the National Institute of Mental Health. We thank Helen Jack and Julia Weigel for reading and commenting on earlier drafts of this manuscript. We would also like to thank Jessica Magidson, Dr. C. Ndlovhu and the personnel on the TENDAI project who have made this study possible. Finally, we thank the participants and healthcare workers at Parirenyatwa OI Clinic for taking time to be part of this study. NR 71 TC 6 Z9 7 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 EI 1365-3156 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD JUL PY 2015 VL 20 IS 7 BP 903 EP 913 DI 10.1111/tmi.12502 PG 11 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CJ7FY UT WOS:000355661200008 PM 25754063 ER PT J AU Christopoulos, G Wyman, RM Alaswad, K Karmpaliotis, D Lombardi, W Grantham, JA Yeh, RW Jaffer, FA Cipher, DJ Rangan, BV Christakopoulos, GE Kypreos, MA Lembo, N Kandzari, D Garcia, S Thompson, CA Banerjee, S Brilakis, ES AF Christopoulos, Georgios Wyman, R. Michael Alaswad, Khaldoon Karmpaliotis, Dimitri Lombardi, William Grantham, J. Aaron Yeh, Robert W. Jaffer, Farouc A. Cipher, Daisha J. Rangan, Bavana V. Christakopoulos, Georgios E. Kypreos, Megan A. Lembo, Nicholas Kandzari, David Garcia, Santiago Thompson, Craig A. Banerjee, Subhash Brilakis, Emmanouil S. TI Clinical Utility of the Japan-Chronic Total Occlusion Score in Coronary Chronic Total Occlusion Interventions Results from a Multicenter Registry SO CIRCULATION-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE chronic total occlusion; complication; J-CTO score; outcome; percutaneous coronary intervention; radiation ID IN-HOSPITAL OUTCOMES; US REGISTRY; PROCEDURAL COMPLICATIONS; ANGIOGRAPHIC SUCCESS; HYBRID APPROACH; INSIGHTS; REVASCULARIZATION; RECANALIZATION; EFFICACY; SUPPORT AB Background-The performance of the Japan-chronic total occlusion (J-CTO) score in predicting success and efficiency of CTO percutaneous coronary intervention has received limited study. Methods and Results-We examined the records of 650 consecutive patients who underwent CTO percutaneous coronary intervention between 2011 and 2014 at 6 experienced centers in the United States. Six hundred and fifty-seven lesions were classified as easy (J-CTO= 0), intermediate (J-CTO= 1), difficult (J-CTO= 2), and very difficult (J-CTO= 3). The impact of the J-CTO score on technical success and procedure time was evaluated with univariable logistic and linear regression, respectively. The performance of the logistic regression model was assessed with the Hosmer-Lemeshow statistic and receiver operator characteristic curves. Antegrade wiring techniques were used more frequently in easy lesions (97%) than very difficult lesions (58%), whereas the retrograde approach became more frequent with increased lesion difficulty (41% for very difficult lesions versus 13% for easy lesions). The logistic regression model for technical success demonstrated satisfactory calibration and discrimination (P for Hosmer-Lemeshow = 0.743 and area under curve = 0.705). The J-CTO score was associated with a 2-fold increase in the odds of technical failure (odds ratio 2.04, 95% confidence interval 1.52-2.80, P< 0.001). Procedure time increased by approximate to 20 minutes for every 1-point increase of the J-CTO score (regression coefficient 22.33, 95% confidence interval 17.45-27.22, P< 0.001). Conclusions-J-CTO score was strongly associated with final success and efficiency in this study, supporting its expanded use in CTO interventions. C1 [Christopoulos, Georgios; Rangan, Bavana V.; Christakopoulos, Georgios E.; Banerjee, Subhash; Brilakis, Emmanouil S.] VA N Texas Hlth Care Syst, Dallas, TX USA. [Christopoulos, Georgios; Rangan, Bavana V.; Christakopoulos, Georgios E.; Banerjee, Subhash; Brilakis, Emmanouil S.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Wyman, R. Michael] Torrance Mem Med Ctr, Torrance, CA USA. [Alaswad, Khaldoon] Henry Ford Hosp, Detroit, MI 48202 USA. [Karmpaliotis, Dimitri] Columbia Univ, New York, NY USA. [Lombardi, William] Univ Washington, Seattle, WA 98195 USA. [Grantham, J. Aaron] Mid Amer Heart Inst, Kansas City, MO USA. [Yeh, Robert W.; Jaffer, Farouc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cipher, Daisha J.] Univ Texas Arlington, Coll Hlth Innovat, Arlington, TX 76019 USA. [Kypreos, Megan A.] Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, El Paso, TX USA. [Lembo, Nicholas; Kandzari, David] Piedmont Heart Inst, Atlanta, GA USA. [Garcia, Santiago] Minneapolis VA Med Ctr, Minneapolis, MN USA. [Thompson, Craig A.] Boston Sci, Natick, MA USA. RP Brilakis, ES (reprint author), Dallas VA Med Ctr 111A, 4500 S Lancaster Rd, Dallas, TX 75216 USA. EM esbrilakis@gmail.com FU National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001105] FX Study data were collected and managed using REDCap electronic data capture tools hosted at University of Texas Southwestern Medical Center.27 REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001105. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. NR 27 TC 22 Z9 22 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-7640 EI 1941-7632 J9 CIRC-CARDIOVASC INTE JI Circ.-Cardiovasc. Interv. PD JUL PY 2015 VL 8 IS 7 AR e002171 DI 10.1161/CIRCINTERVENTIONS.114.002171 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF5XV UT WOS:000390404100004 PM 26162857 ER PT J AU Tritos, NA Yuen, KCJ Kelly, DF AF Tritos, Nicholas A. Yuen, Kevin C. J. Kelly, Daniel F. CA AACE Neuroendocrine Pituitary Sci TI AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: A NEUROENDOCRINE APPROACH TO PATIENTS WITH TRAUMATIC BRAIN INJURY SO ENDOCRINE PRACTICE LA English DT Article ID GROWTH-HORMONE REPLACEMENT; ANEURYSMAL SUBARACHNOID HEMORRHAGE; ANTERIOR-PITUITARY DYSFUNCTION; ADULT GH DEFICIENCY; QUALITY-OF-LIFE; DIABETES-INSIPIDUS; UNITED-STATES; HYPOTHALAMOPITUITARY DYSFUNCTION; POSTTRAUMATIC HYPOPITUITARISM; TESTOSTERONE THERAPY AB Objective: Traumatic brain injury (TBI) is now recognized as a major public health concern in the United States and is associated with substantial morbidity and mortality in both children and adults. Several lines of evidence indicate that TBI-induced hypopituitarism is not infrequent in TBI survivors and may contribute to the burden of illness in this population. The goal of this article is to review the published data and propose an approach for the neuroendocrine evaluation and management of these patients. Methods: To identify pertinent articles, electronic literature searches were conducted using the following keywords: "traumatic brain injury," "pituitary," "hypopituitarism," "growth hormone deficiency," "hypogonadism," "hypoadrenalism," and "hypothyroidism." Relevant articles were identified and considered for inclusion in the present article. Results: TBI-induced hypopituitarism appears to be more common in patients with severe TBI. However, patients with mild TBI or those with repeated, sports-, or blast-related TBI are also at risk for hypopituitarism. Deficiencies of growth hormone and gonadotropins appear to be most common and have been associated with increased morbidity in this population. A systematic approach is advised in order to establish the presence of pituitary hormone deficiencies and implement appropriate replacement therapies. Conclusion: The presence of traumatic hypopituitarism should be considered during the acute phase as well as during the rehabilitation phase of patients with TBI. All patients with moderate to severe TBI require evaluation of pituitary function. In addition, symptomatic patients with mild TBI and impaired quality of life are at risk for hypopituitarism and should be offered neuroendocrine testing. C1 [Tritos, Nicholas A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. [Tritos, Nicholas A.] Harvard Univ, Sch Med, Boston, MA USA. [Yuen, Kevin C. J.] Swedish Neurosci Inst, Swedish Pituitary Ctr, Seattle, WA USA. [Kelly, Daniel F.] St Johns Brain Tumor Ctr, Santa Monica, CA USA. [Kelly, Daniel F.] Pituitary Disorders Program, Santa Monica, CA USA. [Kelly, Daniel F.] John Wayne Canc Inst, Santa Monica, CA USA. RP Tritos, NA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. EM ntritos@partners.org FU Ipsen; Pfizer; Novo Nordisk FX Dr. Tritos has received research support from Ipsen, Pfizer, and Novo Nordisk. The other authors have no multiplicity of interest to disclose. NR 56 TC 2 Z9 2 U1 3 U2 5 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD JUL PY 2015 VL 21 IS 7 BP 823 EP 831 DI 10.4158/EP14567.DSCR PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO7LQ UT WOS:000377964500014 PM 26172127 ER PT J AU Wilkinson, CW AF Wilkinson, Charles W. TI COMMENTARY ON A NEUROENDOCRINE APPROACH TO PATIENTS WITH TRAUMATIC BRAIN INJURY SO ENDOCRINE PRACTICE LA English DT Editorial Material ID PITUITARY DYSFUNCTION C1 [Wilkinson, Charles W.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Wilkinson, Charles W.] Washington Univ, Sch Med, Dept Psychiat & Behav Sci, St Louis, MO 63130 USA. RP Wilkinson, CW (reprint author), VA Puget Sound Hlth Care Syst, S-182 GRECC,1660 South Columbian Way, Seattle, WA 98108 USA. EM wilkinso@uw.edu FU RRD VA [I01 RX000509] NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD JUL PY 2015 VL 21 IS 7 BP 851 EP 853 DI 10.4158/EP15854.CO PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO7LQ UT WOS:000377964500018 PM 26172130 ER PT J AU Hodges, C Williams, R Crabtree, GR Kadoch, C AF Hodges, C. Williams, R. Crabtree, G. R. Kadoch, C. TI Subunit switching of the BAF (mSWI/SNF) complex is governed by an ordered, branched assembly pathway SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 10th European-Biophysical-Societies-Association (EBSA) European Biophysics Congress CY JUL 18-22, 2015 CL Dresden, GERMANY SP European Biophys Soc Assoc C1 [Hodges, C.; Crabtree, G. R.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Williams, R.; Kadoch, C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kadoch, C.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Crabtree, G. R.] Howard Hughes Med Inst, Chevy Chase, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2015 VL 44 SU 1 MA P-623 BP S206 EP S206 PG 1 WC Biophysics SC Biophysics GA DR6GW UT WOS:000380001400624 ER PT J AU Brooks, GA Kansagra, AJ Rao, SR Weitzman, JI Linden, EA Jacobson, JO AF Brooks, Gabriel A. Kansagra, Ankit J. Rao, Sowmya R. Weitzman, James I. Linden, Erica A. Jacobson, Joseph O. TI A Clinical Prediction Model to Assess Risk for Chemotherapy-Related Hospitalization in Patients Initiating Palliative Chemotherapy SO JAMA ONCOLOGY LA English DT Article ID OLDER-ADULTS; CANCER; TOXICITY; CARE; COST; CRITERIA AB IMPORTANCE Chemotherapy-related hospitalizations in patients with advanced cancer are common, distressing, and costly. Methods to identify patients at high risk of chemotherapy toxic effects will permit development of targeted strategies to prevent chemotherapy-related hospitalizations. OBJECTIVE To demonstrate the feasibility of using readily available clinical data to assess patient-specific risk of chemotherapy-related hospitalization. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study conducted from January 2003 through December 2011 at the Mass General/North Shore Cancer Center, a community-based cancer center in northeastern Massachusetts. The parent cohort included 1579 consecutive patients with advanced solid-tumor cancer receiving palliative-intent chemotherapy. Case patients (n = 146) included all patients from the parent cohort who experienced a chemotherapy-related hospitalization. Controls (n = 292) were randomly selected from 1433 patients who did not experience a chemotherapy-related hospitalization. EXPOSURES Putative risk factors for chemotherapy-related hospitalization-including patient characteristics, treatment characteristics, and pretreatment laboratory values-were abstracted from medical records. Multivariable logistic regression was used to model the patient-specific risk of chemotherapy-related hospitalization. MAIN OUTCOMES AND MEASURES Chemotherapy-related hospitalization, as adjudicated by the oncology clinical care team within a systematic quality-assessment program. RESULTS A total of 146 (9.2%) of 1579 patients from the parent cohort experienced a chemotherapy-related hospitalization. In multivariate regression, 7 variables were significantly associated with chemotherapy-related hospitalization: age, Charlson comorbidity score, creatinine clearance, calcium level, below-normal white blood cell and/or platelet count, polychemotherapy (vs monotherapy), and receipt of camptothecin chemotherapy. The median predicted risk of chemotherapy-related hospitalization was 6.0% (interquartile range [IQR], 3.6%-11.4%) in control patients and 14.7%(IQR, 6.8%-22.5%) in case patients. The bootstrap-adjusted C statistic was 0.71 (95% CI, 0.66-0.75). At a risk threshold of 15%, the model exhibited a sensitivity of 49% (95% CI, 41%-57%) and a specificity of 85%(95% CI, 81%-89%) for predicting chemotherapy-related hospitalization. CONCLUSIONS AND RELEVANCE In patients initiating palliative chemotherapy for cancer, readily available clinical data were associated with the patient-specific risk of chemotherapy-related hospitalization. External validation and evaluation in the context of a clinical decision support tool are warranted. C1 [Brooks, Gabriel A.; Jacobson, Joseph O.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Brooks, Gabriel A.; Linden, Erica A.; Jacobson, Joseph O.] Harvard Med Sch, Boston, MA USA. [Kansagra, Ankit J.] Tufts Univ, Sch Med, Baystate Med Ctr, Springfield, MA 01199 USA. [Rao, Sowmya R.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Rao, Sowmya R.] Bedford Veteran Affairs Med Ctr, Bedford, MA USA. [Weitzman, James I.; Linden, Erica A.] Mass Gen North Shore Canc Ctr, Danvers, MA USA. RP Brooks, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM gabriel_brooks@dfci.harvard.edu FU Read Family Trust; Conquer Cancer Foundation of the American Society of Clinical Oncology; National Cancer Institute of the National Institutes of Health [R25CA09220] FX This research was supported by a grant from the Read Family Trust. Dr Brooks was supported by a Young Investigator Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology and by program grant R25CA09220 from the National Cancer Institute of the National Institutes of Health. NR 22 TC 1 Z9 3 U1 1 U2 3 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 JUL PY 2015 VL 1 IS 4 BP 441 EP 447 DI 10.1001/jamaoncol.2015.0828 PG 7 WC Oncology SC Oncology GA DW5GS UT WOS:000383672100010 PM 26181251 ER PT J AU Oh, KS Loeffler, JS AF Oh, Kevin S. Loeffler, Jay S. TI The Changing Landscape of Whole-Brain Radiation Therapy SO JAMA ONCOLOGY LA English DT Editorial Material ID CONTROLLED-TRIAL; METASTASES; RADIOTHERAPY; RADIOSURGERY; MELANOMA; LUNG C1 [Oh, Kevin S.; Loeffler, Jay S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. RP Loeffler, JS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM jloeffler@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 1 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 JUL PY 2015 VL 1 IS 4 BP 464 EP 465 DI 10.1001/jamaoncol.2015.1144 PG 3 WC Oncology SC Oncology GA DW5GS UT WOS:000383672100013 PM 26181255 ER PT J AU Harshman, LC Wang, XD Nakabayashi, M Xie, WL Valenca, L Werner, L Yu, YJ Kantoff, AM Sweeney, CJ Mucci, LA Pomerantz, M Lee, GSM Kantoff, PW AF Harshman, Lauren C. Wang, Xiaodong Nakabayashi, Mari Xie, Wanling Valenca, Loana Werner, Lillian Yu, Yongjiang Kantoff, Aaron M. Sweeney, Christopher J. Mucci, Lorelei A. Pomerantz, Mark Lee, Gwo-Shu Mary Kantoff, Philip W. TI Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer SO JAMA ONCOLOGY LA English DT Article ID BIOCHEMICAL RECURRENCE; RADICAL PROSTATECTOMY; RISK; METAANALYSIS; CASTRATION; SLCO2B1; TESTOSTERONE; SLCO1B3; PATHWAY; IMPACT AB IMPORTANCE Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells. OBJECTIVE To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS In vitro studieswere performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. MAIN OUTCOMES AND MEASURES To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors. RESULTS In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] forM0 disease and 0.84 [95% CI, 0.67-1.06] forM1 disease; P for interaction = .72). CONCLUSIONS AND RELEVANCE Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users. C1 [Harshman, Lauren C.; Nakabayashi, Mari; Valenca, Loana; Sweeney, Christopher J.; Pomerantz, Mark; Kantoff, Philip W.] Harvard Med Sch, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA USA. [Wang, Xiaodong; Yu, Yongjiang; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Harvard Med Sch, Gelb Ctr Translat Oncol, Dana Farber Canc Inst, Boston, MA USA. [Xie, Wanling; Werner, Lillian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Yu, Yongjiang] Shanghai Jiao Tong Univ, Xinhua Hosp, Dept Urol, Sch Med, Shanghai, Peoples R China. [Kantoff, Aaron M.] Apple Tree Partners, New York, NY USA. [Mucci, Lorelei A.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Kantoff, PW (reprint author), Dana Farber Canc Inst, Div Solid Tumor Oncol, 450 Brookline Ave,Dana 1230, Boston, MA 02215 USA. EM philip_kantoff@dfci.harvard.edu FU Dana-Farber Prostate Cancer SPORE [P50CA090381]; Department of Defense [W81XWH-14-1-0515] FX The research was funded by the Dana-Farber Prostate Cancer SPORE P50CA090381 and by the Department of Defense (W81XWH-14-1-0515). NR 30 TC 16 Z9 17 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 JUL PY 2015 VL 1 IS 4 BP 495 EP 504 DI 10.1001/jamaoncol.2015.0829 PG 10 WC Oncology SC Oncology GA DW5GS UT WOS:000383672100018 PM 26181260 ER PT J AU Callahan, AB Skondra, D Krzystolik, M Yonekawa, Y Eliott, D AF Callahan, Alison B. Skondra, Dimitra Krzystolik, Magdalena Yonekawa, Yoshihiro Eliott, Dean TI Wyburn-Mason Syndrome Associated With Cutaneous Reactive Angiomatosis and Central Retinal Vein Occlusion SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID COMPLICATION; MALFORMATION AB Retinal venous occlusive events are a rare complication of arteriovenous malformations of the retina found in Wyburn-Mason syndrome. The authors present a case of a 28-year-old man diagnosed with Wyburn-Mason syndrome and cutaneous reactive angiomatosis, a reactive angioproliferative disorder induced by vascular occlusion. He developed a central retinal vein occlusion complicated by macular edema and received treatment with intravitreal bevacizumab, which led to resolution of the edema. To the best of the authors' knowledge, this is the first report of an antivascular endothelial growth factor agent employed as an effective treatment for macular edema in the setting of Wyburn-Mason syndrome. The association between Wyburn-Mason syndrome and cutaneous reactive angiomatosis is also a novel finding. C1 [Callahan, Alison B.; Skondra, Dimitra; Krzystolik, Magdalena; Yonekawa, Yoshihiro; Eliott, Dean] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02115 USA. RP Eliott, D (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM dean_eliott@meei.harvard.edu FU Heed Ophthalmic Foundation FX Dr. Yonekawa is partially funded by the Heed Ophthalmic Foundation. The foundation had no role in the design or conduct of the study. Dr. Eliott is an ad hoc consultant for Genentech. The remaining authors report no relevant financial disclosures. NR 9 TC 0 Z9 1 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD JUL PY 2015 VL 46 IS 7 BP 760 EP 762 DI 10.3928/23258160-20150730-12 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA DP9TW UT WOS:000378841300013 PM 26247458 ER PT J AU Awh, CC Miller, JB Wu, DM Eliott, D AF Awh, Caroline C. Miller, John B. Wu, David M. Eliott, Dean TI Leukostasis Retinopathy: A New Clinical Manifestation of Chronic Myeloid Leukemia With Severe Hyperleukocytosis SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA AB The authors report a new clinical manifestation of chronic myeloid leukemia. A 41-year-old man presented with significant visual loss, leading to a diagnosis of chronic myeloid leukemia. His white blood count exceeded that of any previously reported case of the disease with documented retinal findings (562,000/mm(3)), and clinical evaluation revealed the blockage of temporal retinal vessels by white blood cells. Hematologic findings resolved within 1 month of chemotherapy with dasatinib, and further treatment with intravitreal anti-VEGF agents resulted in the complete resolution of fundus findings. The authors propose that leukostasis retinopathy be recognized as a clinical manifestation of this life-threatening disease. C1 [Awh, Caroline C.; Miller, John B.; Wu, David M.; Eliott, Dean] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv,Dept Ophthalmol, Boston, MA 02115 USA. RP Eliott, D (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM dean_eliott@meei.harvard.edu NR 9 TC 1 Z9 1 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD JUL PY 2015 VL 46 IS 7 BP 768 EP 770 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA DP9TW UT WOS:000378841300015 PM 26247460 ER PT J AU MacNamara, A Rabinak, CA Fitzgerald, DA Zhou, XJ Shankman, SA Milad, MR Phan, KL AF MacNamara, Annmarie Rabinak, Christine A. Fitzgerald, Daniel A. Zhou, Xiaohong Joe Shankman, Stewart A. Milad, Mohammed R. Phan, K. Luan TI Neural correlates of individual differences in fear learning SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Fear conditioning; Amygdala; fMRI; Skin conductance response; SCR; Individual differences ID SKIN-CONDUCTANCE RESPONSES; HUMAN AMYGDALA ACTIVITY; ANXIETY DISORDER; EXTINCTION; MEMORY; BRAIN; EXPRESSION; HUMANS; FMRI; PTSD AB Variability in fear conditionability is common, and clarity regarding the neural regions responsible for individual differences in fear conditionability could uncover brain-based biomarkers of resilience or vulnerability to trauma-based psychopathologies (e.g., post-traumatic stress disorder). In recent years, neuroimaging work has yielded a detailed understanding of the neural mechanisms underlying fear conditioning common across participants, however only a minority of studies have investigated the brain basis of inter-individual variation in fear learning. Moreover, the majority of these studies have employed small sample sizes (mean n=17; range n=5-27) and all have failed to meet the minimum recommended sample size for functional magnetic resonance imaging (fMRI) studies of individual differences. Here, using fMRI, we analyzed blood-oxygenation level dependent (BOLD) response recorded simultaneously with skin conductance response (SCR) and ratings of unconditioned stimulus (US) expectancy in 49 participants undergoing Pavlovian fear conditioning. On average, participants became conditioned to the conditioned stimulus (CS+; higher US expectancy ratings and SCR for the CS+ compared to the unpaired conditioned stimulus, CS-); the CS+ also robustly increased activation in the bilateral insula. Amygdala activation was revealed from a regression analysis that incorporated individual differences in fear conditionability (i.e., a between-subjects regressor of mean CS+ > CS- SCR). By replicating results observed using much smaller sample sizes, the results confirm that variation in amygdala reactivity covaries with individual differences in fear conditionability. The link between behavior (SCR) and brain (amygdala reactivity) may be a putative endophenotype for the acquisition of fear memories. (C) 2015 Elsevier B.V. All rights reserved. C1 [MacNamara, Annmarie; Fitzgerald, Daniel A.; Shankman, Stewart A.; Phan, K. Luan] Univ Illinois, Dept Psychiat, Chicago, IL 60608 USA. [Rabinak, Christine A.] Wayne State Univ, Dept Pharm Practice, Detroit, MI 48201 USA. [Rabinak, Christine A.] Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI 48201 USA. [Rabinak, Christine A.] Wayne State Univ, Translat Neurosci Program, Detroit, MI 48201 USA. [Fitzgerald, Daniel A.; Phan, K. Luan] Jesse Brown VA Med Ctr, Mental Hlth Serv Line, Chicago, IL 60612 USA. [Zhou, Xiaohong Joe] Univ Illinois, Dept Radiol, Chicago, IL 60612 USA. [Zhou, Xiaohong Joe] Univ Illinois, Ctr Magnet Resonance Res, Chicago, IL 60612 USA. [Shankman, Stewart A.; Phan, K. Luan] Univ Illinois, Dept Psychol, Chicago, IL 60607 USA. [Milad, Mohammed R.] Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. [Milad, Mohammed R.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Phan, K. Luan] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60612 USA. [Phan, K. Luan] Univ Illinois, Grad Program Neurosci, Chicago, IL 60612 USA. RP MacNamara, A (reprint author), Univ Illinois, Dept Psychiat, 1747 West Roosevelt Rd, Chicago, IL 60608 USA. EM annmarie.macnamara@gmail.com OI MacNamara, Annmarie/0000-0003-0399-973X FU National Institutes of Health (NIH) [R21MH093917]; NIH [T32MH067631-09] FX This material is based upon work supported by a National Institutes of Health (NIH) Grant R21MH093917 (K.L.P.); A.M. is supported by NIH Grant T32MH067631-09. The authors would like to thank Katherine Prater for her assistance in the construction of the behavioral-fMRI task, Donald McNair for his assistance in data collection and Edward F. Pace-Schott for his assistance with data analysis. NR 60 TC 3 Z9 3 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 1 PY 2015 VL 287 BP 34 EP 41 DI 10.1016/j.bbr.2015.03.035 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CI8QV UT WOS:000355037700005 PM 25819422 ER PT J AU Cougo-Pinto, PT Chandra, RV Simonsen, CZ Hirsch, JA Leslie-Mazwi, T AF Cougo-Pinto, Pedro Telles Chandra, Ronil V. Simonsen, Claus Z. Hirsch, Joshua A. Leslie-Mazwi, Thabele TI Intra-Arterial Therapy for Acute Ischemic Stroke: a Golden Age SO CURRENT TREATMENT OPTIONS IN NEUROLOGY LA English DT Review DE Acute stroke; Ischemic stroke; Large vessel occlusion; Proximal occlusion; Endovascular therapy; Intra-arterial therapy; Reperfusion; Recanalization; Angiography; Treatment ID BASILAR ARTERY-OCCLUSION; EARLY CT SCORE; ENDOVASCULAR TREATMENT; ANTERIOR CIRCULATION; INTERVENTIONAL MANAGEMENT; MECHANICAL THROMBECTOMY; IMAGING SELECTION; CONSENSUS STATEMENT; CEREBRAL-ISCHEMIA; RANDOMIZED-TRIAL AB With the recent publication of multiple trials demonstrating the superiority of the endovascular treatment of patients presenting with stroke from large vessel occlusion (LVO) over medical management, the emergent care of these patients is entering a new era. This realization justifies an aggressive treatment approach with these stroke patients, given the poor natural history of the disease. In general, treatment should occur as quickly as is reasonably possible. Patients with NIHSS >8 should be considered, and if <6 h from onset imaging selection achieved with CT and CTA. Those with ASPECTS 95, LVO and intermediate or good collaterals should be treated emergently. For patients with clinical deficits presenting in later timeframes MRI should be used to define core infarct size and therefore treatment eligibility. MRI might also be considered for the workup of stroke patients in centers that can offer it rapidly. Recanalization should be attempted with a stentriever or using a direct aspiration technique, with the patient under conscious sedation rather than general anesthesia, if that is a safe option. Angiographically, the goal is reperfusion of mTICI 2b/3. Post-procedure, the patient should be admitted to an intensive care setting and assessed for inpatient rehabilitation placement as soon as stable. Continuous institutional process improvement ensures that optimization of treatment times and logistics is an ongoing endeavor. Finally, patient outcomes should be assessed at three months, most commonly using the modified Rankin score. C1 [Cougo-Pinto, Pedro Telles] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Hirsch, Joshua A.; Leslie-Mazwi, Thabele] Massachusetts Gen Hosp, Neuroendovasc Serv, Boston, MA 02114 USA. [Chandra, Ronil V.] Monash Univ, Monash Hlth, Intervent Neuroradiol, Melbourne, Vic 3004, Australia. [Simonsen, Claus Z.] Aarhus Univ Hosp, Stroke, Dept Neurol, DK-8000 Aarhus, Denmark. [Cougo-Pinto, Pedro Telles] Univ Sao Paulo, Dept Neurosci & Behav Sci, Ribeirao Preto Med Sch, BR-14049 Ribeirao Preto, SP, Brazil. RP Cougo-Pinto, PT (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. EM TLESLIE-MAZWI@MGH.HARVARD.EDU NR 78 TC 0 Z9 0 U1 2 U2 4 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1092-8480 EI 1534-3138 J9 CURR TREAT OPTION NE JI Curr. Treat. Options Neurol. PD JUL PY 2015 VL 17 IS 7 AR 30 DI 10.1007/s11940-015-0360-7 PG 16 WC Clinical Neurology SC Neurosciences & Neurology GA CJ2VS UT WOS:000355343400003 ER PT J AU Bui-Nguyen, B Butrynski, JE Penel, N Blay, JY Isambert, N Milhem, M Kerst, JM Reyners, AKL Litiere, S Marreaud, S Collin, F van der Graaf, WTA AF Bui-Nguyen, B. Butrynski, J. E. Penel, N. Blay, J. Y. Isambert, N. Milhem, M. Kerst, J. M. Reyners, A. K. L. Litiere, S. Marreaud, S. Collin, F. van der Graaf, W. T. A. CA EORTC STBSG SARC TI A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: The TRUSTS trial SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Soft-tissue sarcoma; Metastatic; Clinical trial; Trabectedin; Doxorubicin; First line chemotherapy ID ECTEINASCIDIN-743; CHEMOTHERAPY; LIPOSARCOMA; SAFETY; ET-743 AB Purpose: To evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression-free survival (PFS), compared to doxorubicin and, in the phase IIb part here, to select the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy. Patients and methods: In this randomised multicentre prospective dose-selection phase IIb superiority trial, 133 patients were randomised between doxorubicin (n = 43), trabectedin (3-hour infusion, T3h) (n = 47) and trabectedin (24-hour infusion, T24h) (n = 43). PFS was defined as time from random assignment until objective progression by response evaluation criteria in solid tumours (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause. Results: The study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm. Median PFS was 2.8 months in the T3h arm, 3.1 months in the T24h arm and 5.5 months in the doxorubicin arm. No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.67-1.90, P = .675; T3h versus doxorubicin: HR 1.50, 95% CI 0.91-2.48, P = .944). Only one toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2%) (T3h), 8 (19.5%) (T24h) and 1 (2.5%) doxorubicin patients. Conclusion: Doxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS). Trabectedin 1.5 mg/m(2)/24-hour infusion is the overall proven approach to delivering this agent in the second-line setting for patients with advanced or metastatic STS. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Bui-Nguyen, B.] Inst Bergonie, Ctr Comprehens Canc, Dept Med Oncol, F-33076 Bordeaux, France. [Butrynski, J. E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Penel, N.] Ctr Oscar Lambret, F-59020 Lille, France. [Blay, J. Y.] Univ Lyon 1, F-69365 Lyon, France. [Blay, J. Y.] Ctr Leon Berard, F-69373 Lyon, France. [Isambert, N.; Collin, F.] Ctr GF Leclerc, F-21079 Dijon, France. [Milhem, M.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Kerst, J. M.] Antoni van Leeuwenhoek Ziekenhuis, Netherlands Canc Inst NKI, Amsterdam, Netherlands. [Reyners, A. K. L.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Litiere, S.; Marreaud, S.] EORTC Headquarters, Brussels, Belgium. [van der Graaf, W. T. A.] Radboud Univ Nijmegen, Med Ctr Nijmegen, NL-6525 ED Nijmegen, Netherlands. RP Bui-Nguyen, B (reprint author), Inst Bergonie, 229 Cours Argonne, F-33076 Bordeaux, France. EM b.bui@bordeaux.unicancer.fr RI van der Graaf, Winette/A-5006-2014; Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU Pharmamar FX This study was supported by a donation from La Ligue Nationale Contre le Cancer from France through the EORTC Charitable Trust. We are grateful to Pharmamar for supporting this study through an Educational Grant and for providing trabectedin for this study. NR 17 TC 17 Z9 18 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2015 VL 51 IS 10 BP 1312 EP 1320 DI 10.1016/j.ejca.2015.03.023 PG 9 WC Oncology SC Oncology GA CJ2RK UT WOS:000355332000012 PM 25912752 ER PT J AU Nishino, M Tirumani, SH Ramaiya, NH Hodi, FS AF Nishino, Mizuki Tirumani, Sree H. Ramaiya, Nikhil H. Hodi, F. Stephen TI Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Review DE Immunotherapy; Cancer; Oncologic imaging; Drug toxicity; Tumor response assessment ID CELL LUNG-CANCER; RESISTANT PROSTATE-CANCER; GUIDELINE VERSION 1.1; METASTATIC MELANOMA; CTLA-4 BLOCKADE; TUMOR RESPONSE; SOLID TUMORS; ADVERSE EVENTS; DOUBLE-BLIND; SINGLE-INSTITUTION AB The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists' awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Nishino, Mizuki; Tirumani, Sree H.; Ramaiya, Nikhil H.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Nishino, Mizuki; Tirumani, Sree H.; Ramaiya, Nikhil H.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med, Boston, MA 02215 USA. [Hodi, F. Stephen] Brigham & Womens Hosp, Boston, MA 02215 USA. RP Nishino, M (reprint author), Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. EM Mizuki_Nishino@DFCI.HARVARD.EDU FU NCI [1K23CA157631] FX The investigator, M.N., was supported by 1K23CA157631 (NCI). NR 60 TC 14 Z9 15 U1 2 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD JUL PY 2015 VL 84 IS 7 BP 1259 EP 1268 DI 10.1016/j.ejrad.2015.03.017 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ1AA UT WOS:000355212100007 PM 25937524 ER PT J AU Gao, YM Saksena, MA Brachtel, EF Termeulen, DC Rafferty, EA AF Gao, Yiming Saksena, Mansi A. Brachtel, Elena F. terMeulen, Deborah C. Rafferty, Elizabeth A. TI How to approach breast lesions in children and adolescents SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Review DE Pediatric breast lesions; Breast evaluation in children and adolescents; Developing breast; Breast cancer in children; Breast ultrasound ID OF-THE-LITERATURE; FOLLOW-UP; POLAND-SYNDROME; SECRETORY CARCINOMA; IMAGING FEATURES; UNITED-STATES; US FINDINGS; MASSES; CANCER; MAMMOGRAPHY AB Assessment of a pediatric breast lesion always starts with clinical evaluation. When imaging of a pediatric breast is indicated, ultrasound is the mainstay. The vast majority of pediatric breast complaints are of benign etiology, therefore the diagnostic/management approach emphasizes "first do no harm". Correlation with age and clinical history helps to direct diagnosis. It is essential to be familiar with the imaging appearance of the normal developing breast at various Tanner stages, in order to diagnose physiologic breast findings and to minimize unnecessary biopsies in young breasts vulnerable to injury. Normal anatomic structures, developmental conditions, benign neoplastic and non-neoplastic lesions are common causes of breast complaints in children. Uncommon benign masses and rarely, secondary more than primary malignancies may present in a pediatric breast. Chest wall masses such as Ewing's sarcoma or rhabdomyosarcoma occur in children and may involve the breast via contiguous growth or locoregional metastasis. In addition, special attention should be given to any breast lesion in a child with risk factors predisposing to breast cancer, such as known extramammary malignancy, genetic mutations, prior mantle irradiation, or strong family history of breast cancer, which usually requires biopsy to exclude the possibility of malignancy. Conclusion: The developing breast is vulnerable to injury, and because breast malignancy is uncommon in children, diagnostic and management approach emphasizes "first do no harm". Understanding normal breast development and the spectrum of common and uncommon pediatric breast lesions are key to the correct diagnosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Gao, Yiming] NYU, Langone Med Ctr, New York, NY 10016 USA. [Gao, Yiming; Saksena, Mansi A.; Brachtel, Elena F.; terMeulen, Deborah C.; Rafferty, Elizabeth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gao, YM (reprint author), 221 Lexington Ave, New York, NY 10016 USA. EM yiminggao@gmail.com NR 57 TC 1 Z9 2 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD JUL PY 2015 VL 84 IS 7 BP 1350 EP 1364 DI 10.1016/j.ejrad.2015.04.011 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ1AA UT WOS:000355212100019 PM 25958188 ER PT J AU Wanasekara, ND Ghosh, S Chen, M Chalivendra, VB Bhowmick, S AF Wanasekara, Nandula D. Ghosh, Shouryadipta Chen, Ming Chalivendra, Vijaya B. Bhowmick, Sankha TI Effect of stiffness of micron/sub-micron electrospun fibers in cell seeding SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE electrospun scaffolds; cell seeding; energy approach; 3T3 fibroblasts; vacuum seeding ID ATOMIC-FORCE MICROSCOPY; MAGNETITE NANOPARTICLES; MECHANICAL-PROPERTIES; TISSUE; NANOFIBERS; BIOREACTOR; SCAFFOLDS; MODULUS; SYSTEM AB The objective of this study was to develop a predictive model for cell seeding depth in electrospun scaffold as a function of fiber stiffness. Electrospun scaffolds (micron and submicron) and 3T3 fibroblasts are used as scaffold-cell systems under vacuum seeding conditions. Atomic force microscopy is used to determine the Young's modulus (E) as a function of fiber diameter. A higher E value led to a lower depth of cell seeding (closer to the surface) indicating that nanofibrous scaffolds offer higher resistance to cell movement compared to microfibrous scaffold. An energy balance model was developed to predict cell seeding depth as a function of E for various vacuum pressures. Experimental data was used in the model to extract unknown parameters to predict cell seeding depth as a function of vacuum pressure for different stiffness scaffolds. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103: 2289-2299, 2015. C1 [Wanasekara, Nandula D.] Univ Exeter, Dept Phys & Astron, Exeter EX4 4SB, Devon, England. [Ghosh, Shouryadipta] Indian Inst Technol, Sch Mech Sci, Bhubaneswar 751013, Orissa, India. [Chen, Ming] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Chalivendra, Vijaya B.; Bhowmick, Sankha] Univ Massachusetts Dartmouth, Dept Mech Engn, N Dartmouth, MA 02747 USA. RP Chalivendra, VB (reprint author), Univ Massachusetts Dartmouth, Dept Mech Engn, N Dartmouth, MA 02747 USA. EM vchalivendra@umassd.edu FU National Science Foundation (NSF) [CMS0618119]; National Textile Center [F06-MD04, M08-MD13] FX Contract grant sponsor: National Science Foundation (NSF) Contract grant sponsor: CMS0618119; Contract grant sponsor: National Textile Center; contract grant number: F06-MD04, M08-MD13 NR 30 TC 2 Z9 2 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1549-3296 EI 1552-4965 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD JUL PY 2015 VL 103 IS 7 BP 2289 EP 2299 DI 10.1002/jbm.a.35362 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CJ1LZ UT WOS:000355246400009 PM 25366921 ER PT J AU Lenz, M Wahl, D Gueorguiev, B Jupiter, JB Perren, SM AF Lenz, Mark Wahl, Dieter Gueorguiev, Boyko Jupiter, Jesse B. Perren, Stephan Marcel TI Concept of variable angle lockingevolution and mechanical evaluation of a recent technology SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE variable angle locking; polyaxial locking; fixed angle locking; locking stability; locking strength ID INTERNAL FIXATOR; FRACTURES; PLATE; STABILITY AB Applications for fracture-adapted screw positioning offered by variable angle locking screws are increasing. The locking strength of the variable angle locking mechanism at different insertion angles was compared to conventional fixed angle locking screws. Stainless steel (S) and titanium (Ti) variable and fixed angle 2.4mm locking screws, inserted at different inclinations (0 degrees-15 degrees), and locked at 0.8Nm were subjected to a load-to-failure test. Ultimate failure moment at the screw-head interface and failure mode of the screws were determined. Significant differences were detected by one-way ANOVA (p<0.05). Stainless steel and titanium variable angle locking screws inserted at 2 degrees-10 degrees inclination exhibited a failure moment comparable to the 0 degrees position (S 1.67 +/- 0.04Nm; Ti 1.67 +/- 0.14Nm) and failed predominantly at the screw neck, with the head remaining fixed to the plate. Inserted at 15 degrees inclination, screws revealed a lower failure moment (S 1.33 +/- 0.06Nm, Ti 1.58 +/- 0.05Nm), and failed predominantly by breakout of the head thread. Fixed angle locking screws inserted at an inclination >2 degrees did not lock properly in the plate hole, providing insufficient locking strength. Variable angle locking screws offer a stable head-locking mechanism at different inclinations, comparable to the locking strength of orthogonal inserted fixed angle locking screws. Marginal inclinations >15 degrees should be used with care. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:988-992, 2015. C1 [Lenz, Mark; Wahl, Dieter; Gueorguiev, Boyko; Perren, Stephan Marcel] AO Res Inst Davos, CH-7270 Davos, Switzerland. [Lenz, Mark] Univ Hosp Jena, Dept Trauma Hand & Reconstruct Surg, Jena, Germany. [Jupiter, Jesse B.] Massachusetts Gen Hosp, Dept Orthopaed Surg Hand, Boston, MA 02114 USA. [Jupiter, Jesse B.] Massachusetts Gen Hosp, Upper Extrem Serv, Boston, MA 02114 USA. [Perren, Stephan Marcel] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. RP Lenz, M (reprint author), AO Res Inst Davos, Clavadelerstr 8, CH-7270 Davos, Switzerland. EM mark.lenz@med.uni-jena.de NR 15 TC 2 Z9 2 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2015 VL 33 IS 7 BP 988 EP 992 DI 10.1002/jor.22851 PG 5 WC Orthopedics SC Orthopedics GA CJ2SA UT WOS:000355333600007 PM 25676391 ER PT J AU Davies, MR Ravishankar, B Laron, D Kim, HT Liu, XH Feeley, BT AF Davies, Michael R. Ravishankar, Bharat Laron, Dominique Kim, Hubert T. Liu, Xuhui Feeley, Brian T. TI Rat rotator cuff muscle responds differently from hindlimb muscle to a combined tendon-nerve injury SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE rotator cuff tear; fatty infiltration; sciatic nerve denervation; Akt; mTOR signaling; TGF- signaling ID FIBER-TYPE COMPOSITION; FATTY INFILTRATION; MODEL; TEAR; RECOVERY; ATROPHY; REPAIR; MTOR; SUPRASPINATUS; AUTOPHAGY AB Rotator cuff tears (RCTs) are among the most common musculoskeletal injuries seen by orthopaedic surgeons. Clinically, massive cuff tears lead to unique pathophysiological changes in rotator cuff muscle, including atrophy, and massive fatty infiltration, which are rarely seen in other skeletal muscles. Studies in a rodent model for RCT have demonstrated that these histologic findings are accompanied by activation of the Akt/mammalian target of rapamycin (mTOR) and transforming growth factor- (TGF-) pathways following combined tendon-nerve injury. The purpose of this study was to compare the histologic and molecular features of rotator cuff muscle and gastrocnemius musclea major hindlimb muscle, following combined tendon-nerve injury. Six weeks after injury, the rat gastrocnemius did not exhibit notable fatty infiltration compared to the rotator cuff. Likewise, the adipogenic markers SREBP-1 and PPAR as well as the TGF- canonical pathway were upregulated in the rotator cuff, but not the gastrocnemius. Our study suggests that the rat rotator cuff and hindlimb muscles differ significantly in their response to a combined tendon-nerve injury. Clinically, these findings highlight the unique response of the rotator cuff to injury, and may begin to explain the poor outcomes of massive RCTs compared to other muscle-tendon injuries. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1046-1053, 2015. C1 [Davies, Michael R.; Ravishankar, Bharat; Laron, Dominique; Kim, Hubert T.; Liu, Xuhui; Feeley, Brian T.] Univ Calif San Francisco, Dept Orthopaed Surg, San Francisco, CA 94158 USA. [Ravishankar, Bharat; Kim, Hubert T.; Liu, Xuhui] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. RP Feeley, BT (reprint author), Univ Calif San Francisco, Dept Orthopaed Surg, 1500 Owens St, San Francisco, CA 94158 USA. EM feeleyb@orthosurg.ucsf.edu FU NIH [R03-AR060871]; OREF Career Development Award FX Grant sponsor: NIH; Grant number: R03-AR060871; Grant sponsor: OREF Career Development Award. NR 32 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2015 VL 33 IS 7 BP 1046 EP 1053 DI 10.1002/jor.22864 PG 8 WC Orthopedics SC Orthopedics GA CJ2SA UT WOS:000355333600015 PM 25974842 ER PT J AU Dimitriou, D Tsai, TY Li, JS Nam, KW Park, KK Kwon, YM AF Dimitriou, Dimitris Tsai, Tsung-Yuan Li, Jing-Sheng Nam, Kwang Woo Park, Kwan Kyu Kwon, Young-Min TI In vivo kinematic evaluation of total hip arthroplasty during stair climbing SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE in vivo kinematics; step-up; biomechanics; total hip arthroplasty; component orientation ID ANTERIOR APPROACH; GAIT; MOTION; KNEE; REPLACEMENTS; ORIENTATION; SEPARATION; FORCES; RANGE; HEAD AB Stair climbing is a physically demanding task and a painful limitation for patients suffering from severe hip osteoarthritis. Although total hip arthroplasty (THA) is the definitive treatment for end-stage osteoarthritis, it is not well understood whether THA restores hip kinematics during strenuous activities. The purpose of this study was to compare the 3D kinematics of THA and native hip during physically demanding tasks and correlate potential differences with THA components orientations/positions in patients with unilateral THA. In vivo hip kinematics were determined during step-up and leg stance activities using a validated combination of 3D CT-based computer modeling and dual fluoroscopic imaging system (DFIS). The THA side demonstrated an average 3.4 degrees (+/- 6.5 degrees, range: -5.9 degrees to 15.2 degrees) greater internal rotation than the contralateral native hip, during the step-up activity but not during leg stance. The difference in internal rotation was highly correlated to the difference in femoral anteversion and anterior translation of hip joint center between implanted and native hip (R-2=0.71, p<0.01). The results suggest the importance of accurate THA component placement in restoring normal hip kinematics during functional activities. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1087-1093, 2015. C1 [Dimitriou, Dimitris; Tsai, Tsung-Yuan; Li, Jing-Sheng; Nam, Kwang Woo; Park, Kwan Kyu; Kwon, Young-Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02115 USA. [Park, Kwan Kyu] Yonsei Univ, Coll Med, Dept Orthoped Surg, Seoul, South Korea. [Nam, Kwang Woo] Jeju Natl Univ, Sch Med, Dept Orthoped Surg, Jeju, South Korea. RP Kwon, YM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02115 USA. EM YMKWON@mgh.harvard.edu OI Tsai, Tsung-Yuan/0000-0003-1522-2987; Dimitriou, Dimitris/0000-0002-9558-7080 FU Department of Orthopaedic Surgery, MGH/MAKO Surgical Corp. FX Grant sponsor: Department of Orthopaedic Surgery, MGH/MAKO Surgical Corp., 2555 Davie Road, Ft. Lauderdale, FL 33317. NR 27 TC 1 Z9 1 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2015 VL 33 IS 7 BP 1087 EP 1093 DI 10.1002/jor.22837 PG 7 WC Orthopedics SC Orthopedics GA CJ2SA UT WOS:000355333600020 PM 25626860 ER PT J AU Huh, JY Mantzoros, CS AF Huh, Joo Young Mantzoros, Christos S. TI Irisin physiology, oxidative stress, and thyroid dysfunction: What next? SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Editorial Material ID CIRCULATING IRISIN; ADIPOSE-TISSUE; SELF-DISPROPORTIONATION; CELL-PROLIFERATION; INSULIN-RESISTANCE; FNDC5 GENE; EXERCISE; HUMANS; MUSCLE; SERUM C1 [Huh, Joo Young] Chonnam Natl Univ, Coll Pharm, Gwangju 500757, South Korea. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02215 USA. RP Huh, JY (reprint author), Chonnam Natl Univ, Coll Pharm, 77 Yongbong Ro, Gwangju 500757, South Korea. EM jooyhuh@jnu.ac.kr; cmantzor@bidmc.harvard.edu NR 43 TC 8 Z9 9 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD JUL PY 2015 VL 64 IS 7 BP 765 EP 767 DI 10.1016/j.metabol.2015.02.009 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ1JL UT WOS:000355239800001 PM 25916681 ER PT J AU Chang, WT Jaaskelainen, IP Belliveau, JW Huang, S Hung, AY Rossi, S Ahveninen, J AF Chang, Wei-Tang Jaaskelainen, Iiro P. Belliveau, John W. Huang, Samantha Hung, An-Yi Rossi, Stephanie Ahveninen, Jyrki TI Combined MEG and EEG show reliable patterns of electromagnetic brain activity during natural viewing SO NEUROIMAGE LA English DT Article ID SURFACE-BASED ANALYSIS; CORTICAL ACTIVITY; FMRI; SYSTEM; RECONSTRUCTION; INDIVIDUALS; ATTENTION; CORTEX; SCENES AB Naturalistic stimuli such as movies are increasingly used to engage cognitive and emotional processes during fMRI of brain hemodynamic activity. However, movies have been little utilized during magnetoencephalography (MEG) and EEG that directly measure population-level neuronal activity at a millisecond resolution. Here, subjects watched a 17-min segment from the movie Crash (Lionsgate Films, 2004) twice during simultaneous MEG/EEG recordings. Physiological noise components, including ocular and cardiac artifacts, were removed using the DRIFTER algorithm. Dynamic estimates of cortical activity were calculated using MRI-informed minimum-norm estimation. To improve the signal-to-noise ratio (SNR), principal component analyses (PCA) were employed to extract the prevailing temporal characteristics within each anatomical parcel of the Freesurfer Desikan-Killiany cortical atlas. A variety of alternative inter-subject correlation (ISC) approaches were then utilized to investigate the reliability of inter-subject synchronization during natural viewing. In the first analysis, the ISCs of the time series of each anatomical region over the full time period across all subject pairs were calculated and averaged. In the second analysis, dynamic ISC (dISC) analysis, the correlation was calculated over a sliding window of 200 ms with 3.3 ms steps. Finally, in a between-run ISC analysis, the between-run correlation was calculated over the dynamic ISCs of the two different runs after the Fisher z-transformation. Overall, the most reliable activations occurred in occipital/inferior temporal visual and superior temporal auditory cortices as well as in the posterior cingulate, precuneus, pre- and post-central gyri, and right inferior and middle frontal gyri. Significant between-run ISCs were observed in superior temporal auditory cortices and inferior temporal visual cortices. Taken together, our results show that movies can be utilized as naturalistic stimuli in MEG/EEG similarly as in fMRI studies. (C) 2015 Elsevier Inc. All rights reserved. C1 [Chang, Wei-Tang; Belliveau, John W.; Huang, Samantha; Hung, An-Yi; Rossi, Stephanie; Ahveninen, Jyrki] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Jaaskelainen, Iiro P.] Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, Brain & Mind Lab, Espoo, Finland. [Belliveau, John W.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hung, An-Yi] Natl Yang Ming Univ, Inst Neurosci, Taipei 112, Taiwan. RP Chang, WT (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM welton@nmr.mgh.harvard.edu RI Jaaskelainen, Iiro/C-7392-2012 OI Jaaskelainen, Iiro/0000-0001-6001-6950 FU National Institutes of Health (NIH) [R01MH083744, R21DC014134, R01HD040712, R01NS037462]; National Institute of Biomedical Imaging and Bioengineering (NIBIB) [P41EB015896]; National Center for Research Resources Shared Instrumentation [S10RR014978, S10RR021110, S10RR019307, S10RR014798, S10RR023401]; Academy of Finland [138145] FX We thank Nao Suzuki and Drs. Seppo Ahlfors, Naoaki Tanaka, and Matti Hamalainen for their advice and support. This work was supported by the National Institutes of Health (NIH) grant nos. R01MH083744, R21DC014134, R01HD040712, and R01NS037462. The research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB). The research environment was additionally supported by the National Center for Research Resources Shared Instrumentation grant nos. S10RR014978, S10RR021110, S10RR019307, S10RR014798, and S10RR023401. Author I.P.J. was supported by the Academy of Finland grant no. 138145. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 33 TC 6 Z9 6 U1 2 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2015 VL 114 BP 49 EP 56 DI 10.1016/j.neuroimage.2015.03.066 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CI8ES UT WOS:000355002900004 PM 25842290 ER PT J AU Milekovic, T Truccolo, W Grun, S Riehle, A Brochier, T AF Milekovic, Tomislav Truccolo, Wilson Gruen, Sonja Riehle, Alexa Brochier, Thomas TI Local field potentials in primate motor cortex encode grasp kinetic parameters SO NEUROIMAGE LA English DT Article DE Macaque; Motor cortex; Kinetics; Grasping; Local field potentials; Movement planning ID CORTICO-MOTONEURONAL CELLS; DORSAL PREMOTOR CORTEX; SPIKING ACTIVITY; MACAQUE MONKEY; HIGH-FREQUENCY; REACH; SIGNALS; MOVEMENTS; TETRAPLEGIA; FORCE AB Reach and grasp kinematics are known to be encoded in the spiking activity of neuronal ensembles and in local field potentials (LFPs) recorded from primate motor cortex during movement planning and execution. However, little is known, especially in LFPs, about the encoding of kinetic parameters, such as forces exerted on the object during the same actions. We implanted two monkeys with microelectrode arrays in the motor cortical areas MI and PMd to investigate encoding of grasp-related parameters in motor cortical LFPs during planning and execution of reach-and-grasp movements. We identified three components of the LFP that modulated during grasps corresponding to low (0.3-7 Hz), intermediate(similar to 10-similar to 40 Hz) and high (similar to 80-250 Hz) frequency bands. We show that all three components can be used to classify not only grip types but also object loads during planning and execution of a grasping movement. In addition, we demonstrate that all three components recorded during planning or execution can be used to continuously decode finger pressure forces and hand position related to the grasping movement. Low and high frequency components provide similar classification and decoding accuracies, which were substantially higher than those obtained from the intermediate frequency component. Our results demonstrate that intended reach and grasp kinetic parameters are encoded in multiple LFP bands during both movement planning and execution. These findings also suggest that the LFP is a reliable signal for the control of parameters related to object load and applied pressure forces in brain-machine interfaces. (C) 2015 Elsevier Inc. All rights reserved. C1 [Milekovic, Tomislav] Univ Freiburg, Bernstein Ctr Freiburg, D-79106 Freiburg, Germany. [Milekovic, Tomislav] Univ London Imperial Coll Sci Technol & Med, Dept Bioengn, London, England. [Milekovic, Tomislav] Univ London Imperial Coll Sci Technol & Med, Dept Elect & Elect Engn, London, England. [Truccolo, Wilson] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Truccolo, Wilson] Brown Univ, Inst Brain Sci, Providence, RI 02912 USA. [Truccolo, Wilson] US Dept Vet Affairs, Ctr Neurorestorat & Neurotechnol, Providence, RI 02912 USA. [Gruen, Sonja] Res Ctr Julich, Inst Neurosci & Med INM 6, Julich, Germany. [Gruen, Sonja] Res Ctr Julich, Inst Adv Simulat IAS 6, Julich, Germany. [Gruen, Sonja] Rhein Westfal TH Aachen, Theoret Syst Neurobiol, Aachen, Germany. [Gruen, Sonja; Riehle, Alexa] RIKEN, Brain Sci Inst, Wako, Saitama, Japan. [Riehle, Alexa; Brochier, Thomas] CNRS AMU, Inst Neurosci la Timone, Marseille, France. RP Milekovic, T (reprint author), Swiss Fed Inst Technol EPFL, EPFL SV UPCOURTINE, Ctr Neuroprosthet, Stn 19, CH-1015 Lausanne, Switzerland. EM tomislav.milekovic@epfl.ch; wilson_truccolo@brown.edu; s.gruen@fz-juelich.de; alexa.riehle@univ-amu.fr; thomas.brochier@univ-amu.fr RI Grun, Sonja/I-6321-2013; OI Grun, Sonja/0000-0003-2829-2220; Milekovic, Tomislav/0000-0001-6769-6506 FU German Federal Ministry of Education and Research (BMBF) [01GQ0830]; Imperial College London; IBRO InEurope Short Stay Grant program; RIKEN-CNRS Collaborative Research Agreement; ANR GRASP (France); BrainScaleS (EU) [269912]; Helmoltz portfolio theme "Supercomputing and modeling for the human brain" (SMHB); U.S. National Institute of Neurological Disorders and Stroke (NINDS) [NS057389]; Brown University FX This work was supported by the German Federal Ministry of Education and Research (BMBF) grant 01GQ0830 to BFNT Freiburg and Tubingen, Imperial College London, IBRO InEurope Short Stay Grant program, RIKEN-CNRS Collaborative Research Agreement, ANR GRASP (France), BrainScaleS (EU Grant 269912), Helmoltz portfolio theme "Supercomputing and modeling for the human brain" (SMHB), U.S. National Institute of Neurological Disorders and Stroke (NINDS) K01 Career Award NS057389, and the Pablo J. Salame '88 Goldman Sachs endowed Professorship in Computational Neuroscience, Brown University. NR 63 TC 4 Z9 4 U1 3 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2015 VL 114 BP 338 EP 355 DI 10.1016/j.neuroimage.2015.04.008 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CI8ES UT WOS:000355002900031 PM 25869861 ER PT J AU Freeman, MA Myaskovsky, L AF Freeman, Michael A. Myaskovsky, Larissa TI An overview of disparities and interventions in pediatric kidney transplantation worldwide SO PEDIATRIC NEPHROLOGY LA English DT Review DE Kidney transplantation; Minority health; Organ allocation; Racial disparities; Socioeconomic status ID STAGE RENAL-DISEASE; RACIAL DISPARITIES; ORGAN-TRANSPLANTATION; SOCIOECONOMIC-STATUS; MEDICATION ADHERENCE; REPLACEMENT THERAPY; ETHNIC DISPARITIES; UNITED-STATES; US CHILDREN; DONATION AB Despite the stated goals of the transplant community and the majority of organ allocation systems, persistent racial disparities in pediatric kidney transplantation exist throughout the world. These disparities are evident in both living and deceased donor kidney transplantation and are independent of any clinical differences between racial groups. The reasons for these persistent disparities are multifactorial, reflecting both patient and provider barriers to care. In this review, we examine the most current findings regarding disparities in pediatric kidney transplantation and consider interventions which may help reduce those disparities. C1 [Freeman, Michael A.] Penn State Hershey Childrens Hosp, Div Pediat Nephrol & Hypertens, Hershey, PA 17033 USA. [Myaskovsky, Larissa] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. RP Freeman, MA (reprint author), Penn State Hershey Childrens Hosp, Div Pediat Nephrol & Hypertens, Mail Code H085,500 Univ Dr, Hershey, PA 17033 USA. EM MFreeman3@hmc.psu.edu RI Freeman, Michael/O-1837-2016 OI Freeman, Michael/0000-0001-5022-4377 FU National Institute of Diabetes, Digestive and Kidney Disease [T32DKK091202, R01DK081325]; Veterans Affairs Health Services Research and Development Service [IIR 06-220, CIN 13-405] FX The data reported in the USRDS 2013 report were supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. The data and analyses reported in the 2011 and 2012 Annual Data Report of the U.S. Organ Procurement and Transplantation Network and the SRTR have been supplied by UNOS and the Minneapolis Medical Research Foundation under contract with the U.S. Department of Health and Human Services/Health Resources and Services Administration. The authors alone are responsible for reporting and interpreting these data; the views expressed herein are those of the authors and not necessarily those of the U.S. government. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The work of Dr. Freeman on this paper was supported by Grant #T32DKK091202 from the National Institute of Diabetes, Digestive and Kidney Disease and for Dr. Myaskovsky by Grant #R01DK081325 from the National Institute of Diabetes, Digestive and Kidney Disease, and Grants #IIR 06-220 and #CIN 13-405 from the Veterans Affairs Health Services Research and Development Service. NR 67 TC 5 Z9 5 U1 6 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2015 VL 30 IS 7 BP 1077 EP 1086 DI 10.1007/s00467-014-2879-3 PG 10 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA CJ0UD UT WOS:000355193100006 PM 25315177 ER PT J AU Pekarya, AE Sattin, A Lloyd, RL AF Pekarya, A. Eugene Sattin, Albert Lloyd, Robert L. TI Ketamine modulates TRH and TRH-like peptide turnover in brain and peripheral tissues of male rats SO PEPTIDES LA English DT Article DE Depression; Anxiety; Limbic system; Neuroendocrine ID RAPID ANTIDEPRESSANT RESPONSE; RESISTANT MAJOR DEPRESSION; NMDA RECEPTOR BLOCKADE; D-ASPARTATE ANTAGONIST; INTRANASAL INSULIN; SUICIDAL IDEATION; HORMONE TRH; THYROTROPIN; ANXIETY; ANESTHESIA AB Major depression is the largest single healthcare burden with treatments of slow onset and often limited efficacy. Ketamine, a NMDA antagonist used extensively as a pediatric and veterinary anesthetic, has recently been shown to be a rapid acting antidepressant, making it a potential lifesaver for suicidal patients. Side effects and risk of abuse limit the chronic use of ketamine. More complete understanding of the neurobiochemical mechanisms of ketamine should lead to safer alternatives. Some of the physiological and pharmacological actions of ketamine are consistent with increased synthesis and release of TRH (pGlu-His-Pro-NH2), and TRH-like peptides (pGlu-X-Pro-NH2) where "X" can be any amino acid residue. Moreover, TRH-like peptides are themselves potential therapeutic agents for the treatment of major depression, anxiety, bipolar disorder, epilepsy, Alzheimer's and Parkinson's diseases. For these reasons, male Sprague-Dawley rats were anesthetized with 162 mg/kg ip ketamine and then infused intranasally with 20 mu l of sterile saline containing either 0 or 5 mg/ml Glu-TRH. One, 2 or 4 h later, the brain levels of TRH and TRH-like peptides were measured in various brain regions and peripheral tissues. At 1 h in brain following ketamine only, the levels of TRH and TRH-like peptides were significantly increased in 52 instances (due to increased biosynthesis and/or decreased release) or decreased in five instances. These changes, listed by brain region in order of decreasing number of significant increases (up arrow) and/or decreases (down arrow), were: hypothalamus (9 up arrow); piriform cortex (8 up arrow); entorhinal cortex (7 up arrow); nucleus accumbens (7 up arrow); posterior cingulate (5 up arrow); striatum (4 up arrow); frontal cortex (2 up arrow,3 down arrow); amygdala (3 up arrow); medulla oblongata (1 up arrow,2 down arrow); cerebellum (2 up arrow); hippocampus (2 up arrow); anterior cingulate (2 up arrow). The corresponding changes in peripheral tissues were: adrenals (8 up arrow); epididymis (4 up arrow); testis (1 up arrow,3 down arrow); pancreas (1 up arrow); prostate (1 up arrow). We conclude that TRH and TRH-like peptides may be downstream mediators of the rapid antidepressant actions of ketamine. Published by Elsevier Inc. C1 [Pekarya, A. Eugene; Sattin, Albert] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA 90073 USA. [Pekarya, A. Eugene] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Ctr Ulcer Res & Educ, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90073 USA. [Pekarya, A. Eugene] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. [Lloyd, Robert L.] Univ Minnesota, Dept Psychol, Duluth, MN 55812 USA. RP Pekarya, AE (reprint author), VA Greater Los Angeles Healthcare Syst, Bldg 114,Rm 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Albert.Pekary@va.gov FU Department of Veterans Affairs Medical Research funds; Pekary Trust FX This work was supported by the Department of Veterans Affairs Medical Research funds (AEP and AS) and the Pekary Trust. NR 72 TC 4 Z9 4 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD JUL PY 2015 VL 69 BP 66 EP 76 DI 10.1016/j.peptides.2015.04.003 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA CJ1AR UT WOS:000355214300009 PM 25882008 ER PT J AU Kennelty, KA Chewning, B Wise, M Kind, A Roberts, T Kreling, D AF Kennelty, Korey A. Chewning, Betty Wise, Meg Kind, Amy Roberts, Tonya Kreling, David TI Barriers and facilitators of medication reconciliation processes for recently discharged patients from community pharmacists' perspectives SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Community pharmacy; Medication reconciliation; Transitions of care; Qualitative methods ID SOCIAL DESIRABILITY BIAS; INFORMATION-TRANSFER; TRANSITIONAL CARE; PLANNED BEHAVIOR; REHOSPITALIZATION; QUESTIONNAIRE; INTERVENTION; CONTINUITY; EMERGENCY; OUTCOMES AB Background: Community pharmacists play a vital part in reconciling medications for patients transitioning from hospital to community care, yet their roles have not been fully examined in the extant literature. Objectives: The objectives of this study were to: 1) examine the barriers and facilitators community pharmacists face when reconciling medications for recently discharged patients; and 2) identify pharmacists' preferred content and modes of information transfer regarding updated medication information for recently discharged patients. Methods: Community pharmacists were purposively and conveniently sampled from the Wisconsin (U.S. state) pharmacist-based research network, Pharmacy Practice Enhancement and Action Research Link (PEARL Rx). Community pharmacists were interviewed face-to-face, and transcriptions from audio recordings were analyzed using directed content analysis. The Theory of Planned Behavior (TPB) guided the development of questions for the semi-structured interviews. Results: Interviewed community pharmacists (N = 10) described the medication reconciliation process to be difficult and time-consuming for recently discharged patients. In the context of the TPB, more barriers than facilitators of reconciling medications were revealed. Themes were categorized as organizational and individual-level themes. Major organizational-level factors affecting the medication reconciliation process included: pharmacy resources, discharge communication, and hospital resources. Major individual-level factors affecting the medication reconciliation process included: pharmacists' perceived responsibility, relationships, patient perception of pharmacist, and patient characteristics. Interviewed pharmacists consistently responded that several pieces of information items would be helpful when reconciling medications for recently discharged patients, including the hospital medication discharge list and stop-orders for discontinued medications. Conclusions: The TPB was useful for identifying barriers and facilitators of medication reconciliation for recently discharged patients from community pharmacists' perspectives. The elucidation of these specific facilitators and barriers suggest promising avenues for future research interventions to improve exchange of medication information between the community pharmacy, hospitals, and patients. Published by Elsevier Inc. C1 [Kennelty, Korey A.; Kind, Amy; Roberts, Tonya] William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI 53705 USA. [Kennelty, Korey A.; Chewning, Betty; Wise, Meg; Kreling, David] Univ Wisconsin, Sch Pharm, Sonderegger Res Ctr, Madison, WI 53706 USA. [Kind, Amy] Univ Wisconsin, Dept Med, Div Geriatr, Madison, WI USA. [Roberts, Tonya] Univ Wisconsin, Sch Nursing, Madison, WI USA. RP Kennelty, KA (reprint author), William S Middleton Mem Vet Adm Med Ctr, GRECC, 2500 Overlook Terrace,11-G, Madison, WI 53705 USA. EM kennelty@wisc.edu FU Agency for Healthcare Research and Quality (AHRQ) Health Services Research Dissertation Grant of the National Institutes of Health [1R36HS021984-01]; UW-Madison School of Pharmacy Sonderegger Research Center Dissertation Grant; Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; National Institute on Aging Beeson Career Development Award [K23AG034551]; National Institute on Aging; American Federation for Aging Research; John A. Hartford Foundation; Atlantic Philanthropies; Starr Foundation; Wisconsin Partnership Program New Investigator Award; Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR)from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources [1UL1RR025011] FX Funding support: Research reported in this manuscript was supported by the Agency for Healthcare Research and Quality (AHRQ) Health Services Research Dissertation Grant of the National Institutes of Health under award number 1R36HS021984-01 [PI: Kennelty]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Research reported was also supported by the UW-Madison School of Pharmacy Sonderegger Research Center Dissertation Grant.; The project described was also supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427.; Dr. Kind is supported by a National Institute on Aging Beeson Career Development Award (K23AG034551 [PI: Kind], National Institute on Aging, The American Federation for Aging Research, The John A. Hartford Foundation, The Atlantic Philanthropies and The Starr Foundation). Additional support was provided by the Wisconsin Partnership Program New Investigator Award (PI: Kind) and Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR), grant 1UL1RR025011 from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources, National Institutes of Health. NR 47 TC 6 Z9 6 U1 3 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD JUL-AUG PY 2015 VL 11 IS 4 BP 517 EP 530 DI 10.1016/j.sapharm.2014.10.008 PG 14 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA CJ2UD UT WOS:000355339200004 PM 25586885 ER PT J AU Pennarola, BW Rodday, AM Bingen, K Schwartz, LA Patel, SK Syrjala, KL Mayer, DK Ratichek, SJ Guinan, EC Kupst, MJ Hibbard, JH Parsons, SK AF Pennarola, Brian W. Rodday, Angie Mae Bingen, Kristin Schwartz, Lisa A. Patel, Sunita K. Syrjala, Karen L. Mayer, Deborah K. Ratichek, Sara J. Guinan, Eva C. Kupst, Mary Jo Hibbard, Judith H. Parsons, Susan K. TI Changing factors associated with parent activation after pediatric hematopoietic stem cell transplant SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer; HSCT; Children; Patient activation; Parent-Patient Activation Measure ID OBSTRUCTIVE PULMONARY-DISEASE; QUALITY-OF-LIFE; SELF-MANAGEMENT; DEPRESSIVE SYMPTOMS; EDUCATIONAL-PROGRAM; SOCIAL SUPPORT; CHRONIC GRAFT; HOST-DISEASE; MEASURE PAM; CHILDREN AB To identify factors associated with parent activation in parents of children undergoing pediatric hematopoietic stem cell transplant (HSCT) in the 6 months following HSCT, and to address if their association with parent activation changes over time. Measures for this analysis, including the Parent-Patient Activation Measure (Parent-PAM), were completed by parents (N = 198) prior to their child's HSCT preparative regimen and again at 6 months post-HSCT. Clinical data were also collected. A repeated measures model was built to estimate the association between clinical and demographic factors and parent well-being on Parent-PAM scores. Interactions with time were considered to test for changing effects over time. Throughout the HSCT course, older parent age was associated with lower Parent-PAM scores (beta = -0.29, p = 0.02) and never being married was associated with higher scores (versus married, beta = 12.27, p = 0.03). While higher parent emotional functioning scores were not associated with activation at baseline, they were important at 6 months (baseline, beta = -0.002, p = 0.96; interaction, beta = 0.14, p = 0.03). At baseline, longer duration of illness was associated with increased activation, but this effect diminished with time (baseline, beta = 3.29, p = 0.0002; interaction, beta = -2.40, p = 0.02). Activation levels dropped for parents of children who went from private to public insurance (baseline, beta = 2.95, p = 0.53; interaction, beta = -13.82, p = 0.004). Clinical events did not affect Parent-PAM scores. Our findings reveal important changes in the factors associated with parent activation in the first 6 months after pediatric HSCT. These findings may reflect the emotional and financial toll of pediatric HSCT on parent activation. C1 [Pennarola, Brian W.; Rodday, Angie Mae; Ratichek, Sara J.; Parsons, Susan K.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Bingen, Kristin; Kupst, Mary Jo] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Schwartz, Lisa A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Patel, Sunita K.] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA 91010 USA. [Patel, Sunita K.] City Hope Natl Med Ctr, Dept Pediat, Duarte, CA 91010 USA. [Patel, Sunita K.] City Hope Natl Med Ctr, Dept Support Care Med, Duarte, CA 91010 USA. [Syrjala, Karen L.] Fred Hutchinson Canc Res Ctr, Dept Biobehav Sci, Seattle, WA 98104 USA. [Mayer, Deborah K.] Univ North Carolina Chapel Hill, Sch Nursing, Chapel Hill, NC USA. [Guinan, Eva C.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Guinan, Eva C.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Hibbard, Judith H.] Univ Oregon, Dept Planning Publ Policy & Management, Eugene, OR 97403 USA. [Parsons, Susan K.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Parsons, Susan K.] Tufts Univ, Sch Med, Dept Pediat, Boston, MA 02111 USA. RP Parsons, SK (reprint author), Tufts Univ, Sch Med, Dept Med, 800 Washington St,345, Boston, MA 02111 USA. EM bwpennarola@gmail.com; arodday@tuftsmedicalcenter.org; kbingen@mcw.edu; schwartzl@email.chop.edu; spatel@coh.org; ksyrjala@fhcrc.org; dkmayer@email.unc.edu; sjratichek@gmail.com; eva_guinan@dfci.harvard.edu; mkupst@mcw.edu; judithhibbard@mac.com; sparsons@tuftsmedicalcenter.org FU National Cancer Institute [R01 CA 119196] FX The authors would like to thank Doris Hernandez for her help with manuscript preparation and submission. The authors gratefully acknowledge funding from the National Cancer Institute for this study (R01 CA 119196, SKP). NR 45 TC 1 Z9 1 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUL PY 2015 VL 23 IS 7 BP 1997 EP 2006 DI 10.1007/s00520-014-2544-1 PG 10 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA CJ1PI UT WOS:000355255600021 PM 25519755 ER PT J AU Zhang, SJ Sodroski, J AF Zhang, Shijian Sodroski, Joseph TI Efficient human immunodeficiency virus (HIV-1) infection of cells lacking PDZD8 SO VIROLOGY LA English DT Article DE Retrovirus; Host factor; Uncoating; Capsid; Stabilization; CRISPR-CAS9; Knockout ID STABLE MICROTUBULE FORMATION; RETROVIRAL INFECTION; TYPE-1; CORE; CAPSIDS AB PDZD8 can bind the capsid proteins of different retroviruses, and transient knockdown of PDZD8 results in a decrease in the efficiency of an early, post-entry event in the retrovirus life cycle. Here we used the CRISPR-CAS9 system to create cell lines in which PDZD8 expression is stably eliminated. The PDZD8-knockout cell lines were infected by human immunodeficiency virus (HIV-1) and murine leukemia virus as efficiently as the parental PDZD8-expressing cells. These results indicate that PDZD8 is not absolutely necessary for HIV-1 infection and diminishes its attractiveness as a potential target for intervention. (C) 2015 Elsevier Inc. All rights reserved. C1 [Zhang, Shijian; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02215 USA. RP Sodroski, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,CLS 1010, Boston, MA 02215 USA. EM joseph_sodroski@dfci.harvard.edu RI Zhang, Shijian/P-9353-2015 OI Zhang, Shijian/0000-0002-2017-6754 FU National Institutes of Health [AI063987]; National Institutes of Health (Center for AIDS Research) [AI06354]; International AIDS Vaccine Initiative FX We thank Ms. Yvette McLaughlin and Ms. Elizabeth Carpelan for manuscript preparation. We acknowledge the support of the National Institutes of Health (AI063987 and a Center for AIDS Research Award AI06354), the International AIDS Vaccine Initiative, and the late William F. McCarty-Cooper. NR 25 TC 4 Z9 4 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL PY 2015 VL 481 BP 73 EP 78 DI 10.1016/j.virol.2015.01.034 PG 6 WC Virology SC Virology GA CI9CW UT WOS:000355069000008 PM 25771112 ER PT J AU Mefford, ME Kunstman, K Wolinsky, SM Gabuzda, D AF Mefford, Megan E. Kunstman, Kevin Wolinsky, Steven M. Gabuzda, Dana TI Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5 SO VIROLOGY LA English DT Article DE HIV; Envelope; Macrophage; Tropism; CD4; CCR5; Bridging sheet; V1/V2 stem ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; TYPE-1 R5 ENVELOPES; CD4 BINDING LOOP; N-LINKED GLYCAN; NEUTRALIZING ANTIBODIES; ENTRY INHIBITORS; MONOCLONAL-ANTIBODIES; VIRAL INFECTIVITY; LYMPHOID-TISSUES AB Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the beta 3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120-CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mefford, Megan E.; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Kunstman, Kevin; Wolinsky, Steven M.] Northwestern Univ, Sch Med, Chicago, IL 60611 USA. [Gabuzda, Dana] Harvard Univ, Sch Med, Dept Neurol Microbiol & Immunobiol, Boston, MA USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM megan_mefford@hms.harvard.edu; kunstman@northwestern.edu; s-wolinsky@northwestern.edu; dana_gabuzda@dfci.harvard.edu OI Wolinsky, Steven/0000-0002-9625-6697 FU NIH [MH83588, MH97659, F31NS060611]; DFCI/Harvard Cancer Center [P30 AI060354, P30 CA06516] FX We thank J. Cunningham, J. Sodroski, and B. Chen for helpful discussions, R. Bosch for helpful discussions regarding statistical analysis of HIV sequences, N. Letvin for TZM-bl cells, B. Lee for Affinofile cells, and Will (Po-Jen) Yen for help with structural modeling. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID: monoclonal antibody 17b from Dr. James E. Robinson, goat anti-gp120, and TAK-779. This work was supported by NIH Grants MH83588 and MH97659 to D.G. M.E.M. was supported in part by NIH fellowship F31NS060611. Core facilities were supported by Harvard Medical School Center for AIDS Research (CFAR) and DFCI/Harvard Cancer Center Grants P30 AI060354 and P30 CA06516. NR 89 TC 3 Z9 3 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL PY 2015 VL 481 BP 210 EP 222 DI 10.1016/j.virol.2015.01.032 PG 13 WC Virology SC Virology GA CI9CW UT WOS:000355069000022 PM 25797607 ER PT J AU Keuthen, NJ Tung, ES Woods, DW Franklin, ME Altenburger, EM Pauls, DL Flessner, CA AF Keuthen, Nancy J. Tung, Esther S. Woods, Douglas W. Franklin, Martin E. Altenburger, Erin M. Pauls, David L. Flessner, Christopher A. TI Replication Study of the Milwaukee Inventory for Subtypes of Trichotillomania-Adult Version in a Clinically Characterized Sample SO BEHAVIOR MODIFICATION LA English DT Article DE trichotillomania; hair pulling; styles of pulling; assessment ID RANDOMIZED CONTROLLED-TRIAL; PSYCHOMETRIC PROPERTIES; FUNCTIONAL IMPACT; BEHAVIOR-THERAPY; HABIT REVERSAL; PHENOMENOLOGY; STYLES; SEVERITY; SCALES AB In the present study, we evaluated the Milwaukee Inventory for Subtypes of Trichotillomania-Adult Version (MIST-A) in a replication sample of clinically characterized hair pullers using exploratory factor analysis (EFA; N = 193). EFA eigenvalues and visual inspection of our scree plot revealed a two-factor solution. Factor structure coefficients and internal consistencies suggested a 13-item scale with an 8-item Intention scale and a 5-item Emotion scale. Both scales displayed good construct and discriminant validity. These findings indicate the need for a revised scale that provides a more refined assessment of pulling phenomenology that can facilitate future treatment advances. C1 [Keuthen, Nancy J.] Massachusetts Gen Hosp, Trichotillomania Clin, Boston, MA 02114 USA. [Tung, Esther S.] Massachusetts Gen Hosp, Trichotillomania Clin, OCD & Related Disorders Clin, Boston, MA 02114 USA. [Pauls, David L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Psychiat Genet, Boston, MA 02114 USA. [Woods, Douglas W.] Texas A&M Univ, Dept Psychol, College Stn, TX USA. [Franklin, Martin E.] Univ Penn, Clin Psychol Psychiat, Philadelphia, PA 19104 USA. [Altenburger, Erin M.] Ohio State Univ, Clin Psychol Program, Columbus, OH 43210 USA. [Flessner, Christopher A.] Kent State Univ, Dept Psychol, Wright Patterson AFB, OH USA. RP Keuthen, NJ (reprint author), Massachusetts Gen Hosp, OCD & Related Disorders Program, 185 Cambridge St,Suite 2200, Boston, MA 02114 USA. EM nkeuthen@partners.org RI Flessner, Christopher/K-1483-2015 FU Greater Kansas City Foundation; Trichotillomania Learning Center and its Body-Focused Repetitive Behaviors Precision Medicine Initiative FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by grants from the Greater Kansas City Foundation and the Trichotillomania Learning Center and its Body-Focused Repetitive Behaviors Precision Medicine Initiative. NR 30 TC 1 Z9 1 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 EI 1552-4167 J9 BEHAV MODIF JI Behav. Modificat. PD JUL PY 2015 VL 39 IS 4 BP 580 EP 599 DI 10.1177/0145445515580533 PG 20 WC Psychology, Clinical SC Psychology GA CI8BQ UT WOS:000354992900006 PM 25868534 ER PT J AU Pfarr, N Kriegsmann, M Sinn, P Klauschen, F Endris, V Herpel, E Muckenhuber, A Jesinghaus, M Klosterhalfen, B Penzel, R Lennerz, JK Weichert, W Stenzinger, A AF Pfarr, Nicole Kriegsmann, Mark Sinn, Peter Klauschen, Frederick Endris, Volker Herpel, Esther Muckenhuber, Alexander Jesinghaus, Moritz Klosterhalfen, Bernd Penzel, Roland Lennerz, Jochen K. Weichert, Wilko Stenzinger, Albrecht TI Distribution of MED12 mutations in fibroadenomas and phyllodes tumors of the breastimplications for tumor biology and pathological diagnosis SO GENES CHROMOSOMES & CANCER LA English DT Article ID SMOOTH-MUSCLE TUMORS; COLORECTAL-CANCER; UTERINE LEIOMYOMA; EXON-2 MUTATIONS; BREAST; MEDIATOR; LEIOMYOSARCOMA; PROGNOSIS; FEATURES; LESIONS AB Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty-two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare. (c) 2015 Wiley Periodicals, Inc. C1 [Pfarr, Nicole; Kriegsmann, Mark; Sinn, Peter; Endris, Volker; Herpel, Esther; Muckenhuber, Alexander; Jesinghaus, Moritz; Penzel, Roland; Weichert, Wilko; Stenzinger, Albrecht] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany. [Klauschen, Frederick] Charite, Inst Pathol, D-10117 Berlin, Germany. [Herpel, Esther] Natl Ctr Tumor Dis NCT, Tissue Bank, Heidelberg, Germany. [Klosterhalfen, Bernd] Dueren Hosp, Inst Pathol, D-52351 Duren, Germany. [Lennerz, Jochen K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol,CID, Boston, MA 02114 USA. [Weichert, Wilko] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. RP Stenzinger, A (reprint author), Univ Heidelberg Hosp, Inst Pathol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany. EM albrecht.stenzinger@med.uni-heidelberg.de FU German Cancer Consortium (DKTK) FX Supported by: The German Cancer Consortium (DKTK; to WW). NR 36 TC 16 Z9 16 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 2015 VL 54 IS 7 BP 444 EP 452 DI 10.1002/gcc.22256 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA CI4SY UT WOS:000354745000005 PM 25931199 ER PT J AU Muller, LPD Sargoy, A Fernandez-Sanchez, L Rodriguez, A Liu, J Cuenca, N Brecha, N AF Mueller, Luis Perez de Sevilla Sargoy, Allison Fernandez-Sanchez, Laura Rodriguez, Allen Liu, Janelle Cuenca, Nicolas Brecha, Nicholas TI Expression and cellular localization of the voltage-gated calcium channel alpha(2)delta(3) in the rodent retina SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Review DE calcium channel; retina; alpha(2)delta(3) subunit; amacrine cell; ganglion cell; photoreceptor ID PHOTORECEPTOR RIBBON SYNAPSE; ACID TRANSPORTER EXPRESSION; TISSUE-SPECIFIC EXPRESSION; DISPLACED AMACRINE CELLS; DEVELOPING MOUSE RETINA; PIG HORIZONTAL CELLS; RNA-BINDING PROTEIN; MAMMALIAN RETINA; RAT RETINA; BIPOLAR CELLS AB High-voltage-activated calcium channels are hetero-oligomeric protein complexes that mediate multiple cellular processes, including the influx of extracellular Ca2+, neurotransmitter release, gene transcription, and synaptic plasticity. These channels consist of a primary (1) pore-forming subunit, which is associated with an extracellular (2) subunit and an intracellular auxiliary subunit, which alter the gating properties and trafficking of the calcium channel. The cellular localization of the (23) subunit in the mouse and rat retina is unknown. In this study using RT-PCR, a single band at approximate to 305 bp corresponding to the predicted size of the (23) subunit fragment was found in mouse and rat retina and brain homogenates. Western blotting of rodent retina and brain homogenates showed a single 123-kDa band. Immunohistochemistry with an affinity-purified antibody to the (23) subunit revealed immunoreactive cell bodies in the ganglion cell layer and inner nuclear layer and immunoreactive processes in the inner plexiform layer and the outer plexiform layer. (23) immunoreactivity was localized to multiple cell types, including ganglion, amacrine, and bipolar cells and photoreceptors, but not horizontal cells. The expression of the (23) calcium channel subunit to multiple cell types suggests that this subunit participates widely in Ca-channel-mediated signaling in the retina. J. Comp. Neurol. 523:1443-1460, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Mueller, Luis Perez de Sevilla; Sargoy, Allison; Rodriguez, Allen; Liu, Janelle; Brecha, Nicholas] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Sargoy, Allison; Brecha, Nicholas] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Sargoy, Allison; Brecha, Nicholas] Univ Calif Los Angeles, Jules Stein Eye Inst, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Fernandez-Sanchez, Laura; Cuenca, Nicolas] Univ Alicante, Physiol Genet & Microbiol, Alicante 03690, Spain. [Brecha, Nicholas] Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. [Brecha, Nicholas] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Muller, LPD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med Los Angeles, Dept Neurobiol, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM luisperez@mednet.ucla.edu FU U.S. Army Medical Research & Materiel Command (USAMRMC); Telemedicine & Advanced Technology Research Center (TATRC) [W81XWH-10-2-0077]; National Institutes of Health [EY04067]; VA Merit Review FX Grant sponsor: U.S. Army Medical Research & Materiel Command (USAMRMC); Grant sponsor: Telemedicine & Advanced Technology Research Center (TATRC); Grant number: W81XWH-10-2-0077; Grant sponsor: National Institutes of Health; Grant number: EY04067; Grant sponsor: VA Merit Review (to N.B.). NR 110 TC 1 Z9 1 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2015 VL 523 IS 10 BP 1443 EP 1460 DI 10.1002/cne.23751 PG 18 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA CI4QQ UT WOS:000354737600001 ER PT J AU Gow, DW Olson, BB AF Gow, David W., Jr. Olson, Bruna B. TI Lexical mediation of phonotactic frequency effects on spoken word recognition: A Granger causality analysis of MRI-constrained MEG/EEG data SO JOURNAL OF MEMORY AND LANGUAGE LA English DT Article DE Phonotactic frequency; Effective connectivity; Magnetoencephalography; Granger causation; Speech perception; Lexical effect ID CONTINUOUS SPEECH RECOGNITION; EVENT-RELATED POTENTIALS; SURFACE-BASED ANALYSIS; CORTICAL SURFACE; NEIGHBORHOOD ACTIVATION; TIME-COURSE; COORDINATE SYSTEM; WORKING-MEMORY; PERCEPTION; MODEL AB Phonotactic frequency effects play a crucial role in a number of debates over language processing and representation. It is unclear however, whether these effects reflect prelexical sensitivity to phonotactic frequency, or lexical "gang effects" in speech perception. In this paper, we use Granger causality analysis of MR-constrained MEG/EEG data to understand how phonotactic frequency influences neural processing dynamics during auditory lexical decision. Effective connectivity analysis showed weaker feedforward influence from brain regions involved in acoustic-phonetic processing (superior temporal gyrus) to lexical areas (supramarginal gyrus) for high phonotactic frequency words, but stronger top-down lexical influence for the same items. Low entropy nonwords (nonwords judged to closely resemble real words) showed a similar pattern of interactions between brain regions involved in lexical and acoustic-phonetic processing. These results contradict the predictions of a feedforward model of phonotactic frequency facilitation, but support the predictions of a lexically mediated account. (C) 2015 Elsevier Inc. All rights reserved. C1 [Gow, David W., Jr.; Olson, Bruna B.] Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. [Gow, David W., Jr.] Salem State Univ, Dept Psychol, Salem, MA 01970 USA. [Gow, David W., Jr.; Olson, Bruna B.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gow, David W., Jr.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Gow, DW (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, 175 Cambridge St,CPZ S340, Boston, MA 02114 USA. EM gow@helix.mgh.harvard.edu; bbolson@partners.org FU National Institute of Deafness and Communicative Disorders [R01 DC003108]; NCRR Regional Resource Grant [41RR14075]; MIND Institute FX We would like to thank Nao Suzuki, and Reid Vancelette for their assistance in running the experiment, Conrad Nied for all aspects of the work including the development of our processing stream, Jennifer Michaud, Mark Vangel and Juliane Venturelli Silva Lima for statistical advice and review, and Michael Vitevitch, James Magnuson, David Caplan, James McQueen, Arthur Samuel and an anonymous reviewer for their thoughtful feedback. This work was supported by the National Institute of Deafness and Communicative Disorders (R01 DC003108) to D.W.G. and benefited from support from the MIND Institute and the NCRR Regional Resource Grant (41RR14075) for the development of technology and analysis tools at the Athinoula A. Martinos Center for Biomedical Imaging. NR 91 TC 3 Z9 3 U1 3 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0749-596X EI 1096-0821 J9 J MEM LANG JI J. Mem. Lang. PD JUL PY 2015 VL 82 BP 41 EP 55 DI 10.1016/j.jml.2015.03.004 PG 15 WC Linguistics; Psychology; Psychology, Experimental SC Linguistics; Psychology GA CI8SL UT WOS:000355041900003 PM 25883413 ER PT J AU Marron, JM Mack, JW AF Marron, Jonathan M. Mack, Jennifer W. TI When to say when: How aggressively to care for children with multiply relapsed cancer? SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID PALLIATIVE CARE; PARENTS; CHEMOTHERAPY C1 [Marron, Jonathan M.; Mack, Jennifer W.] Harvard Univ, Sch Med, Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. RP Marron, JM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D-1109, Boston, MA 02215 USA. EM jonathan_marron@dfci.harvard.edu OI Marron, Jonathan/0000-0001-8935-8524 FU NCI NIH HHS [5T32 CA136432, T32 CA136432] NR 10 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2015 VL 62 IS 7 BP 1119 EP 1120 DI 10.1002/pbc.25476 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CI1YQ UT WOS:000354541600002 PM 25755229 ER PT J AU Lim, SY Pannikath, D Nugent, K AF Lim, Sian Yik Pannikath, Deepa Nugent, Kenneth TI A retrospective study of septic arthritis in a tertiary hospital in West Texas with high rates of methicillin-resistant Staphylococcus aureus infection SO RHEUMATOLOGY INTERNATIONAL LA English DT Article DE Septic arthritis; Methicillin-resistant Staphylococcus aureus; Outcomes; Epidemiology ID ANTIBIOTIC-TREATMENT; BACTERIAL ARTHRITIS; PATIENT OUTCOMES; RISK-FACTORS; BACTEREMIA; PERIOD; ADULTS; HEALTH; IMPACT AB Septic arthritis is an important concern for rheumatologists in the evaluation of joint disease. Very few studies have addressed the microbiologic epidemiology and outcomes of septic arthritis in the USA since the year 2000. We performed a retrospective study of septic arthritis in a tertiary hospital in West Texas from the year 2000 to 2013. We recorded data on patient demographics, microbiologic etiology, treatment patterns, and outcomes. The most common causative organisms were Staphylococcus aureus and Streptococcus spp. Methicillin-resistant Staphylococcus aureus (MRSA) caused septic arthritis in 22.6 % of the cases. MRSA septic arthritis was associated with low rates of adequate empiric antimicrobial therapy. The mortality due to sepsis in our study was 5.5 %. Patients with septic arthritis had a mean length of stay of 13.5 +/- A 12.1 days and required 2.1 +/- A 1.4 joint operations. Many patients (29.2 %) had readmissions due to complications, and these patients had high rates of home health utilization and transfers to other facilities post hospital discharge. In our logistic regression analysis model, factors associated with poor outcomes in septic arthritis were MRSA, older age, and prosthetic joint infection. Septic arthritis is associated with significant mortality, morbidity, and health care costs, and more studies are needed to improve outcomes, especially considering the increasing rates of MRSA as the pathogen. C1 [Lim, Sian Yik] Harvard Univ, Sch Med, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pannikath, Deepa; Nugent, Kenneth] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Lubbock, TX 79430 USA. RP Lim, SY (reprint author), Harvard Univ, Sch Med, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, 55 Fruit St Bulfinch 165, Boston, MA 02114 USA. EM limsianyik@gmail.com NR 24 TC 6 Z9 6 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0172-8172 EI 1437-160X J9 RHEUMATOL INT JI Rheumatol. Int. PD JUL PY 2015 VL 35 IS 7 BP 1251 EP 1256 DI 10.1007/s00296-014-3206-9 PG 6 WC Rheumatology SC Rheumatology GA CI4HO UT WOS:000354709500015 PM 25572838 ER PT J AU Surov, A Nagata, S Abd Razek, AA Tirumani, SH Wienke, A Kahn, T AF Surov, Alexey Nagata, Shuji Abd Razek, Ahmed A. Tirumani, Sree Harsha Wienke, Andreas Kahn, Thomas TI Comparison of ADC values in different malignancies of the skeletal musculature: a multicentric analysis SO SKELETAL RADIOLOGY LA English DT Article DE Skeletal muscle tumors; Magnetic resonance imaging; Diffusion-weighted imaging; Apparent diffusion coefficient ID SOFT-TISSUE TUMORS; DIFFUSION-WEIGHTED MRI; COEFFICIENT AB Diffusion-weighted imaging (DWI) provides essential information regarding tumor composition, such as cellularity and/or perfusion. DWI is helpful in distinguishing between malignant and benign lesions. Malignant intramuscular/soft tissue lesions consist of a wide spectrum of tumors that have different cell counts and matrix. It is presumed that these different tumors have different DWI findings and have different apparent diffusion coefficient (ADC) values. The aim of this study was to analyze DWI findings of different intramuscular malignancies in a multicentric study by using a standardized DWI protocol, and to compare the ADC values acquired. The data banks of four radiology departments were screened retrospectively for malignant intramuscular tumors. Only lesions that were investigated by MRI (with a 1.5-T scanner) using DWI (multishot EPI sequence with b values of 0 and 1,000 s/mm(2)) were included in the study. Overall, 51 patients (28 women, 23 men; mean age 58.8 +/- 16.1 years) with 57 different malignant intramuscular lesions were collected. In every case apparent diffusion constant (ADC) maps were calculated. In 14 patients muscle lymphoma, 11 patients intramuscular metastases from different primary tumors, and in 26 cases several muscle sarcomas were identified. The mean ADC value of the estimated lesions was 1.24 +/- 0.53 x 10(-3) mm(2)s(-1), median value, 1.11 x 10(-3) mm(2)s(-1), range, 0.54-2.9 x 10(-3) mm(2)s(-1). The mean ADC value in muscle metastases was 1.28 +/- 0.24 x 10(-3) mm(2)s(-1), in muscle lymphoma 0.76 +/- 0.14 x 10(-3) mm(2)s(-1), and in muscle sarcomas 1.82 +/- 0.63 x 10(-3) mm(2)s(-1). Muscle lymphoma showed statistically significant lower ADC values in comparison to muscle metastases (p = 0.01) and muscle sarcoma (p = 0.001). There was no significant differences between ADC values in muscle metastases and sarcomas (p = 0.48). ADC values in muscle lymphoma were homogeneous with less inter-patient variability and were within a relatively close range. Muscle sarcomas had a broad range of ADC values. Intramuscular malignant lesions had different ADC values on DWI. 22.8 % of the tumors analyzed had low ADC values, 26.3 % moderate, and 50.9 % high ADC values. Muscle lymphoma had statistically significantly lower ADC values in comparison to muscle metastases and sarcomas. Muscle sarcomas presented with a broad range of ADC values. C1 [Surov, Alexey] Univ Halle Wittenberg, Dept Radiol, D-06108 Halle, Germany. [Surov, Alexey; Kahn, Thomas] Univ Leipzig, Dept Diagnost & Intervent Radiol, D-04109 Leipzig, Germany. [Nagata, Shuji] Kurume Univ, Sch Med, Dept Radiol, Kurume, Fukuoka 830, Japan. [Abd Razek, Ahmed A.] Mansoura Fac Med, Dept Diagnost Radiol, Mansoura, Egypt. [Tirumani, Sree Harsha] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Imaging,Dana Farber Canc Inst, Boston, MA 02115 USA. [Tirumani, Sree Harsha] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wienke, Andreas] Univ Halle Wittenberg, Inst Med Epidemiol Biometry & Stat, D-06108 Halle, Germany. RP Surov, A (reprint author), Univ Halle Wittenberg, Dept Radiol, D-06108 Halle, Germany. EM alex.surow@medizin.uni-halle.de RI Abdel Razek, Ahmed/J-6737-2016; OI Abdel Razek, Ahmed/0000-0002-9613-5932; Surov, Alexey/0000-0002-9273-3943 NR 17 TC 2 Z9 2 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 JUL PY 2015 VL 44 IS 7 BP 995 EP 1000 DI 10.1007/s00256-015-2141-5 PG 6 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA CI4KZ UT WOS:000354718800008 PM 25916616 ER PT J AU Kacimi, R Yenari, MA AF Kacimi, Rachid Yenari, Midori A. TI Pharmacologic Heat Shock Protein 70 Induction Confers Cytoprotection against Inflammation in Gliovascular Cells SO GLIA LA English DT Article DE cytoprotection; HSP70; HSP90; microglia; endothelial cells ID HEAT-SHOCK-PROTEIN; ISCHEMIA-REPERFUSION INJURY; OXYGEN-GLUCOSE DEPRIVATION; BLOOD-BRAIN-BARRIER; NF-KAPPA-B; MATRIX METALLOPROTEINASES; EXPERIMENTAL STROKE; HSP90 INHIBITORS; CLINICAL DEVELOPMENT; CEREBRAL-ISCHEMIA AB The inhibition of the 90-kDa heat shock protein (HSP90) leads to upregulation of the 70-kDa-inducible HSP70. HSP70 has been previously shown to be neuroprotective and anti-inflammatory. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents in cancer, presumably owing to their ability to upregulate HSP70. However, the effects of HSP90 inhibition in brain inflammation are still unclear. We investigate the effect of a panel of HSP90 inhibitors on endotoxin-activated microglia and eventual protection from brain-derived endothelial cells. Prior studies have shown that GA protects brain cells from oxidative stress. We show here that when astrocytes or microglial BV2 cells were pretreated with GA or other HSP90 inhibitors, endotoxin-induced cell death was reduced in cocultures of BV2 microglia and brain-derived endothelial cells (bEND.3). Endotoxin-stimulated BV2 cells led to increased nitric oxide (NO) and inducible nitric oxide synthase which was prevented by treatment with all HSP90 inhibitors. HSP90 inhibitors also prevented lipopolysaccharide (LPS)-induced BV2 cell death. We also found that HSP90 inhibition blocked nuclear translocation of nuclear factor kappa B and attenuated IB degradation, and inhibited LPS-activated JAK-STAT phosphorylation. We show that pharmacologic inhibition of HSP90 with subsequent HSP70 induction protects cells that comprise the cerebral vasculature against cell death owing to proinflammatory stimuli. This approach may have therapeutic potential in neurological conditions with an inflammatory component. C1 [Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Yenari, MA (reprint author), Univ Calif San Francisco, Dept Neurol, Neurol 127 VAMC 4150 Clement St, San Francisco, CA 94143 USA. EM yenari@alum.mit.edu FU National Institutes of Health [NS40516]; Veteran's Merit Award [BX000589]; Department of Defense [DAMD17-03-1-0532]; Northern California Institute for Research and Education, Resources of the Veterans Affairs Medical Center, San Francisco, California FX Grant sponsor: The National Institutes of Health; Grant number: NS40516; Grant sponsor: Veteran's Merit Award; Grant number: BX000589; Grant sponsor: The Department of Defense;; Grant number: DAMD17-03-1-0532; Grant sponsor: The Northern California Institute for Research and Education, Resources of the Veterans Affairs Medical Center, San Francisco, California. NR 42 TC 5 Z9 6 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD JUL PY 2015 VL 63 IS 7 BP 1200 EP 1212 DI 10.1002/glia.22811 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CG6IC UT WOS:000353402100007 PM 25802219 ER PT J AU Song, MY Gong, J Giovannucci, EL Berndt, SI Brenner, H Chang-Claude, J Curtis, KR Harrison, TA Hoffmeister, M Hsu, L Jiao, S Le Marchand, L Potter, JD Schoen, RE Seminara, D Slattery, ML White, E Wu, KN Ogino, S Fuchs, CS Hunter, DJ Tworoger, SS Hu, FB Rimm, E Jensen, M Peters, U Chan, AT AF Song, Mingyang Gong, Jian Giovannucci, Edward L. Berndt, Sonja I. Brenner, Hermann Chang-Claude, Jenny Curtis, Keith R. Harrison, Tabitha A. Hoffmeister, Michael Hsu, Li Jiao, Shuo Le Marchand, Loic Potter, John D. Schoen, Robert E. Seminara, Daniela Slattery, Martha L. White, Emily Wu, Kana Ogino, Shuji Fuchs, Charles S. Hunter, David J. Tworoger, Shelley S. Hu, Frank B. Rimm, Eric Jensen, Majken Peters, Ulrike Chan, Andrew T. TI Genetic variants of adiponectin and risk of colorectal cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE adiponectin; single-nucleotide polymorphism; Mendelian randomization; colorectal cancer; lifestyle factors ID MOLECULAR-WEIGHT ADIPONECTIN; GENOME-WIDE ASSOCIATION; SOLUBLE LEPTIN RECEPTOR; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; MENDELIAN RANDOMIZATION; CIRCULATING ADIPONECTIN; SUSCEPTIBILITY LOCI; METABOLIC SYNDROME; SERUM ADIPONECTIN AB Circulating adiponectin has been associated with lower risk of colorectal cancer (CRC). Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with adiponectin levels. However, it is unclear whether these SNPs are associated with CRC risk. In addition, previous data on SNPs in the adiponectin pathway and their associations with CRC are inconsistent. Therefore, we examined 19 SNPs in genes related to adiponectin or its receptors and their associations with CRC using logistic regression among 7,020 cases and 7,631 controls drawn from ten studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium. Using data from a subset of two large cohort studies, we also assessed the contribution of individual SNPs and an adiponectin genetic score to plasma adiponectin after accounting for lifestyle factors among 2,217 women and 619 men. We did not find any statistically significant association between the 19 adiponectin-associated SNPs and CRC risk (multivariable-adjusted odds ratios ranged from 0.89 to 1.05, all p>0.05). Each SNP explained less than 2.50% of the variance of plasma adiponectin, and the genetic score collectively accounted for 2.95 and 1.42% of the variability of adiponectin in women and men, respectively, after adjustment for age, body mass index, physical activity, smoking, alcohol consumption, regular use of aspirin or nonsteroidal anti-inflammatory drug and postmenopausal hormone use. In conclusion, our findings do not support an association between known adiponectin-related common SNPs and CRC incidence. However, known common SNPs account for only a limited proportion of the interindividual variance in circulating adiponectin. Further work is warranted to investigate the relationship between adiponectin and CRC while accounting for other components in the pathway. What's new? Obesity is a well-established risk factor for colorectal cancer, and mounting evidence suggests that the adipocyte-derived hormone adiponectin is behind that link. In the present investigation, common genetic variants in the adiponectin (ADIPOQ) gene were analyzed for potential relationships with colorectal cancer risk. However, no statistically significant associations were identified. Because common genetic determinants account for only a limited proportion of the variance in circulating adiponectin concentrations, factors that influence adiponectin receptors and other components of the adiponectin pathway should be investigated. C1 [Song, Mingyang; Giovannucci, Edward L.; Wu, Kana; Hunter, David J.; Hu, Frank B.; Rimm, Eric; Jensen, Majken] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Song, Mingyang; Giovannucci, Edward L.; Ogino, Shuji; Hunter, David J.; Tworoger, Shelley S.; Hu, Frank B.; Rimm, Eric] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gong, Jian; Curtis, Keith R.; Harrison, Tabitha A.; Hsu, Li; Jiao, Shuo; Potter, John D.; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Giovannucci, Edward L.; Ogino, Shuji; Fuchs, Charles S.; Hunter, David J.; Tworoger, Shelley S.; Hu, Frank B.; Rimm, Eric; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Ogino, Shuji; Fuchs, Charles S.; Hunter, David J.; Tworoger, Shelley S.; Hu, Frank B.; Rimm, Eric; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Heidelberg, Germany. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Hsu, Li] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Potter, John D.; White, Emily; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM achan@partners.org RI Hoffmeister, Michael/B-5745-2012; Song, Mingyang/M-6701-2013; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Song, Mingyang/0000-0002-1324-0316; Brenner, Hermann/0000-0002-6129-1572; Tworoger, Shelley/0000-0002-6986-7046; Potter, John/0000-0001-5439-1500 FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, R01 CA60987, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, K05 CA154337, K24 DK098311]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Harvard Transdisciplinary Research Center on Energetics and Cancer (TREC) [1U54CA155626] FX Grant sponsor: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services; Grant numbers: U01 CA137088, R01 CA059045, R01 CA60987, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, K05 CA154337, K24 DK098311; Grant sponsor: German Research Council (Deutsche Forschungsgemeinschaft); Grant numbers: BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1; Grant sponsor: German Federal Ministry of Education and Research; Grant numbers: 01KH0404, 01ER0814; Grant sponsor: Harvard Transdisciplinary Research Center on Energetics and Cancer (TREC); Grant number: 1U54CA155626 NR 50 TC 2 Z9 2 U1 1 U2 13 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 JUL 1 PY 2015 VL 137 IS 1 BP 154 EP 164 DI 10.1002/ijc.29360 PG 11 WC Oncology SC Oncology GA CG4ZH UT WOS:000353297600015 PM 25431318 ER PT J AU Ferder, IC Wang, N AF Ferder, Ianina C. Wang, Ning TI Hypermaintenance and hypofunction of aged spermatogonia: insight from age-related increase of Plzf expression SO ONCOTARGET LA English DT Article DE spermatogonial stem cell; aging; Plzf; mTORC1; differentiation ID CELL SELF-RENEWAL; MALE GERM-CELLS; STEM-CELLS; LIFE-SPAN; RETINOIC ACID; DROSOPHILA; DIFFERENTIATION; MICE; TOR; INITIATION AB Like stem cells in other tissues, spermatogonia, including spermatogonial stem cells (SSCs) at the foundation of differentiation hierarchy, undergo age-related decline in function. The promyelocytic leukemia zinc finger (Plzf) protein plays an essential role in spermatogonia maintenance by preventing their differentiation. To evaluate whether there is an age-related change in Plzf expression, we found that aged mouse testes exhibited a robust "Plzf overexpression" phenotype, in that they showed not only a higher frequency of Plzf-expressing cells but also an increased level of Plzf expression in these cells. Moreover, some Plzf-expressing cells in aged testes even aberrantly appeared in the differentiating spermatogonia compartment, which is usually low or negative for Plzf expression. Importantly, ectopic Plzf expression in F9 cells suppressed retinoic acid (RA)-induced Stra8 activation, a gene required for meiosis initiation. These data, together with our observation of a lack of meiosis-initiating spermatocytes associated with high Plzf-expressing spermatogonia in the aged testes, particularly in the degenerative seminiferous tubules, suggest that age-related increase in Plzf expression represents a novel molecular signature of spermatogonia aging by functionally arresting their differentiation. C1 [Ferder, Ianina C.; Wang, Ning] Massachusetts Gen Hosp, MGH Vincent Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Ferder, Ianina C.; Wang, Ning] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Wang, N (reprint author), Massachusetts Gen Hosp, MGH Vincent Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. EM nwang3@mgh.harvard.edu FU NIH; National Institute on Aging [K99/R00-AG039512]; Vincent Department of Obstetrics and Gynecology at Massachusetts General Hospital FX We would like to thank HSCI flow cytometry core facility for assistance with FACS analysis. N.W. is a recipient of an NIH Pathway-to-Independence Award from National Institute on Aging (K99/R00-AG039512). This work was also supported by the Vincent Department of Obstetrics and Gynecology at Massachusetts General Hospital. NR 35 TC 1 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 JUN 30 PY 2015 VL 6 IS 18 BP 15891 EP 15901 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2UL UT WOS:000359012000035 PM 25986924 ER PT J AU Ma, WH Yu, J Qi, XL Liang, L Zhang, Y Ding, Y Lin, XS Li, GX Ding, YQ AF Ma, Wenhui Yu, Jiang Qi, Xiaolong Liang, Li Zhang, Yan Ding, Yi Lin, Xiaoshan Li, Guoxin Ding, Yanqing TI Radiation-induced microRNA-622 causes radioresistance in colorectal cancer cells by down-regulating Rb SO ONCOTARGET LA English DT Article DE radiosensitivity; microRNA-622; apoptosis; RB1; Rb ID TUMOR-SUPPRESSOR; RECTAL-CANCER; PREOPERATIVE CHEMORADIOTHERAPY; ONCOGENIC RESISTANCE; EXPRESSION; APOPTOSIS; PROTEIN; IDENTIFICATION; REGRESSION; SIGNATURE AB The standard treatment for patients with locally advanced rectal cancer is preoperative 5-fluorouracil-based chemoradiotherapy followed by total mesorectal excision. However, tumor response to standard dose radiation varies. In this study, we found that miR-622 was increased significantly in ionizing radiation-treated colorectal cancer (CRC) cells compared to the cells cultured with irradiated medium, and persisted stably in surviving cells treated with continuous low-dose radiation. Overexpression of miR-622 induced the radioresistance in vitro. In addition, miR-622 inhibited Rb expression by directly targeting RB1-3'UTR. Overexpression of Rb reversed miR-622-induced radioresistance in vitro. In response to ionizing radiation, the Rb-E2F1-P/CAF complex activated proapoptotic genes. Importantly, miR-622 was highly expressed in tumors of rectal cancer patients with non-regression after standard dose radiotherapy. In conclusion, miR-622 overexpressing cells are induced or selected by radiotherapy, causing in turn radioresistance and poor response to further therapy. MiR-622 is a potential biomarker of responders for radiotherapy and a potential therapeutic target. C1 [Ma, Wenhui; Yu, Jiang; Zhang, Yan; Li, Guoxin] Southern Med Univ, Dept Gen Surg, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. [Yu, Jiang; Liang, Li; Ding, Yanqing] Southern Med Univ, Dept Pathol, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. [Qi, Xiaolong] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Qi, Xiaolong] Harvard Univ, Sch Med, Boston, MA USA. [Ding, Yi; Lin, Xiaoshan] Southern Med Univ, Dept Radiat Oncol, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. [Qi, Xiaolong] Tongji Univ, Dept Gastroenterol, Tongji Hosp, Sch Med, Shanghai 200092, Peoples R China. RP Ding, YQ (reprint author), Southern Med Univ, Dept Pathol, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. EM gzliguoxin@163.com; dyqgz@126.com FU National Natural Science Foundation of China [81071735]; Major projects of National Natural Science Foundation of China [81090422]; State Key Program of National Natural Science Foundation of China [U1201226]; National Basic Research Program of China (973 Program) [2010CB529402, 2010CB529403]; Science and Technology Innovation Foundation of Guangdong Higher Education [GXZD1016]; Key Program of Science and Technology Foundation of Guangzhou City, China [201300000056]; Natural Science Foundation of Guangdong Province [S2011010005301]; Key Clinical Specialty Discipline Construction Program FX This work was supported by the National Natural Science Foundation of China (No. 81071735), Major projects of National Natural Science Foundation of China (No. 81090422), State Key Program of National Natural Science Foundation of China (U1201226), National Basic Research Program of China (973 Program, No. 2010CB529402 and 2010CB529403), Science and Technology Innovation Foundation of Guangdong Higher Education (GXZD1016), Key Program of Science and Technology Foundation of Guangzhou City, China (201300000056), Natural Science Foundation of Guangdong Province (No. S2011010005301), and Key Clinical Specialty Discipline Construction Program. NR 38 TC 9 Z9 10 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 JUN 30 PY 2015 VL 6 IS 18 BP 15984 EP 15994 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2UL UT WOS:000359012000041 PM 25961730 ER PT J AU Shin, M Yang, EG Song, HK Jeon, H AF Shin, Miyoung Yang, Eun Gyeong Song, Hyun Kyu Jeon, Hyesung TI Insulin activates EGFR by stimulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells SO BMB REPORTS LA English DT Article DE EGFR activation; IGF-1R interaction; Insulin; MDA-MB-436; Triple-negative breast cancer cells ID GROWTH-FACTOR RECEPTOR; FACTOR-I-RECEPTOR; NEGATIVE BREAST-CANCER; RESISTANCE; INHIBITOR; NEOPLASIA; ERLOTINIB; THERAPY; NETWORK; PATHWAY AB The expression of epidermal growth factor receptor (EGFR) is an important diagnostic marker for triple-negative breast cancer (TNBC)cells, which lack three hormonal receptors: estrogen and progesterone receptors as well as epidermal growth factor receptor 2. EGFR transactivation can cause drug resistance in many cancers including TNBC, but the mechanism underlying this phenomenon is poorly defined. Here, we demonstrate that insulin treatment induces EGFR activation by stimulating the interaction of EGFR with insulin-like growth factor receptor 1 (IGF-1R) in the MDA-MB-436 TNBC cell line. These cells express low levels of EGFR, while exhibiting high levels of IGF-1R expression and phosphorylation. Low-EGFR-expressing MDA-MB-436 cells show high sensitivity to insulin-stimulated cell growth. Therefore, unexpectedly, insulin stimulation induced EGFR transactivation by regulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells. C1 [Shin, Miyoung; Song, Hyun Kyu] Korea Univ, Div Life Sci, Seoul 136701, South Korea. [Shin, Miyoung; Yang, Eun Gyeong; Jeon, Hyesung] Korea Inst Sci & Technol, Biomed Res Inst, Ctr Theragnosis, Seoul 136791, South Korea. [Jeon, Hyesung] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. RP Song, HK (reprint author), Korea Univ, Div Life Sci, Seoul 136701, South Korea. EM hksong@korea.ac.kr; hjeon@red.dfci.harvard.edu RI Song, Hyun Kyu/D-6763-2016 OI Song, Hyun Kyu/0000-0001-5684-4059 FU Intramural Research Program of the Korea Institute of Science and Technology (KIST); Korea University Grant; National Research Foundation of Kore agrant - Korean government [NRF 2011-0028168] FX We are grateful to Dr. Yosef Yarden (Weizmann Institute of Science, Israel) for his gift of the full-length EGFR plasmid. This study was supported by the Intramural Research Program of the Korea Institute of Science and Technology (KIST) and a Korea University Grant. This work was also supported by a National Research Foundation of Korea (NRF 2011-0028168) grant funded by the Korean government. NR 26 TC 2 Z9 2 U1 0 U2 3 PU KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY PI SEOUL PA KOREA SCIENCE & TECHNOLOGY CENTER, # 801, 635-4 , YEOKSAM-DONG, KANGNAM-KU, SEOUL, 135-703, SOUTH KOREA SN 1976-6696 EI 1976-670X J9 BMB REP JI BMB Rep. PD JUN 30 PY 2015 VL 48 IS 6 BP 342 EP 347 DI 10.5483/BMBRep.2015.48.6.157 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN3YA UT WOS:000358363200008 PM 25341922 ER PT J AU Konishi, M McLaren, DG Engen, H Smallwood, J AF Konishi, Mahiko McLaren, Donald George Engen, Haakon Smallwood, Jonathan TI Shaped by the Past: The Default Mode Network Supports Cognition that Is Independent of Immediate Perceptual Input SO PLOS ONE LA English DT Article ID EVENT-RELATED FMRI; FUNCTIONAL CONNECTIVITY; SOCIAL COGNITION; WORKING-MEMORY; BRAIN-FUNCTION; FUTURE; MIND; THOUGHT; SELF; PROSPECTION AB Although many different accounts of the functions of the default mode network (DMN) have been proposed, few can adequately account for the spectrum of different cognitive functions that utilize this network. The current study used functional magnetic resonance imaging (fMRI) to explore the hypothesis that the role of the DMN in higher order cognition is to allow cognition to be shaped by information from stored representations rather than information in the immediate environment. Using a novel task paradigm, we observed increased BOLD activity in regions of the medial prefrontal cortex and posterior cingulate cortex when individuals made decisions on the location of shapes from the prior trial and decreased BOLD activity when individuals made decisions on the location of shapes on the current trial. These data are inconsistent with views of the DMN as a task-negative system or one that is sensitive only to stimuli with strong personal or emotional ties. Instead the involvement of the DMN when people make decisions about where a shape was, rather than where it is now, supports the hypothesis that the core hubs of the DMN allow cognition to be guided by information other than the immediate perceptual input. We propose that a variety of different forms of higher order thought (such as imagining the future or considering the perspective of another person) engage the DMN because these more complex introspective forms of higher order thought all depend on the capacity for cognition to be shaped by representations that are not present in the external environment. C1 [Konishi, Mahiko; Smallwood, Jonathan] Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. [Konishi, Mahiko; Smallwood, Jonathan] Univ York, York Neuroimaging Ctr, York YO10 5DD, N Yorkshire, England. [McLaren, Donald George] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McLaren, Donald George] Harvard Univ, Sch Med, Boston, MA USA. [Engen, Haakon] Max Plank Inst Human Cognit Brain Sci, Dept Social Neurosci, Leipzig, Germany. RP Konishi, M (reprint author), Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. EM mk947@york.ac.uk OI McLaren, Donald/0000-0002-0566-4610 NR 73 TC 15 Z9 15 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2015 VL 10 IS 6 AR e0132209 DI 10.1371/journal.pone.0132209 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BR UT WOS:000358151300069 PM 26125559 ER PT J AU Sampson, JF Hasegawa, E Mulki, L Suryawanshi, A Jiang, SH Chen, WS Rabinovich, GA Connor, KM Panjwani, N AF Sampson, James F. Hasegawa, Eiichi Mulki, Lama Suryawanshi, Amol Jiang, Shuhong Chen, Wei-Sheng Rabinovich, Gabriel A. Connor, Kip M. Panjwani, Noorjahan TI Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response SO PLOS ONE LA English DT Article ID LEISHMANIA-MAJOR INFECTION; STEM-CELLS; IN-VIVO; DISEASE; UVEITIS; UVEORETINITIS; TH17; INFLAMMATION; SUPPRESSES; TOLERANCE AB Galectins have emerged as potent immunoregulatory agents that control chronic inflammation through distinct mechanisms. Here, we report that treatment with Galectin-8 (Gal-8), a tandem-repeat member of the galectin family, reduces retinal pathology and prevents photoreceptor cell damage in a murine model of experimental autoimmune uveitis. Gal-8 treatment increased the number of regulatory T cells (Treg) in both the draining lymph node (dLN) and the inflamed retina. Moreover, a greater percentage of Treg cells in the dLN and retina of Gal-8 treated animals expressed the inhibitory coreceptor cytotoxic T lymphocyte antigen (CTLA)-4, the immunosuppressive cytokine IL-10, and the tissue-homing integrin CD103. Treg cells in the retina of Gal-8-treated mice were primarily inducible Treg cells that lack the expression of neuropilin-1. In addition, Gal-8 treatment blunted production of inflammatory cytokines by retinal T helper type (T-H) 1 and T(H)17 cells. The effect of Gal-8 on T cell differentiation and/or function was specific for tissues undergoing an active immune response, as Gal-8 treatment had no effect on T cell populations in the spleen. Given the need for rational therapies for managing human uveitis, Gal-8 emerges as an attractive therapeutic candidate not only for treating retinal autoimmune diseases, but also for other T(H)1-and T(H)17-mediated inflammatory disorders. C1 [Sampson, James F.; Panjwani, Noorjahan] Tufts Univ, Sackler Sch Grad Biomed Sci, Program Immunol, Boston, MA 02111 USA. [Hasegawa, Eiichi; Mulki, Lama; Connor, Kip M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Suryawanshi, Amol; Panjwani, Noorjahan] Tufts Univ, Sch Med, New England Eye Ctr, Dept Ophthalmol, Boston, MA 02111 USA. [Jiang, Shuhong] Tufts Univ, JM USDA HNRCA, Lab Nutr & Vis Res, Boston, MA 02111 USA. [Jiang, Shuhong; Panjwani, Noorjahan] Peoples Hosp Inner Mongolia, Dept Ophthalmol, Hohhot, Peoples R China. [Chen, Wei-Sheng] Tufts Univ, Sackler Sch Grad Biomed Sci, Cell Mol & Dev Biol, Boston, MA 02111 USA. [Rabinovich, Gabriel A.] Consejo Nacl Invest Cient & Tecn, Lab Inmunopatol, IBYME, RA-1033 Buenos Aires, DF, Argentina. RP Connor, KM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. EM kip_connor@meei.harvard.edu; Noorjahan.panjwani@tufts.edu OI Connor, Kip/0000-0002-2048-9080 FU National Eye Institute [R01EY007088, R01EY009349, R01EY022084-01/S1]; Mass Lions Eye Research fund; New England Corneal Transplant Fund; Research to Prevent Blindness FX This work was generously supported by National Eye Institute (https://www.nei.nih.gov/) Grants R01EY007088 (NP), R01EY009349 (NP), R01EY022084-01/S1 (KMC), Mass Lions Eye Research fund (NP), New England Corneal Transplant Fund (NP) and an unrestricted award from Research to Prevent Blindness (http://www.rpbusa.org/rpb/NP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 3 Z9 3 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 JUN 30 PY 2015 VL 10 IS 6 AR e0130772 DI 10.1371/journal.pone.0130772 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BR UT WOS:000358151300025 PM 26126176 ER PT J AU Goodman, A AF Goodman, Annekathryn TI HPV testing as a screen for cervical cancer SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Review ID HUMAN-PAPILLOMAVIRUS DNA; RANDOMIZED CONTROLLED-TRIAL; RISK HUMAN-PAPILLOMAVIRUS; POPULATION-BASED COHORT; LIQUID-BASED CYTOLOGY; INTRAEPITHELIAL NEOPLASIA; FOLLOW-UP; COST-EFFECTIVENESS; UNITED-STATES; POOLED ANALYSIS AB Human papillomavirus (HPV) has been identified as a necessary factor in the development of pre-invasive and invasive cancers of the lower genital tract, of which cervical cancer is the most prevalent. A molecular understanding of malignant transformation and epidemiologic information has led to the development of many strategies for detection and early intervention. Newer tests for oncogenic subtypes of HPV have made it possible to predict the risk of future development of cervical cancer. This review summarizes the current understanding of HPV related disease and examines the role of HPV testing as a screening tool for cervical cancer. It summarizes the data from prospective and randomized controlled trials on HPV screening from Europe and North America and includes smaller studies from low and middle income countries where cervical cancer is the most common cancer in women. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol, Boston, MA 02114 USA. RP Goodman, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol, Boston, MA 02114 USA. EM agoodman@partners.org NR 75 TC 9 Z9 13 U1 5 U2 16 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 JUN 30 PY 2015 VL 350 AR h2372 DI 10.1136/bmj.h2372 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CM3TN UT WOS:000357607400001 PM 26126623 ER PT J AU Nipp, RD Currow, DC Cherny, NI Strasser, F Abernethy, AP Zafar, SY AF Nipp, R. D. Currow, D. C. Cherny, N. I. Strasser, F. Abernethy, A. P. Zafar, S. Y. TI Best supportive care in clinical trials: review of the inconsistency in control arm design SO BRITISH JOURNAL OF CANCER LA English DT Article DE research design; health services research; randomized controlled trial; palliative care; symptom assessment ID PHASE-III TRIAL; CELL LUNG-CANCER; MALIGNANT PLEURAL MESOTHELIOMA; RANDOMIZED CONTROLLED-TRIAL; EARLY PALLIATIVE CARE; COLORECTAL-CANCER; AMERICAN SOCIETY; PEMETREXED PLUS; GASTRIC-CANCER; OPEN-LABEL AB Background: Best supportive care (BSC) as a control arm in clinical trials is poorly defined. We conducted a review to evaluate clinical trials' concordance with published, consensus-based framework for BSC delivery in trials. Methods: A consensus-based Delphi panel previously identified four key domains of BSC delivery in trials: multidisciplinary care; supportive care documentation; symptom assessment; and symptom management. We reviewed trials including BSC control arms from 2002 to 2014 to assess concordance to BSC standards and to selected items from the CONSORT 2010 guidelines. Results: Of 408 articles retrieved, we retained 18 after applying exclusion criteria. Overall, trials conformed to the CONSORT guidelines better than the BSC standards (28% vs 16%). One-third of articles offered a detailed description of BSC, 61% reported regular symptom assessment, and 44% reported using validated symptom assessment measures. One-third reported symptom assessment at identical intervals in both arms. None documented evidence-based symptom management. No studies reported educating patients about symptom management or goals of therapy. No studies reported offering access to palliative care specialists. Conclusions: Reporting of BSC in trials is incomplete, resulting in uncertain internal and external validity. Such studies risk systematically over-estimating the net clinical effect of the comparator arms. C1 [Nipp, R. D.] Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Dana Farber Harvard Canc Ctr, Boston, MA 02114 USA. [Currow, D. C.] Flinders Univ S Australia, Sch Hlth Sci, Discipline Palliat & Support Serv, Adelaide, SA 5001, Australia. [Cherny, N. I.] Canc Pain & Palliat Med Unit, Dept Oncol, IL-91031 Jerusalem, Israel. [Strasser, F.] Cantonal Hosp, Dept Internal Med, CH-9007 St Gallen, Switzerland. [Strasser, F.] Cantonal Hosp, Palliat Care Ctr, Div Oncol, Oncol Palliat Med, CH-9007 St Gallen, Switzerland. [Abernethy, A. P.; Zafar, S. Y.] Duke Univ, Med Ctr, Div Med Oncol, Dept Med, Durham, NC 27710 USA. RP Nipp, RD (reprint author), Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Dana Farber Harvard Canc Ctr, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM rnipp@mgh.harvard.edu OI Currow, David/0000-0003-1988-1250 NR 33 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 30 PY 2015 VL 113 IS 1 BP 6 EP 11 DI 10.1038/bjc.2015.192 PG 6 WC Oncology SC Oncology GA CL7YJ UT WOS:000357188500002 PM 26068397 ER PT J AU Yoon, C Lee, HJ Park, DJ Lee, YJ Tap, WD Eisinger-Mathason, TSK Hart, CP Choy, E Simon, MC Yoon, SS AF Yoon, C. Lee, H-J Park, D. J. Lee, Y-J Tap, W. D. Eisinger-Mathason, T. S. K. Hart, C. P. Choy, E. Simon, M. C. Yoon, S. S. TI Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas SO BRITISH JOURNAL OF CANCER LA English DT Article DE VEGF-A; radiation; sarcoma; hypoxia ID SOFT-TISSUE SARCOMA; ENDOTHELIAL GROWTH-FACTOR; ANTI-ANGIOGENIC THERAPY; PRODRUG TH-302; COMBINATION THERAPY; TUMOR ANGIOGENESIS; MOUSE MODEL; CANCER; RADIOTHERAPY; RESISTANCE AB Background: Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and HIF-1 alpha target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy). Methods: Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. Results: In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1 alpha activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. Conclusions: The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1 alpha activity. C1 [Yoon, C.; Park, D. J.; Yoon, S. S.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Lee, H-J; Lee, Y-J] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lee, H-J; Lee, Y-J] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lee, H-J; Lee, Y-J] Korea Inst Radiol & Med Sci, Div Radiat Effects, Seoul, South Korea. [Park, D. J.] Seoul Natl Univ, Bundang Hosp, Dept Surg, Songnam, South Korea. [Tap, W. D.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Eisinger-Mathason, T. S. K.; Simon, M. C.] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Hart, C. P.] Threshold Pharmaceut, San Francisco, CA 94080 USA. [Choy, E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Choy, E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Simon, M. C.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Yoon, SS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, H 1209,1275 York Ave, New York, NY 10021 USA. EM yoons@mskcc.org OI Hart, Charles/0000-0003-4440-726X FU NIH [1R21 CA117128-02, 1R01 CA158301-01]; Society for Surgical Oncology Clinical Investigator Award FX This work was supported by NIH Grants 1R21 CA117128-02 (SSY) and 1R01 CA158301-01 (SSY and MCS), and the Society for Surgical Oncology Clinical Investigator Award (SSY). NR 37 TC 4 Z9 4 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 30 PY 2015 VL 113 IS 1 BP 46 EP 56 DI 10.1038/bjc.2015.186 PG 11 WC Oncology SC Oncology GA CL7YJ UT WOS:000357188500007 PM 26010414 ER PT J AU Wang, LL Teshiba, R Ikegaki, N Tang, XX Naranjo, A London, WB Hogarty, MD Gastier-Foster, JM Look, AT Park, JR Maris, JM Cohn, SL Seeger, RC Asgharzadeh, S Shimada, H AF Wang, L. L. Teshiba, R. Ikegaki, N. Tang, X. X. Naranjo, A. London, W. B. Hogarty, M. D. Gastier-Foster, J. M. Look, A. T. Park, J. R. Maris, J. M. Cohn, S. L. Seeger, R. C. Asgharzadeh, S. Shimada, H. TI Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children's Oncology Group study SO BRITISH JOURNAL OF CANCER LA English DT Article DE neuroblastoma; MYCN protein; MYC protein; immunohistochemistry; prognosis ID N-MYC; PATHOLOGY CLASSIFICATION; C-MYC; AMPLIFICATION; TUMORS; CELLS; DIFFERENTIATION; SUPPRESSION; PHENOTYPE; COMMITTEE AB Background: MYCN amplification with subsequent MYCN protein overexpression is a powerful indicator of poor prognosis of neuroblastoma patients. Little is known regarding the prognostic significance of the homologous MYC protein expression in neuroblastoma. Methods: Immunostaining for MYCN and MYC protein was performed on 357 undifferentiated/poorly differentiated neuroblastomas. Results were analysed with other prognostic markers. Results: Sixty-seven (19%) tumours were MYCN(+), 38 (11%) were MYC(+), and one(0.3%) had both proteins(+). MYCN(+) tumours and MYC(+) tumours were more likely diagnosed in children > 18months with stage4-disease. MYCN(+) tumours were associated with amplified MYCN, Unfavourable Histology (UH), and High-MKI (Mitosis-Karyorrhexis Index). MYC(+) tumours were also frequently UH but not associated with MYCN amplification, and more likely to have low-/intermediate-MKI. Favourable Histology patients without MYC/MYCN expressions exhibited the best survival (N = 167, 89.7 +/- 5.5% 3-year EFS, 97.0 +/- 3.2% 3-year OS), followed by UH patients without MYC/MYCN expressions (N = 84, 63.1 +/- 13.6% 3-year EFS, 83.5 +/- 9.4% 3-year OS). MYCN(+) patients and MYC(+) patients had similar and significantly low (P<0.0001) survivals (46.2 +/- 12.0% 3-year EFS, 63.2 +/- 12.1% 3-year OS and 43.4 +/- 23.1% 3-year EFS, 63.5 +/- 19.2% 3-year OS, respectively). Notably, the prognostic impact imparted by MYC expression was independent from other markers. Conclusions: In this series, similar to 30% of neuroblastomas had augmented MYCN or MYC expression with dismal survivals. Prospective study of MYC/MYCN protein expression signature as a new biomarker for high-risk neuroblastomas should be conducted. C1 [Wang, L. L.; Teshiba, R.; Shimada, H.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA. [Ikegaki, N.] Univ Illinois, Coll Med, Dept Anat & Cell Biol, Chicago, IL 60612 USA. [Ikegaki, N.] Univ Florida, Dept Biostat, Childrens Oncol Grp Stat, Gainesville, FL 32607 USA. [Naranjo, A.] Univ Florida, Ctr Data, Gainesville, FL 32607 USA. [London, W. B.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. [London, W. B.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Hogarty, M. D.; Maris, J. M.] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Hogarty, M. D.; Maris, J. M.] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Gastier-Foster, J. M.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43210 USA. [Gastier-Foster, J. M.] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Gastier-Foster, J. M.] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. [Look, A. T.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Park, J. R.] Univ Washington, Sch Med, Seattle Childrens Hosp, Dept Pediat, Seattle, WA 98105 USA. [Park, J. R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98105 USA. [Cohn, S. L.] Univ Chicago, Dept Pediat, Div Hematol Oncol, Chicago, IL 60637 USA. [Seeger, R. C.; Asgharzadeh, S.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. RP Shimada, H (reprint author), Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA. EM hshimada@chla.usc.edu OI Cohn, Susan/0000-0001-5749-7650 FU NIH [U10CA98413, U10CA98543, PO1CA081403, R01CA127571] FX This work was in part supported by NIH grants: U10CA98413, U10CA98543, PO1CA081403, and R01CA127571. NR 32 TC 9 Z9 9 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 30 PY 2015 VL 113 IS 1 BP 57 EP 63 DI 10.1038/bjc.2015.188 PG 7 WC Oncology SC Oncology GA CL7YJ UT WOS:000357188500008 PM 26035700 ER PT J AU Menger, KE James, AM Cocheme, HM Harbour, ME Chouchani, ET Ding, SJ Fearnley, IM Partridge, L Murphy, MP AF Menger, Katja E. James, Andrew M. Cocheme, Helena M. Harbour, Michael E. Chouchani, Edward T. Ding, Shujing Fearnley, Ian M. Partridge, Linda Murphy, Michael P. TI Fasting, but Not Aging, Dramatically Alters the Redox Status of Cysteine Residues on Proteins in Drosophila melanogaster SO CELL REPORTS LA English DT Article ID DIETARY RESTRICTION; OXIDATIVE STRESS; IN-VIVO; THIOL; ANTIOXIDANT; PROTEOMICS; ROLES; LIFE AB Altering the redox state of cysteine residues on protein surfaces is an important response to environmental challenges. Although aging and fasting alter many redox processes, the role of cysteine residues is uncertain. To address this, we used a redox proteomic technique, oxidative isotope-coded affinity tags (OxICAT), to assess cysteine-residue redox changes in Drosophila melanogaster during aging and fasting. This approach enabled us to simultaneously identify and quantify the redox state of several hundred cysteine residues in vivo. Cysteine residues within young flies had a bimodal distribution with peaks at similar to 10% and similar to 85% reversibly oxidized. Surprisingly, these cysteine residues did not become more oxidized with age. In contrast, 24 hr of fasting dramatically oxidized cysteine residues that were reduced under fed conditions while also reducing cysteine residues that were initially oxidized. We conclude that fasting, but not aging, dramatically alters cysteine-residue redox status in D. melanogaster. C1 [Menger, Katja E.; James, Andrew M.; Harbour, Michael E.; Chouchani, Edward T.; Ding, Shujing; Fearnley, Ian M.; Murphy, Michael P.] MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England. [Menger, Katja E.] UCL, Inst Ophthalmol, London EC1V 9EL, England. [Cocheme, Helena M.; Partridge, Linda] UCL, Inst Hlth Ageing, London WC1E 6BT, England. [Cocheme, Helena M.; Partridge, Linda] UCL, GEE, London WC1E 6BT, England. [Cocheme, Helena M.; Partridge, Linda] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. [Cocheme, Helena M.] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, London W12 0NN, England. [Chouchani, Edward T.] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England. [Chouchani, Edward T.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Chouchani, Edward T.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Murphy, MP (reprint author), MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England. EM mpm@mrc-mbu.cam.ac.uk RI James, Andrew/A-2639-2015 OI James, Andrew/0000-0002-0515-9649 FU Medical Research Council UK [MC-A070-5PS30]; Biotechnology and Biological Sciences Research Council UK [BB/D020786/1] FX This work was supported by the Medical Research Council UK (MC-A070-5PS30) and the Biotechnology and Biological Sciences Research Council UK (BB/D020786/1). We are grateful to Alan Robinson for assistance with data analysis algorithms. NR 24 TC 8 Z9 8 U1 1 U2 13 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 JUN 30 PY 2015 VL 11 IS 12 BP 1856 EP 1865 DI 10.1016/j.celrep.2015.05.033 PG 10 WC Cell Biology SC Cell Biology GA CM0UF UT WOS:000357393500002 PM 26095360 ER PT J AU Begun, J Lassen, KG Jijon, HB Baxt, LA Goel, G Heath, RJ Ng, A Tam, JM Kuo, SY Villablanca, EJ Fagbami, L Oosting, M Kumar, V Schenone, M Carr, SA Joosten, LAB Vyas, JM Daly, MJ Netea, MG Brown, GD Wijmenga, C Xavier, RJ AF Begun, Jakob Lassen, Kara G. Jijon, Humberto B. Baxt, Leigh A. Goel, Gautam Heath, Robert J. Ng, Aylwin Tam, Jenny M. Kuo, Szu-Yu Villablanca, Eduardo J. Fagbami, Lola Oosting, Marije Kumar, Vinod Schenone, Monica Carr, Steven A. Joosten, Leo A. B. Vyas, Jatin M. Daly, Mark J. Netea, Mihai G. Brown, Gordon D. Wijmenga, Cisca Xavier, Ramnik J. TI Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy SO CELL REPORTS LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; HOST-DEFENSE; SALMONELLA-TYPHIMURIUM; LISTERIA-MONOCYTOGENES; GENETIC ARCHITECTURE; SUSCEPTIBILITY LOCI; REGULATORY NETWORKS; EXPRESSION DATA; INFECTION AB The polymorphism ATG16L1 T300A, associated with increased risk of Crohn's disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1*300A risk allele. Clec12a(-/-) mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease. C1 [Begun, Jakob; Jijon, Humberto B.; Ng, Aylwin; Villablanca, Eduardo J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Begun, Jakob; Lassen, Kara G.; Jijon, Humberto B.; Baxt, Leigh A.; Goel, Gautam; Heath, Robert J.; Ng, Aylwin; Villablanca, Eduardo J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Begun, Jakob; Lassen, Kara G.; Jijon, Humberto B.; Baxt, Leigh A.; Goel, Gautam; Heath, Robert J.; Ng, Aylwin; Villablanca, Eduardo J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Begun, Jakob] Univ Queensland, Mater Res Inst, Brisbane, Qld 4101, Australia. [Lassen, Kara G.; Heath, Robert J.; Ng, Aylwin; Kuo, Szu-Yu; Villablanca, Eduardo J.; Fagbami, Lola; Schenone, Monica; Carr, Steven A.; Daly, Mark J.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Jijon, Humberto B.] Univ Calgary, Dept Med, Div Gastroenterol, Calgary, AB T2N 4N1, Canada. [Tam, Jenny M.; Vyas, Jatin M.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Tam, Jenny M.; Vyas, Jatin M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Oosting, Marije; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Oosting, Marije; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 GA Nijmegen, Netherlands. [Kumar, Vinod; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Daly, Mark J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Brown, Gordon D.] Univ Aberdeen, Inst Med Sci, CLSM, Div Appl Med,Aberdeen Fungal Grp, Aberdeen AB25 2ZD, Scotland. RP Lassen, KG (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM klassen@broadinstitute.org; xavier@molbio.mgh.harvard.edu RI Netea, Mihai/N-5155-2014; Oosting, Marije/H-7437-2015; Begun, Jakob/J-6793-2014; OI Begun, Jakob/0000-0001-5256-7672; Villablanca, Eduardo/0000-0001-9522-9729 FU Leona M. and Harry B. Helmsley Charitable Trust; Crohn's and Colitis Foundation of America; NIH [AI109725, DK097485]; European Research Council under the European Union [2012-322698]; ERC Consolidator Grant [310372]; Wellcome Trust; Alberta Innovates-Health Solutions (AIHS), Alberta, Canada FX We thank Mathieu Platteel (UMCG) for microarray experiments and Natalia Nedelsky for editorial assistance. R.J.X. was supported by the Leona M. and Harry B. Helmsley Charitable Trust, the Crohn's and Colitis Foundation of America, and grants AI109725 and DK097485 from the NIH. C.W. is supported by funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Advanced grant agreement 2012-322698). M.G.N was supported by an ERC Consolidator Grant (no. 310372). G.D.B. was supported by the Wellcome Trust. H.B.J. was supported by a clinical fellowship from Alberta Innovates-Health Solutions (AIHS), Alberta, Canada. NR 72 TC 5 Z9 5 U1 4 U2 8 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 JUN 30 PY 2015 VL 11 IS 12 BP 1905 EP 1918 DI 10.1016/j.celrep.2015.05.045 PG 14 WC Cell Biology SC Cell Biology GA CM0UF UT WOS:000357393500007 PM 26095365 ER PT J AU Barac, A Murtagh, G Carver, JR Chen, MH Freeman, AM Herrmann, J Iliescu, C Ky, B Mayer, EL Okwuosa, TM Plana, JC Ryan, TD Rzeszut, AK Douglas, PS AF Barac, Ana Murtagh, Gillian Carver, Joseph R. Chen, Ming Hui Freeman, Andrew M. Herrmann, Joerg Iliescu, Cezar Ky, Bonnie Mayer, Erica L. Okwuosa, Tochi M. Plana, Juan Carlos Ryan, Thomas D. Rzeszut, Anne K. Douglas, Pamela S. TI Cardiovascular Health of Patients With Cancer and Cancer Survivors A Roadmap to the Next Level SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cancer survivorship; cardiooncology; cardiovascular risk prevention; cardiovascular toxicity ID DOXORUBICIN-INDUCED CARDIOTOXICITY; VENTRICULAR SYSTOLIC DYSFUNCTION; HIGH-DOSE CHEMOTHERAPY; BREAST-CANCER; HEART-FAILURE; EUROPEAN ASSOCIATION; EJECTION FRACTION; AMERICAN SOCIETY; EXPERT CONSENSUS; CARDIO-ONCOLOGY AB Many existing and emerging cancer therapies have a significant effect on the cardiovascular health of patients with cancer and cancer survivors. This paper examines current aspects of interdisciplinary cardio-oncology clinical care delivery and education in the United States and outlines how these data provide a platform for future development of the field. We present the results of the nationwide survey on cardio-oncology services, practices, and opinions, conducted among chiefs of cardiology and program directors, which demonstrate ranges of clinical activities and identify significant interest for increased educational opportunities and expert training of cardiovascular physicians in this field. The survey respondents recognized clinical relevance but emphasized lack of national guidelines, lack of funds, and limited awareness and infrastructure as the main challenges for development and growth of cardio-oncology. We discuss potential solutions to unmet needs through interdisciplinary collaboration and the active roles of professional societies and other stakeholders. (C) 2015 by the American College of Cardiology Foundation. C1 [Barac, Ana] MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Washington, DC 20010 USA. [Murtagh, Gillian] NW Mem Hosp, Chicago, IL 60611 USA. [Carver, Joseph R.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Chen, Ming Hui] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Chen, Ming Hui] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA USA. [Freeman, Andrew M.] Natl Jewish Hlth, Denver, CO USA. [Herrmann, Joerg] Mayo Clin, Rochester, MN USA. [Herrmann, Joerg] Coll Med, Rochester, MN USA. [Iliescu, Cezar] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ky, Bonnie] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mayer, Erica L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Okwuosa, Tochi M.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Plana, Juan Carlos] Baylor Coll Med, Houston, TX 77030 USA. [Ryan, Thomas D.] Inst Heart, Cincinnati, OH USA. [Rzeszut, Anne K.] Amer Coll Cardiol, Washington, DC USA. [Douglas, Pamela S.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. RP Barac, A (reprint author), MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, 110 Irving St Northwest,Suite 1F1222, Washington, DC 20010 USA. EM Ana.Barac@medstar.net FU National Institutes of Health; Cell Therapeutics, Inc.; Pfizer; PA Cure Health; Eisai; Myriad; National Cancer Institute; University of South Florida; [NIH/5KL2TR000102-04] FX This work was supported in part by NIH/5KL2TR000102-04 (to Dr. Barac). Dr. Barac has received research support from the National Institutes of Health; research support and honoraria for lectures from Genentech, Inc.; and consultancy fees from Cell Therapeutics, Inc. Dr. Murtagh will be an employee of Abbott Diagnostics in July 2015 but was not affiliated with this company at the time this paper was written. Dr. Freeman has served as a consultant to Gilead; and has served as a speaker for Medtronic. Dr. Hermann has served as a consultant to ARIAD Pharmaceuticals and Bristol-Myers Squibb; and as a member of advisory boards for ARIAD Pharmaceuticals and Bristol-Myers Squibb. Dr. Ky has received research support from Pfizer, the National Institutes of Health, and PA Cure Health. Dr. Mayer has received research support from Pfizer, Eisai, and Myriad. Dr. Douglas has received research grants from the National Cancer Institute and the University of South Florida. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 43 TC 10 Z9 10 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 30 PY 2015 VL 65 IS 25 BP 2739 EP 2746 DI 10.1016/j.jacc.2015.04.059 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL2LJ UT WOS:000356775100011 PM 26112199 ER PT J AU Horton, LE Tarbox, SI Olino, TM Haas, GL AF Horton, Leslie E. Tarbox, Sarah I. Olino, Thomas M. Haas, Gretchen L. TI Trajectories of premorbid childhood and adolescent functioning in schizophrenia-spectrum psychoses: A first-episode study SO PSYCHIATRY RESEARCH LA English DT Article DE Premorbid adjustment; Social amotivation; First-episode schizophrenia (FEP); Psychosis; Schizophrenia-spectrum ID NEGATIVE SYMPTOMS; NONAFFECTIVE PSYCHOSIS; EPISODE SCHIZOPHRENIA; UNTREATED PSYCHOSIS; ADJUSTMENT SCALE; DISORDERS; PATTERNS; ONSET; DETERIORATION; ANHEDONIA AB Evidence of social and behavioral problems preceding the onset of schizophrenia-spectrum psychoses is consistent with a neurodevelopmental model of these disorders. Here we predict that individuals with a first episode of schizophrenia-spectrum psychoses will evidence one of three patterns of premorbid adjustment: an early deficit, a deteriorating pattern, or adequate or good social adjustment. Participants were 164(38% female; 31% black) individuals ages 15-50 with a first episode of schizophrenia-spectrum psychoses. Premorbid adjustment was assessed using the Cannon-Spoor Premorbid Adjustment Scale. We compared the fit of a series of growth mixture models to examine premorbid adjustment trajectories, and found the following 3-class model provided the best fit with: a "stable-poor" adjustment class (54%), a "stable-good" adjustment class (39%), and a "deteriorating" adjustment class (7%). Relative to the "stable-good" class, the "stable-poor" class experienced worse negative symptoms at 1-year follow-up, particularly in the social amotivation domain. This represents the first known growth mixture modeling study to examine premorbid functioning patterns in first-episode schizophrenia-spectrum psychoses. Given that the stable-poor adjustment pattern was most prevalent, detection of social and academic maladjustment as early as childhood may help identify people at increased risk for schizophrenia-spectrum psychoses, potentially increasing feasibility of early interventions. Published by Elsevier Ireland Ltd. C1 [Horton, Leslie E.; Olino, Thomas M.; Haas, Gretchen L.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. [Horton, Leslie E.; Haas, Gretchen L.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA 15240 USA. [Tarbox, Sarah I.] Yale Univ, Sch Med, Connecticut Mental Hlth Ctr, Dept Psychiat, New Haven, CT 06159 USA. [Olino, Thomas M.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. RP Haas, GL (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM hortonle2@upmc.edu; sarah.tarbox@yale.edu; thomas.olino@temple.edu; haasgl@upmc.edu FU NIMH [MH48492]; NIH [UL1 RR024153, UL1 TR000005]; NIH/NCRR/GCRC [M01 RR00056] FX This publication was supported by funds received MH48492 (NIMH; PI: G L. Haas) and the NIH-funded UL1 RR024153, UL1 TR000005, and NIH/NCRR/GCRC Grant M01 RR00056. NR 58 TC 2 Z9 2 U1 2 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUN 30 PY 2015 VL 227 IS 2-3 BP 339 EP 346 DI 10.1016/j.psychres.2015.02.013 PG 8 WC Psychiatry SC Psychiatry GA CK0GU UT WOS:000355884500033 PM 25829134 ER PT J AU Fulford, D Eisner, LR Johnson, SL AF Fulford, Daniel Eisner, Lori R. Johnson, Sheri L. TI Differentiating risk for mania and borderline personality disorder: The nature of goal regulation and impulsivity SO PSYCHIATRY RESEARCH LA English DT Article DE Bipolar disorder; Borderline personality disorder; Goal regulation; Impulsivity; Approach/avoidance motivation ID BIPOLAR SPECTRUM DISORDERS; BEHAVIORAL-APPROACH SYSTEM; BIS-BAS SCALES; HYPOMANIC PERSONALITY; AFFECTIVE INSTABILITY; II-DISORDER; ACTIVATION SYSTEM; COMMUNITY SAMPLE; BIS/BAS SCALES; 4-FACTOR MODEL AB Researchers and clinicians have long noted the overlap among features and high comorbidity of bipolar disorder and borderline personality disorder. The shared features of impulsivity and labile mood in both disorders make them challenging to distinguish. We tested the hypothesis that variables related to goal dysregulation would be uniquely related to risk for mania, while emotion-relevant impulsivity would be related to risk for both disorders. We administered a broad range of measures related to goal regulation traits and impulsivity to 214 undergraduates. Findings confirmed that risk for mania, but not for borderline personality disorder, was related to higher sensitivity to reward and intense pursuit of goals. In contrast, borderline personality disorder symptoms related more strongly than did mania risk with threat sensitivity and with impulsivity in the context of negative affect. Results highlight potential differences and commonalities in mania risk versus borderline personality disorder risk. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Fulford, Daniel] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Fulford, Daniel] Palo Alto Med Fdn Res Inst, Mountain View, CA 94040 USA. [Eisner, Lori R.] Harvard Univ, Sch Med, Dept Psychiat, Bipolar Clin,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Eisner, Lori R.] Harvard Univ, Sch Med, Dept Psychiat, Res Program,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Johnson, Sheri L.] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. RP Fulford, D (reprint author), Univ Calif San Francisco, Dept Psychiat, 795 El Camino Real, Palo Alto, CA 94301 USA. EM daniel.fulford@ucsf.edu FU [2T32MH018261-27]; [1K12HS021700-01] FX Preparation of this manuscript was supported in part by the following grants to Dr. Fulford: 2T32MH018261-27, 1K12HS021700-01. NR 73 TC 5 Z9 5 U1 2 U2 13 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 JUN 30 PY 2015 VL 227 IS 2-3 BP 347 EP 352 DI 10.1016/j.psychres.2015.02.001 PG 6 WC Psychiatry SC Psychiatry GA CK0GU UT WOS:000355884500034 PM 25892256 ER PT J AU Goldstein, JM Lacaster, K Longenecker, JM Abbs, B Holsen, LM Cherkerzian, S Whitfield-Gabrieli, S Makris, N Tsuang, MT Buka, SL Seidman, LJ Klibanski, A AF Goldstein, Jill M. Lacaster, Katie Longenecker, Julia M. Abbs, Brandon Holsen, Laura M. Cherkerzian, Sara Whitfield-Gabrieli, Susan Makris, Nicolas Tsuang, Ming T. Buka, Stephen L. Seidman, Larry J. Klibanski, Anne TI Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Schizophrenia; Sex differences; HPA axis; HPG axis; Stress response; Negative valence affect ID ESTROGEN-RECEPTOR-ALPHA; FACIAL EMOTION DISCRIMINATION; POSITRON-EMISSION-TOMOGRAPHY; NEW-ENGLAND FAMILY; ADULT HUMAN BRAIN; GENDER-DIFFERENCES; PARAVENTRICULAR NUCLEUS; AMYGDALA ACTIVITY; SCHIZOPHRENIC OUTPATIENTS; AROUSAL CIRCUITRY AB Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactiviLy in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F=7.00, p=0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry -hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Goldstein, Jill M.; Lacaster, Katie; Longenecker, Julia M.; Abbs, Brandon; Holsen, Laura M.; Cherkerzian, Sara] Brigham & Womens Hosp, Div Womens Hlth, Connors Ctr Women Hlth & Gender Biol, Boston, MA 02120 USA. [Goldstein, Jill M.; Holsen, Laura M.; Makris, Nicolas; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Goldstein, Jill M.; Holsen, Laura M.; Makris, Nicolas; Klibanski, Anne] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Goldstein, Jill M.; Holsen, Laura M.; Makris, Nicolas; Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Athinoula A Martinos Ctr, Div Psychiat Neurosci, Boston, MA 02114 USA. [Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, San Diego, CA 92103 USA. [Buka, Stephen L.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Seidman, Larry J.] Massachusetts Mental Hlth Ctr, Div Publ Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Boston, MA USA. [Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, OBC, 3rd Floor,1620 Tremont St, Boston, MA 02120 USA. EM jill_goldstein@hms.harvard.edu; katie.lancaster@virginia.edu; longenecker.julia@gmail.com; brandon.abbs@gmail.com; lholsen@partners.org; scherkerzian@partners.org; swg@mit.edu; nmakris@partners.org; mtsuang@ucsd.edu; stephen_buka@brown.edu; lseidman@bidmc.harvard.edu; aklibanski@partners.org FU National Institute of Mental Health (NIMH) [RO1 MH56956]; Stanley Medical Research Institute, United States; NARSAD; NIMH [R01MH63951]; Harvard Catalyst I Harvard Clinical and Translational Science Center (CTSC) [UL1 RR025758] FX This study was supported by National Institute of Mental Health (NIMH) RO1 MH56956 (JMG, P.I.). In addition, original sample ascertainment was in part also supported by Grants from the Stanley Medical Research Institute, United States (SLB & JMG, US 1994-1997), NARSAD (LJS) and NIMH R01MH63951 (LJS, RI) and with support from the Harvard Catalyst I Harvard Clinical and Translational Science Center (CTSC) (NIH Award UL1 RR025758). NR 122 TC 3 Z9 3 U1 4 U2 22 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUN 30 PY 2015 VL 232 IS 3 BP 226 EP 236 DI 10.1016/j.pscychresns.2015.03.006 PG 11 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CI2CQ UT WOS:000354552900005 PM 25914141 ER PT J AU Yehia, BR Stewart, L Momplaisir, F Mody, A Holtzman, CW Jacobs, LM Hines, J Mounzer, K Glanz, K Metlay, JP Shea, JA AF Yehia, Baligh R. Stewart, Leslie Momplaisir, Florence Mody, Aaloke Holtzman, Carol W. Jacobs, Lisa M. Hines, Janet Mounzer, Karam Glanz, Karen Metlay, Joshua P. Shea, Judy A. TI Barriers and facilitators to patient retention in HIV care SO BMC INFECTIOUS DISEASES LA English DT Article DE Retention; Engagement; HIV; Care; Barriers; Facilitators ID ACTIVE ANTIRETROVIRAL THERAPY; UNITED-STATES; MEDICAL-CARE; INFECTED PERSONS; POSITIVE WOMEN; RANDOMIZED-TRIAL; SEXUAL-ABUSE; RISK-FACTORS; HEALTH-CARE; ENGAGEMENT AB Background: Retention in HIV care improves survival and reduces the risk of HIV transmission to others. Multiple quantitative studies have described demographic and clinical characteristics associated with retention in HIV care. However, qualitative studies are needed to better understand barriers and facilitators. Methods: Semi-structured interviews were conducted with 51 HIV-infected individuals, 25 who were retained in care and 26 not retained in care, from 3 urban clinics. Interview data were analyzed for themes using a modified grounded theory approach. Identified themes were compared between the two groups of interest: patients retained in care and those not retained in care. Results: Overall, participants identified 12 barriers and 5 facilitators to retention in HIV care. On average, retained individuals provided 3 barriers, while persons not retained in care provided 5 barriers. Both groups commonly discussed depression/mental illness, feeling sick, and competing life activities as barriers. In addition, individuals not retained in care commonly reported expensive and unreliable transportation, stigma, and insufficient insurance as barriers. On average, participants in both groups referenced 2 facilitators, including the presence of social support, patient-friendly clinic services (transportation, co-location of services, scheduling/reminders), and positive relationships with providers and clinic staff. Conclusions: In our study, patients not retained in care faced more barriers, particularly social and structural barriers, than those retained in care. Developing care models where social and financial barriers are addressed, mental health and substance abuse treatment is integrated, and patient-friendly services are offered is important to keeping HIV-infected individuals engaged in care. C1 [Yehia, Baligh R.; Stewart, Leslie; Mody, Aaloke; Hines, Janet; Mounzer, Karam; Shea, Judy A.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Momplaisir, Florence] Drexel Univ, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Holtzman, Carol W.] Temple Univ, Dept Pharm Practice, Sch Pharm, Philadelphia, PA 19122 USA. [Jacobs, Lisa M.] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mounzer, Karam] Philadelphia FIGHT, Jonathan Lax Ctr, Philadelphia, PA USA. [Glanz, Karen] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Glanz, Karen] Univ Penn, Sch Nursing, Dept Biobehav Hlth Sci, Philadelphia, PA 19104 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Yehia, Baligh R.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Yehia, BR (reprint author), Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM byehia@upenn.edu FU National Institutes of Health [K23-MH097647] FX This work was supported by the National Institutes of Health (K23-MH097647 to BRY). NR 61 TC 11 Z9 11 U1 4 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUN 28 PY 2015 VL 15 AR 246 DI 10.1186/s12879-015-0990-0 PG 10 WC Infectious Diseases SC Infectious Diseases GA CL6IX UT WOS:000357071900001 PM 26123158 ER PT J AU Matlis, S Boric, K Chu, CJ Kramer, MA AF Matlis, Sean Boric, Katica Chu, Catherine J. Kramer, Mark A. TI Robust disruptions in electroencephalogram cortical oscillations and large-scale functional networks in autism SO BMC NEUROLOGY LA English DT Article DE ASD; EEG; Functional networks; Biomarker; Classification; Autism; Power spectra; Validation ID COMPLEX BRAIN NETWORKS; SPECTRUM QUOTIENT AQ; INFANT EEG ACTIVITY; SENTENCE COMPREHENSION; PHASE-SYNCHRONIZATION; PROMISING APPROACH; ASPERGERS-SYNDROME; VOLUME-CONDUCTION; EVOKED-POTENTIALS; OCCIPITAL CORTEX AB Background: Autism spectrum disorders (ASD) are increasingly prevalent and have a significant impact on the lives of patients and their families. Currently, the diagnosis is determined by clinical judgment and no definitive physiological biomarker for ASD exists. Quantitative biomarkers obtainable from clinical neuroimaging data - such as the scalp electroencephalogram (EEG) - would provide an important aid to clinicians in the diagnosis of ASD. The interpretation of prior studies in this area has been limited by mixed results and the lack of validation procedures. Here we use retrospective clinical data from a well-characterized population of children with ASD to evaluate the rhythms and coupling patterns present in the EEG to develop and validate an electrophysiological biomarker of ASD. Methods: EEG data were acquired from a population of ASD (n = 27) and control (n = 55) children 4-8 years old. Data were divided into training (n = 13 ASD, n = 24 control) and validation (n = 14 ASD, n = 31 control) groups. Evaluation of spectral and functional network properties in the first group of patients motivated three biomarkers that were computed in the second group of age-matched patients for validation. Results: Three biomarkers of ASD were identified in the first patient group: (1) reduced posterior/anterior power ratio in the alpha frequency range (8-14 Hz), which we label the "peak alpha ratio", (2) reduced global density in functional networks, and (3) a reduction in the mean connectivity strength of a subset of functional network edges. Of these three biomarkers, the first and third were validated in a second group of patients. Using the two validated biomarkers, we were able to classify ASD subjects with 83 % sensitivity and 68 % specificity in a post-hoc analysis. Conclusions: This study demonstrates that clinical EEG can provide quantitative biomarkers to assist diagnosis of autism. These results corroborate the general finding that ASD subjects have decreased alpha power gradients and network connectivities compared to control subjects. In addition, this study demonstrates the necessity of using statistical techniques to validate EEG biomarkers identified using exploratory methods. C1 [Matlis, Sean] Boston Univ, Grad Program Neurosci, Boston, MA 02215 USA. [Boric, Katica; Chu, Catherine J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Boric, Katica; Chu, Catherine J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Kramer, MA (reprint author), Boston Univ, Dept Math & Stat, 111 Cummington Mall, Boston, MA 02215 USA. EM mak@bu.edu FU National Institutes of Health [NIH-5K12NS066225-02]; Career Award at the Scientific Interface from the Burroughs Wellcome Fund FX This work was supported by the National Institutes of Health through grant NIH-5K12NS066225-02, and by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund (MAK, SM). NR 104 TC 2 Z9 2 U1 6 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD JUN 27 PY 2015 VL 15 AR 97 DI 10.1186/s12883-015-0355-8 PG 17 WC Clinical Neurology SC Neurosciences & Neurology GA CL9ON UT WOS:000357308100001 PM 26111798 ER PT J AU Abazari, A Meimetis, LG Budin, G Bale, SS Weissleder, R Toner, M AF Abazari, Alireza Meimetis, Labros G. Budin, Ghyslain Bale, Shyam Sundhar Weissleder, Ralph Toner, Mehmet TI Engineered Trehalose Permeable to Mammalian Cells SO PLOS ONE LA English DT Article ID RED-BLOOD-CELLS; INTRACELLULAR TREHALOSE; DESICCATION TOLERANCE; PHASE-SEPARATION; PRESERVATION; PROTECTION; LIPOSOMES; ACCUMULATION; MITOCHONDRIA; DEHYDRATION AB Trehalose is a naturally occurring disaccharide which is associated with extraordinary stress-tolerance capacity in certain species of unicellular and multicellular organisms. In mammalian cells, presence of intra- and extracellular trehalose has been shown to confer improved tolerance against freezing and desiccation. Since mammalian cells do not synthesize nor import trehalose, the development of novel methods for efficient intracellular delivery of trehalose has been an ongoing investigation. Herein, we studied the membrane permeability of engineered lipophilic derivatives of trehalose. Trehalose conjugated with 6 acetyl groups (trehalose hexaacetate or 6-O-Ac-Tre) demonstrated superior permeability in rat hepatocytes compared with regular trehalose, trehalose diacetate (2-O-Ac-Tre) and trehalose tetraacetate (4-O-Ac-Tre). Once in the cell, intracellular esterases hydrolyzed the 6-O-Ac-Tre molecules, releasing free trehalose into the cytoplasm. The total concentration of intracellular trehalose (plus acetylated variants) reached as high as 10 fold the extracellular concentration of 6-O-Ac-Tre, attaining concentrations suitable for applications in biopreservation. To describe this accumulation phenomenon, a diffusion-reaction model was proposed and the permeability and reaction kinetics of 6-O-Ac-Tre were determined by fitting to experimental data. Further studies suggested that the impact of the loading and the presence of intracellular trehalose on cellular viability and function were negligible. Engineering of trehalose chemical structure rather than manipulating the cell, is an innocuous, cell-friendly method for trehalose delivery, with demonstrated potential for trehalose loading in different types of cells and cell lines, and can facilitate the wide-spread application of trehalose as an intracellular protective agent in biopreservation studies. C1 [Abazari, Alireza; Bale, Shyam Sundhar; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Ctr Engn Med, Boston, MA 02114 USA. [Abazari, Alireza; Bale, Shyam Sundhar; Toner, Mehmet] Shriners Hosp Children, Boston, MA USA. [Meimetis, Labros G.; Budin, Ghyslain; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Meimetis, Labros G.; Budin, Ghyslain; Weissleder, Ralph] Harvard Univ, Sch Med, Boston, MA USA. RP Toner, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Ctr Engn Med, Boston, MA 02114 USA. EM mtoner@hms.harvard.edu FU Natural Sciences and Engineering Research Council (NSERC) of Canada; NIH [2 R01 DK046270-14A1, R01 EB010011.] FX Alireza Abazari held a Postdoctoral Fellowship from The Natural Sciences and Engineering Research Council (NSERC) of Canada. This research was also funded by NIH grants 2 R01 DK046270-14A1 and R01 EB010011. NR 37 TC 9 Z9 9 U1 1 U2 10 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 JUN 26 PY 2015 VL 10 IS 6 AR e0130323 DI 10.1371/journal.pone.0130323 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1AM UT WOS:000358147500066 PM 26115179 ER PT J AU Zhang, WQ Yu, Y Hertwig, F Thierry-Mieg, J Zhang, WW Thierry-Mieg, D Wang, J Furlanello, C Devanarayan, V Cheng, J Deng, YP Hero, B Hong, HX Jia, MW Li, L Lin, SM Nikolsky, Y Oberthuer, A Qing, T Su, ZQ Volland, R Wang, C Wang, MD Ai, JM Albanese, D Asgharzadeh, S Avigad, S Bao, WJ Bessarabova, M Brilliant, MH Brors, B Chierici, M Chu, TM Zhang, JB Grundy, RG He, MM Hebbring, S Kaufman, HL Lababidi, S Lancashire, LJ Li, Y Lu, XX Luo, H Ma, XW Ning, BT Noguera, R Peifer, M Phan, JH Roels, F Rosswog, C Shao, SS Shen, J Theissen, J Tonini, GP Vandesompele, J Wu, PY Xiao, WZ Xu, JS Xu, WH Xuan, JK Yang, Y Ye, Z Dong, ZR Zhang, KK Yin, Y Zhao, C Zheng, YT Wolfinger, RD Shi, TL Malkas, LH Berthold, F Wang, J Tong, WD Shi, LM Peng, ZY Fischer, M AF Zhang, Wenqian Yu, Ying Hertwig, Falk Thierry-Mieg, Jean Zhang, Wenwei Thierry-Mieg, Danielle Wang, Jian Furlanello, Cesare Devanarayan, Viswanath Cheng, Jie Deng, Youping Hero, Barbara Hong, Huixiao Jia, Meiwen Li, Li Lin, Simon M. Nikolsky, Yuri Oberthuer, Andre Qing, Tao Su, Zhenqiang Volland, Ruth Wang, Charles Wang, May D. Ai, Junmei Albanese, Davide Asgharzadeh, Shahab Avigad, Smadar Bao, Wenjun Bessarabova, Marina Brilliant, Murray H. Brors, Benedikt Chierici, Marco Chu, Tzu-Ming Zhang, Jibin Grundy, Richard G. He, Min Max Hebbring, Scott Kaufman, Howard L. Lababidi, Samir Lancashire, Lee J. Li, Yan Lu, Xin X. Luo, Heng Ma, Xiwen Ning, Baitang Noguera, Rosa Peifer, Martin Phan, John H. Roels, Frederik Rosswog, Carolina Shao, Susan Shen, Jie Theissen, Jessica Tonini, Gian Paolo Vandesompele, Jo Wu, Po-Yen Xiao, Wenzhong Xu, Joshua Xu, Weihong Xuan, Jiekun Yang, Yong Ye, Zhan Dong, Zirui Zhang, Ke K. Yin, Ye Zhao, Chen Zheng, Yuanting Wolfinger, Russell D. Shi, Tieliu Malkas, Linda H. Berthold, Frank Wang, Jun Tong, Weida Shi, Leming Peng, Zhiyu Fischer, Matthias TI Comparison of RNA-seq and microarray-based models for clinical endpoint prediction SO GENOME BIOLOGY LA English DT Article ID EXPRESSION-BASED CLASSIFICATION; GENE-EXPRESSION; NEUROBLASTOMA PATIENTS; RISK STRATIFICATION; PROSTATE-CANCER; BREAST-CANCER; TRANSCRIPTOME; SIGNATURE; DIFFERENTIATION; REPRODUCIBILITY AB Background: Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. Results: We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. Conclusions: We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice. C1 [Zhang, Wenqian; Zhang, Wenwei; Zhang, Jibin; Dong, Zirui; Yin, Ye; Wang, Jun] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China. [Yu, Ying; Jia, Meiwen; Qing, Tao; Zhao, Chen; Zheng, Yuanting; Shi, Leming] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Yu, Ying; Jia, Meiwen; Qing, Tao; Zhao, Chen; Zheng, Yuanting; Shi, Leming] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China. [Yu, Ying; Jia, Meiwen; Qing, Tao; Zhao, Chen; Zheng, Yuanting; Shi, Leming] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. [Hertwig, Falk; Hero, Barbara; Oberthuer, Andre; Volland, Ruth; Roels, Frederik; Rosswog, Carolina; Theissen, Jessica; Berthold, Frank; Fischer, Matthias] Univ Childrens Hosp Cologne, Dept Pediat Oncol & Hematol, D-50924 Cologne, Germany. [Hertwig, Falk; Peifer, Martin; Roels, Frederik; Berthold, Frank; Fischer, Matthias] Univ Cologne, Fac Med, Ctr Mol Med CMMC, D-50924 Cologne, Germany. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NIH NCBI, Bethesda, MD 20894 USA. [Wang, Jian; Yang, Yong] Eli Lilly & Co Res Informat, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Furlanello, Cesare; Chierici, Marco] FBK, I-38123 Trento Povo, TN, Italy. [Devanarayan, Viswanath] AbbVie Inc, Global Pharmaceut R&D, Souderton, PA 18964 USA. [Cheng, Jie] GlaxoSmithKline, Discovery Analyt, Collegeville, PA 19426 USA. [Deng, Youping; Ai, Junmei; Kaufman, Howard L.; Li, Yan] Rush Univ, Ctr Canc, Dept Internal Med, Chicago, IL 60612 USA. [Hong, Huixiao; Su, Zhenqiang; Luo, Heng; Ning, Baitang; Shen, Jie; Xu, Joshua; Xuan, Jiekun; Tong, Weida; Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Li; Bao, Wenjun; Chu, Tzu-Ming; Shao, Susan; Wolfinger, Russell D.] SAS Inst Inc, Cary, NC 27513 USA. [Lin, Simon M.; He, Min Max; Ye, Zhan] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI 54449 USA. [Nikolsky, Yuri; Bessarabova, Marina; Lancashire, Lee J.] Thomson Reuters IP & Sci, Carlsbad, CA 92008 USA. [Wang, Charles] Loma Linda Univ, Ctr Genom, Loma Linda, CA 92350 USA. [Wang, Charles] Loma Linda Univ, Sch Med, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA. [Wang, May D.; Phan, John H.] GeorgiaTech, Dept Biomed Engn, Atlanta, GA 30332 USA. [Wang, May D.; Phan, John H.] Emory Univ, Atlanta, GA 30332 USA. [Albanese, Davide] CRI CBC, Fdn Edmund Mach, San Michele All Adige, TN, Italy. [Asgharzadeh, Shahab] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Avigad, Smadar] Schneider Childrens Med Ctr Israel, Felsenstein Med Res Ctr, Dept Pediat Hematol Oncol, Mol Oncol, IL-49202 Petah Tiqwa, Israel. [Brilliant, Murray H.; Hebbring, Scott] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA. [Brors, Benedikt] German Canc Res Ctr, Dept Theoret Bioinformat, D-69120 Heidelberg, Germany. [Grundy, Richard G.] Univ Nottingham, Queens Med Ctr, Childrens Brain Tumour Res Ctr, Nottingham NG7 2UH, England. [Lababidi, Samir] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Lu, Xin X.] AbbVie Inc, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA. [Luo, Heng] Univ Arkansas, UALR UAMS Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Ma, Xiwen] Eli Lilly & Co, Lilly Corp Ctr, Discovery Stat, Indianapolis, IN 46285 USA. [Noguera, Rosa] Univ Valencia, Sch Med, Dept Pathol, Valencia 46010, Spain. [Peifer, Martin] Univ Cologne, Dept Translat Genom, D-50924 Cologne, Germany. [Tonini, Gian Paolo] Univ Padua, Pediat Res Inst, SDB Dept, Neuroblastoma Lab,Onco Hematol Lab, Padua, Italy. [Vandesompele, Jo] Univ Ghent, Ctr Med Genet, Dept Pediat & Genet, B-9000 Ghent, Belgium. [Wu, Po-Yen] Georgia Inst Technol, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. [Xiao, Wenzhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Xu, Weihong] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Zhang, Ke K.] Univ N Dakota, Sch Med, Dept Pathol, Grand Forks, ND 58202 USA. [Shi, Tieliu] E China Normal Univ, Ctr Bioinformat & Computat Biol, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China. [Shi, Tieliu] Sch Life Sci, Shanghai 200241, Peoples R China. [Malkas, Linda H.] City Hope Comprehens Canc Ctr, Beckman Res Inst, Dept Mol & Cellular Biol, Duarte, CA 91010 USA. [Wang, Jun] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark. [Wang, Jun] King Abdulaziz Univ, Jeddah 21589, Saudi Arabia. [Wang, Jun] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark. [Peng, Zhiyu] Guangzhou Higher Educ Mega Ctr, BGI Guangzhou, Guangzhou 510006, Guangdong, Peoples R China. RP Shi, LM (reprint author), Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. EM lemingshi@fudan.edu.cn; pengzhiyu@genomics.org.cn; matthias.fischer@uk-koeln.de RI Brors, Benedikt/E-5620-2013; Wang, Jun/C-8434-2016; Luo, Heng/D-3616-2016; THIERRY-MIEG, Jean/F-1975-2017; Wang, Jun/B-9503-2016; OI Brors, Benedikt/0000-0001-5940-3101; Grundy, Richard/0000-0002-2585-2539; Wang, Jun/0000-0002-8540-8931; Luo, Heng/0000-0001-5192-8878; THIERRY-MIEG, Jean/0000-0002-0396-6789; Chierici, Marco/0000-0001-9791-9301; Wang, Jun/0000-0002-2113-5874; Hertwig, Falk/0000-0003-4784-6516 FU National High Technology Research and Development Program of China - 863 Program [2015AA020104, 2012AA02A201]; National Science Foundation of China [31471239]; Intramural Research Program of the NIH, National Library of Medicine (USA); Cologne Center for Molecular Medicine; Bundesministerium fur Bildung und Forschung (BMBF) through the National Genome Research Network plus (NGFNplus) [01GS0895]; German Cancer Aid (Deutsche Krebshilfe) [110122]; Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V.; National Institutes of Health [U54CA119338, 1RC2CA148265, R01CA163256]; Georgia Cancer Coalition; BMBF through the Competence Network Pediatric Oncology and Hematology (KPOH); Italian Neuroblastoma Foundation; China National Supercomputing Center in Guangzhou; China National Supercomputing Center in Tianjin FX We are grateful to Yvonne Kahlert, Anne Engesser, and Simona Coco for technical assistance. This work was supported by grants from the National High Technology Research and Development Program of China - 863 Program (2015AA020104 to LS and 2012AA02A201 to TS), the National Science Foundation of China (31471239 to LS), the Intramural Research Program of the NIH, National Library of Medicine (USA), the Cologne Center for Molecular Medicine (to MF), the Bundesministerium fur Bildung und Forschung (BMBF) through the National Genome Research Network plus (NGFNplus, grant 01GS0895 to MF), the German Cancer Aid (Deutsche Krebshilfe, grant 110122 to MF), the Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V. (to FB and MF), and the National Institutes of Health (U54CA119338, 1RC2CA148265, and R01CA163256) and Georgia Cancer Coalition (to MDW). Tumor sample collection was supported by the BMBF through the Competence Network Pediatric Oncology and Hematology (KPOH) and by the Italian Neuroblastoma Foundation. We gratefully acknowledge support by China's National Supercomputing Centers in Guangzhou and Tianjin. NR 39 TC 12 Z9 12 U1 3 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD JUN 25 PY 2015 VL 16 AR 133 DI 10.1186/s13059-015-0694-1 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CN0PZ UT WOS:000358117100001 PM 26109056 ER PT J AU Flynn, R Allen, JL Luznik, L MacDonald, KP Paz, K Alexander, KA Vulic, A Du, J Panoskaltsis-Mortari, A Taylor, PA Poe, JC Serody, JS Murphy, WJ Hill, GR Maillard, I Koreth, J Cutler, CS Soiffer, RJ Antin, JH Ritz, J Chao, NJ Clynes, RA Sarantopoulos, S Blazar, BR AF Flynn, Ryan Allen, Jessica L. Luznik, Leo MacDonald, Kelli P. Paz, Katelyn Alexander, Kylie A. Vulic, Ante Du, Jing Panoskaltsis-Mortari, Angela Taylor, Patricia A. Poe, Jonathan C. Serody, Jonathan S. Murphy, William J. Hill, Geoffrey R. Maillard, Ivan Koreth, John Cutler, Corey S. Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome Chao, Nelson J. Clynes, Raphael A. Sarantopoulos, Stefanie Blazar, Bruce R. TI Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease SO BLOOD LA English DT Article ID TOLL-LIKE RECEPTORS; CHRONIC GVHD; BRONCHIOLITIS OBLITERANS; SIGNALING PATHWAY; TYROSINE KINASE; BAFF; TRANSPLANTATION; RESPONSES; SURVIVAL; ANTIBODY AB Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, non-sclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD. C1 [Flynn, Ryan; Paz, Katelyn; Du, Jing; Panoskaltsis-Mortari, Angela; Taylor, Patricia A.; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Masonic Canc Ctr, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Allen, Jessica L.; Poe, Jonathan C.; Chao, Nelson J.; Sarantopoulos, Stefanie] Duke Univ, Dept Med, Duke Canc Inst, Div Hematol Malignancies & Cellular Therapy, Durham, NC USA. [Luznik, Leo; Vulic, Ante] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA. [MacDonald, Kelli P.; Alexander, Kylie A.; Hill, Geoffrey R.] Queensland Inst Med Res, Dept Immunol, Brisbane, Qld 4006, Australia. [Serody, Jonathan S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC 27599 USA. [Murphy, William J.] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Maillard, Ivan] Univ Michigan, Dept Internal Med, Inst Life Sci, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Boston, MA 02115 USA. [Clynes, Raphael A.] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Clynes, Raphael A.] Columbia Univ, Dept Microbiol, New York, NY 10032 USA. RP Blazar, BR (reprint author), Univ Minnesota, Dept Pediat, Masonic Canc Ctr, 420 Delaware St SE,MMC 109, Minneapolis, MN 55455 USA. EM blaza001@umn.edu RI Hill, Geoffrey/O-2630-2016; MacDonald, Kelli/O-2722-2016; Alexander, Kylie /P-2666-2016; OI Hill, Geoffrey/0000-0003-2994-0429; MacDonald, Kelli/0000-0003-3451-4221; Alexander, Kylie /0000-0001-5772-0277; Serody, Jonathan/0000-0003-4568-1092; Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health National Cancer Institute [P01 CA142106-06A1, 5P01-CA047741-20]; National Heart, Lung, and Blood Institute [R01 HL126530, K08HL107756]; National Institute of Allergy and Infectious Diseases [P01 AI 056299, T32 AI 007313]; Leukemia and Lymphoma Society [6458-15, 6462-15]; Children's Cancer Research Fund, Minneapolis, MN FX The authors thank Rigel Pharmaceuticals for providing fostamatinib (R788/R406). This work was supported in part by National Institutes of Health National Cancer Institute grants P01 CA142106-06A1 and 5P01-CA047741-20; National Heart, Lung, and Blood Institute grants R01 HL126530 and K08HL107756; National Institute of Allergy and Infectious Diseases grants P01 AI 056299, and T32 AI 007313; and Leukemia and Lymphoma Society translational research grants 6458-15 and 6462-15. R.F. is supported by the Children's Cancer Research Fund, Minneapolis, MN. NR 36 TC 17 Z9 18 U1 1 U2 3 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 JUN 25 PY 2015 VL 125 IS 26 BP 4085 EP 4094 DI 10.1182/blood-2014-08-595470 PG 10 WC Hematology SC Hematology GA CL9GF UT WOS:000357284300020 PM 25852057 ER PT J AU Leveroni, CL Leveroni, CL Tanaka, N Emerton, BC Cole, AC Reinsberger, C Stufflebeam, SM AF Douw, Linda Leveroni, Catherine L. Tanaka, Naoaki Emerton, Britt C. Cole, Andrew C. Reinsberger, Claus Stufflebeam, Steven M. TI Loss of Resting-State Posterior Cingulate Flexibility Is Associated with Memory Disturbance in Left Temporal Lobe Epilepsy SO PLOS ONE LA English DT Article ID HUMAN CEREBRAL-CORTEX; FUNCTIONAL BRAIN NETWORKS; DEFAULT MODE NETWORK; CONNECTIVITY; SCALE; ORGANIZATION; PERFORMANCE; SYSTEM; FMRI; MRI AB The association between cognition and resting-state fMRI (rs-fMRI) has been the focus of many recent studies, most of which use stationary connectivity. The dynamics or flexibility of connectivity, however, may be seminal for understanding cognitive functioning. In temporal lobe epilepsy (TLE), stationary connectomic correlates of impaired memory have been reported mainly for the hippocampus and posterior cingulate cortex (PCC). We therefore investigate resting-state and task-based hippocampal and PCC flexibility in addition to stationary connectivity in left TLE (LTLE) patients. Sixteen LTLE patients were analyzed with respect to rs-fMRI and task-based fMRI (t-fMRI), and underwent clinical neuropsychological testing. Flexibility of connectivity was calculated using a sliding-window approach by determining the standard deviation of Fisher-transformed Pearson correlation coefficients over all windows. Stationary connectivity was also calculated. Disturbed memory was operationalized as having at least one memory subtest score equal to or below the 5th percentile compared to normative data. Lower PCC flexibility, particularly in the contralateral (i.e. right) hemisphere, was found in memory-disturbed LTLE patients, who had up to 22% less flexible connectivity. No significant group differences were found with respect to hippocampal flexibility, stationary connectivity during both rs-fMRI and t-fMRI, or flexibility during t-fMRI. Contralateral resting-state PCC flexibility was able to classify all but one patient with respect to their memory status (94% accuracy). Flexibility of the PCC during rest relates to memory functioning in LTLE patients. Loss of flexible connectivity to the rest of the brain originating from the PCC, particularly contralateral to the seizure focus, is able to discern memory disturbed patients from their preserved counterparts. This study indicates that the dynamics of resting-state connectivity are associated with cognitive status of LTLE patients, rather than stationary connectivity. C1 [Douw, Linda; Tanaka, Naoaki; Reinsberger, Claus; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Douw, Linda; Tanaka, Naoaki; Stufflebeam, Steven M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Douw, Linda] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. [Leveroni, Catherine L.; Emerton, Britt C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cole, Andrew C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Reinsberger, Claus] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Reinsberger, Claus] Univ Paderborn, Fac Sci, Inst Sports Med, D-33098 Paderborn, Germany. RP Leveroni, CL (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM douw@nmr.mgh.harvard.edu FU NCRR [S10RR014978]; NIH [5R01-NS060918, U01MH093765, 1S10RR023043, R01-NS069696]; Dutch Organization for Scientific Research Rubicon [825.11.002, Veni 016.146.086]; Society in Science-Branco Weiss Fellowship FX This study was supported by the following grants: NCRR S10RR014978 (http://www.nih.gov/about/almanac/organization/NCRR.htm;SMS), NIH 5R01-NS060918, U01MH093765, 1S10RR023043, R01-NS069696 (http://www.nih.gov/;SMS), the Dutch Organization for Scientific Research Rubicon 825.11.002 and Veni 016.146.086 (http://www.nwo.nl/en; LD), and a Society in Science-Branco Weiss Fellowship (http://www.society-in-science.org/;LD). NR 39 TC 0 Z9 0 U1 1 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 JUN 25 PY 2015 VL 10 IS 6 DI 10.1371/journal.pone.0131209 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4OY UT WOS:000356933800130 ER PT J AU Caskey, M Klein, F Lorenzi, JCC Seaman, MS West, AP Buckley, N Kremer, G Nogueira, L Braunschweig, M Scheid, JF Horwitz, JA Shimeliovich, I Ben-Avraham, S Witmer-Pack, M Platten, M Lehmann, C Burke, LA Hawthorne, T Gorelick, RJ Walker, BD Keler, T Gulick, RM Fatkenheuer, G Schlesinger, SJ Nussenzweig, MC AF Caskey, Marina Klein, Florian Lorenzi, Julio C. C. Seaman, Michael S. West, Anthony P., Jr. Buckley, Noreen Kremer, Gisela Nogueira, Lilian Braunschweig, Malte Scheid, Johannes F. Horwitz, Joshua A. Shimeliovich, Irina Ben-Avraham, Sivan Witmer-Pack, Maggi Platten, Martin Lehmann, Clara Burke, Leah A. Hawthorne, Thomas Gorelick, Robert J. Walker, Bruce D. Keler, Tibor Gulick, Roy M. Faetkenheuer, Gerd Schlesinger, Sarah J. Nussenzweig, Michel C. TI Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117 SO NATURE LA English DT Article ID MONOCLONAL-ANTIBODIES; HIV-1 NEUTRALIZATION; GENETIC-DETERMINANTS; PASSIVE TRANSFER; IN-VIVO; THERAPY; VIRUS; IMMUNOTHERAPY; VACCINE; MICE AB HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned(1-3). However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated(6-10). Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody(11), in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log(10) and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure. C1 [Caskey, Marina; Klein, Florian; Lorenzi, Julio C. C.; Buckley, Noreen; Nogueira, Lilian; Braunschweig, Malte; Scheid, Johannes F.; Horwitz, Joshua A.; Shimeliovich, Irina; Ben-Avraham, Sivan; Witmer-Pack, Maggi; Burke, Leah A.; Schlesinger, Sarah J.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Seaman, Michael S.] Harvard Univ, Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [West, Anthony P., Jr.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Kremer, Gisela; Platten, Martin; Lehmann, Clara; Faetkenheuer, Gerd] Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany. [Kremer, Gisela] Univ Cologne, Clin Trials Ctr Cologne, ZKS Koln, D-50931 Cologne, Germany. [Braunschweig, Malte] Univ Freiburg, D-79085 Freiburg, Germany. [Platten, Martin; Lehmann, Clara; Faetkenheuer, Gerd] Partner Site Bonn Cologne, German Ctr Infect Res DZIF, Cologne, Germany. [Burke, Leah A.; Gulick, Roy M.] Cornell Univ, Div Infect Dis, Weill Med Coll, New York, NY 10065 USA. [Hawthorne, Thomas; Keler, Tibor] Celldex Therapeut Inc, Hampton, NJ 08827 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Walker, Bruce D.] Massachusetts Gen Hosp, Radon Inst MGH MIT & Harvard, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Walker, Bruce D.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu RI Cetrulo Lorenzi, Julio Cesar/B-5264-2008; OI Cetrulo Lorenzi, Julio Cesar/0000-0003-2492-3961; Ben-Avraham, Sivan/0000-0002-9130-0062 FU CNPq "Ciencia sem Fronteiras" Brazil [248676/2013-0]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) [OPP1033115, OPP1092074, OPP1040753, OPP1032144]; Cooperative Centers on Human Immunology from NIH [U19A1111825-01]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000043]; Robertson Foundation; NCI/NIH [HHSN261200800001E]; German Center for Infection Research (DZIF) [3BNC117]; Mark and Lisa Schwartz Foundation; CAVD [43307] FX We thank all individuals who participated in this study. We thank the Rockefeller University Hospital Clinical Research Support Office and nursing staff, as well as T. Kummerle, C. Wyen, and L. Siegel for help with recruitment; S. Kiss for ophthalmologic assessments; F. Maldarelli and J. Lifson for single-copy analysis and B. Freemire for technical assistance; J. Pring, A. Almaktari, C. Unsen, S. Hadrigan, E. Thomas, H. Gruell, D. Gillor, and U. Sandaradura de Silva for sample processing and study coordination, and N. Rodziewicz for help with HIV-1 culturing. We thank A. Louie and C. Conrad for help with regulatory submissions; L. Thomas for IND-enabling studies, L Vitale for cell line and anti-idiotype antibody development, B. Riordan, A. Rayo and J. Andreozzi for anti-idiotype ELISA method development and sample analysis, R. Hammond for process development, and S. DiSciullo for 3BNC117 manufacturing; J. Perry for performing neutralization assays. We thank M. Suarez-Farinas for support with statistical analysis; P. Fast and H. Park for clinical monitoring; and E. Gotschlich and B. Caller for input on study design. J.C.C.L. is supported by an award from CNPq "Ciencia sem Fronteiras" Brazil (248676/2013-0). This work was supported in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grants OPP1033115 (M.C.N.), OPP1092074 (M.C.N.), OPP1040753 (A.P.W.) and OPP1032144 (M.S.S.), and U19A1111825-01 Cooperative Centers on Human Immunology from NIH to M.C.N., by grant #UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), by a grant from the Robertson Foundation to M.C.N., in part with Federal funds from the NCI/NIH, under Contract No. HHSN261200800001E, and a grant from the German Center for Infection Research (DZIF) to G.F. 3BNC117 was generated from a subject in the International HIV Controller Study, supported by the Mark and Lisa Schwartz Foundation and CAVD Grant 43307. M.C.N. and B.D.W. are Howard Hughes Medical Institute Investigators. The authors declare no competing financial interests. NR 40 TC 142 Z9 144 U1 9 U2 53 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 JUN 25 PY 2015 VL 522 IS 7557 BP 487 EP + DI 10.1038/nature14411 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL2OC UT WOS:000356782900052 PM 25855300 ER PT J AU Roumiantsev, S Shah, U Westra, SJ Misdraji, J AF Roumiantsev, Serguei Shah, Uzma Westra, Sjirk J. Misdraji, Joseph TI Case 20-2015: A Newborn Girl with Hypotension, Coagulopathy, Anemia, and Hyperbilirubinemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ALLOIMMUNE LIVER-DISEASE; NEONATAL HEMOCHROMATOSIS; MITOCHONDRIAL HEPATOPATHIES; FAILURE; EXPERIENCE; MANAGEMENT; METABOLISM; DIAGNOSIS; HEPATITIS; INFANTS C1 [Roumiantsev, Serguei] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Westra, Sjirk J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Roumiantsev, Serguei] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Westra, Sjirk J.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Misdraji, Joseph] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Roumiantsev, S (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 29 TC 1 Z9 1 U1 0 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 JUN 25 PY 2015 VL 372 IS 26 BP 2542 EP 2553 DI 10.1056/NEJMcpc1404334 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CL2QD UT WOS:000356788200011 PM 26107055 ER PT J AU Phimister, EG AF Phimister, Elizabeth G. TI TREM2 and Risk of Alzheimer's Disease - Friend or Foe? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Phimister, Elizabeth G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Phimister, Elizabeth G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Phimister, EG (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 8 TC 2 Z9 2 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 JUN 25 PY 2015 VL 372 IS 26 BP 2564 EP 2565 DI 10.1056/NEJMcibr1503954 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CL2QD UT WOS:000356788200014 ER PT J AU Vaduganathan, M Johnson, JH AF Vaduganathan, Muthiah Johnson, Jacob H. TI Ping-Pong Gaze SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Vaduganathan, Muthiah; Johnson, Jacob H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Vaduganathan, M (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mvaduganathan@partners.org NR 0 TC 0 Z9 0 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 JUN 25 PY 2015 VL 372 IS 26 BP E34 EP E34 DI 10.1056/NEJMicm1408161 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CL2QD UT WOS:000356788200001 PM 26107068 ER PT J AU Rashidian, M Keliher, EJ Dougan, M Juras, PK Cavallari, M Wojtkiewicz, GR Jacobsen, JT Edens, JG Tas, JMJ Victora, G Weissleder, R Ploegh, H AF Rashidian, Mohammad Keliher, Edmund J. Dougan, Michael Juras, Patrick K. Cavallari, Marco Wojtkiewicz, Gregory R. Jacobsen, Johanne T. Edens, Jerre G. Tas, Jeroen M. J. Victora, Gabriel Weissleder, Ralph Ploegh, Hidde TI Use of F-18-2-Fluorodeoxyglucose to Label Antibody Fragments for Immuno-Positron Emission Tomography of Pancreatic Cancer SO ACS CENTRAL SCIENCE LA English DT Article ID COLORECTAL-CANCER; PET; SORTASE; LIGATION; PROTEINS; NANOBODY; CELLS; BIOCONJUGATION; CONJUGATION AB We generated F-18-labeled antibody fragments for positron emission tomography (PET) imaging using a sortase-mediated reaction to install a trans-cyclooctene-functionalized short peptide onto proteins of interest, followed by reaction with a tetrazine-labeled-F-18-2-deoxyfluoroglucose (FDG). The method is rapid, robust, and site-specific (radiochemical yields > 25%, not decay corrected). The availability of F-18-2-deoxyfluoroglucose avoids the need for more complicated chemistries used to generate carbon-fluorine bonds. We demonstrate the utility of the method by detecting heterotopic pancreatic tumors in mice by PET, using anti-Class II MHC single domain antibodies. We correlate macroscopic PET images with microscopic two-photon visualization of the tumor. Our approach provides easy access to F-18-labeled antibodies and their fragments at a level of molecular specificity that complements conventional F-18-FDG imaging. C1 [Rashidian, Mohammad; Dougan, Michael; Juras, Patrick K.; Cavallari, Marco; Jacobsen, Johanne T.; Edens, Jerre G.; Tas, Jeroen M. J.; Victora, Gabriel; Ploegh, Hidde] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Keliher, Edmund J.; Wojtkiewicz, Gregory R.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol Dept, Boston, MA 02114 USA. [Keliher, Edmund J.; Wojtkiewicz, Gregory R.; Weissleder, Ralph] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dougan, Michael] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Rashidian, Mohammad; Juras, Patrick K.; Ploegh, Hidde] MIT, Dept Biol, Cambridge, MA 02142 USA. RP Ploegh, H (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM ploegh@wi.mit.edu FU NCI NIH HHS [P01 CA117969, P50 CA086355]; NIAID NIH HHS [R01 AI087879, R21 AI117373]; NIBIB NIH HHS [R01 EB010011]; NIGMS NIH HHS [DP1 GM106409, R01 GM100518] NR 38 TC 14 Z9 14 U1 4 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2374-7943 EI 2374-7951 J9 ACS CENTRAL SCI JI ACS Central Sci. PD JUN 24 PY 2015 VL 1 IS 3 BP 142 EP 147 DI 10.1021/acscentsci.5b00121 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA CX8QB UT WOS:000365967600009 PM 26955657 ER PT J AU Martinet, LE Ahmed, OJ Lepage, KQ Cash, SS Kramer, MA AF Martinet, Louis-Emmanuel Ahmed, Omar J. Lepage, Kyle Q. Cash, Sydney S. Kramer, Mark A. TI Slow Spatial Recruitment of Neocortex during Secondarily Generalized Seizures and Its Relation to Surgical Outcome SO JOURNAL OF NEUROSCIENCE LA English DT Article DE epilepsy; focal seizure; intracranial EEG; seizure propagation; seizure spread ID INDUCED EPILEPTIFORM ACTIVITY; TEMPORAL-LOBE SEIZURES; SMALL-WORLD NETWORKS; INTRACRANIAL EEG; ONSET PATTERNS; FOCAL EPILEPSY; GAP-JUNCTIONS; EVOKED-RESPONSES; PROPAGATION TIME; BRAIN-SLICES AB Understanding the spatiotemporal dynamics of brain activity is crucial for inferring the underlying synaptic and nonsynaptic mechanisms of brain dysfunction. Focal seizures with secondary generalization are traditionally considered to begin in a limited spatial region and spread to connected areas, which can include both pathological and normal brain tissue. The mechanisms underlying this spread are important to our understanding of seizures and to improve therapies for surgical intervention. Here we study the properties of seizure recruitment-how electrical brain activity transitions to large voltage fluctuations characteristic of spike-and-wave seizures. We do so using invasive subdural electrode arrays from a population of 16 patients with pharmacoresistant epilepsy. We find an average delay of similar to 30 s for a broad area of cortex (8 x 8 cm) to be recruited into the seizure, at an estimated speed of similar to 4 mm/s. The spatiotemporal characteristics of recruitment reveal two categories of patients: one in which seizure recruitment of neighboring cortical regions follows a spatially organized pattern consistent from seizure to seizure, and a second group without consistent spatial organization of activity during recruitment. The consistent, organized recruitment correlates with a more regular, compared with small-world, connectivity pattern in simulation and successful surgical treatment of epilepsy. We propose that an improved understanding of how the seizure recruits brain regions into large amplitude voltage fluctuations provides novel information to improve surgical treatment of epilepsy and highlights the slow spread of massive local activity across a vast extent of cortex during seizure. C1 [Martinet, Louis-Emmanuel; Lepage, Kyle Q.; Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ahmed, Omar J.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Kramer, MA (reprint author), Boston Univ, Dept Math & Stat, 111 Cummington Mall, Boston, MA 02215 USA. EM mak@bu.edu FU National Institute of Neurological Disorders and Stroke Award [R01NS072023, SNS062092]; Epilepsy Foundation [222178] FX This research is supported by National Institute of Neurological Disorders and Stroke Award R01NS072023 (to M.A.K. and S.S.C.) and Grant SNS062092 (to S.S.C.) and by the Epilepsy Foundation Grant 222178. We thank the patients who participated in this study and the nursing and physician staff. We also thank Jason Naftulin for technical assistance. NR 93 TC 5 Z9 5 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 24 PY 2015 VL 35 IS 25 BP 9477 EP 9490 DI 10.1523/JNEUROSCI.0049-15.2015 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CN2LG UT WOS:000358252000022 PM 26109670 ER PT J AU Tseng, JC Kung, AL AF Tseng, Jen-Chieh Kung, Andrew L. TI In vivo imaging of endogenous enzyme activities using luminescent 1,2-dioxetane compounds SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Article DE In vivo imaging; Luminescence; Fluorescence; 1,2-dioxetane; CIEEL energy transfer ID INTESTINAL ALKALINE-PHOSPHATASE; FLUORESCENT COMPOUNDS; HUMAN-GRANULOCYTES; HYDROGEN-PEROXIDE; CHEMILUMINESCENCE; BIOLUMINESCENCE; ABILITY; CDNA AB Background: Here we present a non-invasive imaging method for visualizing endogenous enzyme activities in living animals. This optical imaging method is based on an energy transfer principle termed chemically initiated electron exchange luminescence (CIEEL). The light energy is provided by enzymatic activation of metastable 1,2-dioxetane substrates, whose protective groups are removed by hydrolytic enzymes such as beta-galactosidase and alkaline phosphatase. In the presence of a nearby fluorescent recipient, the chemical energy within the activated substrate is then transferred via formation of a charge-transfer complex with the fluorophore, a mechanism closely related to glow stick chemistry. Results: Efficient CIEEL energy transfer requires close proximity between the trigger enzyme and the fluorescent recipient. Using cells stained with fluorescent dialkylcarbocyanines as the energy recipients, we demonstrated CIEEL imaging of cellular beta-galactosidase or alkaline phosphatase activity. In living animals, we used a similar approach to non-invasively image alkaline phosphatase activity in the peritoneal cavity. Conclusions: In this report, we provide proof-of-concept for CIEEL imaging of in vivo enzymatic activity. In addition, we demonstrate the use of CIEEL energy transfer for visualizing elevated alkaline phosphatase activity associated with tissue inflammation in living animals. C1 [Tseng, Jen-Chieh] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02215 USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, New York, NY 10032 USA. RP Tseng, JC (reprint author), PerkinElmer Inc, 68 Elm St, Hopkinton, MA 01748 USA. EM jct223@gmail.com OI Kung, Andrew/0000-0002-9091-488X FU Nancy Lurie Marks Foundation FX This work was supported by the Nancy Lurie Marks Foundation. NR 28 TC 1 Z9 1 U1 4 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1021-7770 EI 1423-0127 J9 J BIOMED SCI JI J. Biomed. Sci. PD JUN 24 PY 2015 VL 22 DI 10.1186/s12929-015-0155-x PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CL0TU UT WOS:000356656800002 ER PT J AU Cornelissen, L Kim, SE Purdon, PL Brown, EN Berde, CB AF Cornelissen, Laura Kim, Seong-Eun Purdon, Patrick L. Brown, Emery N. Berde, Charles B. TI Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants SO ELIFE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; PROPOFOL-INDUCED UNCONSCIOUSNESS; NERVOUS-SYSTEM MYELINATION; INDUCED ALPHA-RHYTHM; PEDIATRIC ANESTHESIA; CONNECTIVITY CHANGES; COHERENCE ANALYSIS; BRAIN-DEVELOPMENT; CONSCIOUSNESS; CHILDREN AB Electroencephalogram (EEG) approaches may provide important information about developmental changes in brain-state dynamics during general anesthesia. We used multi-electrode EEG, analyzed with multitaper spectral methods and video recording of body movement to characterize the spatio-temporal dynamics of brain activity in 36 infants 0-6 months old when awake, and during maintenance of and emergence from sevoflurane general anesthesia. During maintenance: (1) slow-delta oscillations were present in all ages; (2) theta and alpha oscillations emerged around 4 months; (3) unlike adults, all infants lacked frontal alpha predominance and coherence. Alpha power was greatest during maintenance, compared to awake and emergence in infants at 4-6 months. During emergence, theta and alpha power decreased with decreasing sevoflurane concentration in infants at 4-6 months. These EEG dynamic differences are likely due to developmental factors including regional differences in synaptogenesis, glucose metabolism, and myelination across the cortex. We demonstrate the need to apply age-adjusted analytic approaches to develop neurophysiologic-based strategies for pediatric anesthetic state monitoring. C1 [Cornelissen, Laura; Berde, Charles B.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Kim, Seong-Eun; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Purdon, Patrick L.; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Cornelissen, L (reprint author), Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. EM laura.cornelissen@childrens.harvard.edu FU Sara Page Mayo Endowment for Pediatric Pain Research and Treatment; Boston Children's Hospital (BCH); National Institutes of Health (NIH) [R01-GM104948, DP2-OD006454]; Massachusetts General Hospital (MGH) FX Sara Page Mayo Endowment for Pediatric Pain Research and Treatment Laura Cornelissen, Charles B Berde; Boston Children's Hospital (BCH) Laura Cornelissen, Charles B Berde; National Institutes of Health (NIH) R01-GM104948; DP2-OD006454 Seong-Eun Kim, Patrick L Purdon, Emery N Brown; Massachusetts General Hospital (MGH) Patrick L Purdon, Emery N Brown NR 53 TC 1 Z9 1 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 JUN 23 PY 2015 VL 4 AR e06513 DI 10.7554/eLife.06513 PG 25 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ5MI UT WOS:000374252300001 PM 26102526 ER PT J AU Smucny, J Stevens, KE Olincy, A Tregellas, JR AF Smucny, J. Stevens, K. E. Olincy, A. Tregellas, J. R. TI Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID NICOTINIC ACETYLCHOLINE-RECEPTORS; DEFICIENT SENSORY INHIBITION; FREELY MOVING RATS; MEDIAL PREFRONTAL CORTEX; DRUG-INDUCED PSYCHOSIS; PURSUIT EYE-MOVEMENTS; PROOF-OF-CONCEPT; DBA/2 MICE; CIGARETTE-SMOKING; P50 SUPPRESSION AB Impaired gating of the auditory evoked P50 potential is one of the most pharmacologically well-characterized features of schizophrenia. This deficit is most commonly modeled in rodents by implanted electrode recordings from the hippocampus of the rodent analog of the P50, the P20-N40. The validity and effectiveness of this tool, however, has not been systematically reviewed. Here, we summarize findings from studies that have examined the effects of pharmacologic modulation on gating of the rodent hippocampal P20-N40 and the human P50. We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges. Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings. We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied. Overall, this review supports continued use of hippocampal P20-N40 gating as a translational tool for schizophrenia research. C1 [Smucny, J.; Tregellas, J. R.] Univ Colorado, Neurosci Program, Aurora, CO 80045 USA. [Smucny, J.; Olincy, A.; Tregellas, J. R.] Denver VA Med Ctr, Res Serv, Denver, CO USA. [Smucny, J.; Stevens, K. E.; Olincy, A.; Tregellas, J. R.] Univ Colorado, Dept Psychiat, Aurora, CO 80045 USA. RP Tregellas, JR (reprint author), Univ Colorado, Dept Psychiat, Anschutz Med Campus,Bldg 500,MS 546, Aurora, CO 80045 USA. EM jason.tregellas@ucdenver.edu FU VA Biomedical Laboratory and Clinical Science Research and Development Service; Brain and Behavior Foundation; Blowitz-Ridgeway Foundation [MH-086383-01, 1F31-MH102879-01A1] FX This work was supported by the VA Biomedical Laboratory and Clinical Science Research and Development Service, the Brain and Behavior Foundation, the Blowitz-Ridgeway Foundation, MH-086383-01 and 1F31-MH102879-01A1. NR 180 TC 4 Z9 5 U1 2 U2 3 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 JUN 23 PY 2015 VL 5 AR e587 DI 10.1038/tp.2015.77 PG 13 WC Psychiatry SC Psychiatry GA DA2WZ UT WOS:000367659200002 PM 26101850 ER PT J AU Melman, YF Shah, R Danielson, K Xiao, JJ Simonson, B Barth, A Chakir, K Lewis, GD Lavender, Z Truong, QA Kleber, A Das, R Rosenzweig, A Wang, YY Kass, DA Singh, JP Das, S AF Melman, Yonathan F. Shah, Ravi Danielson, Kirsty Xiao, Junjie Simonson, Bridget Barth, Andreas Chakir, Khalid Lewis, Gregory D. Lavender, Zachary Truong, Quynh A. Kleber, Andre Das, Ranendra Rosenzweig, Anthony Wang, Yaoyu Kass, David A. Singh, Jagmeet P. Das, Saumya TI Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis A Translational Pilot Study SO CIRCULATION LA English DT Article DE biological markers; heart failure; microRNAs; stress; biological ID QRS DURATION; MADIT-CRT; DYSSYNCHRONY; OUTCOMES; TARGETS; TRIAL; EXPRESSION; BIOMARKERS; MORPHOLOGY; MYOCYTES AB Background Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined. Methods and Results Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as an increase in left ventricular ejection fraction 10%). MiR-30d was enriched in coronary sinus blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. In HFDYS patients, miR-30d plasma levels inversely correlated with high-sensitivity troponin T, a marker of myocardial necrosis. Conclusions Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling. C1 [Melman, Yonathan F.; Shah, Ravi; Danielson, Kirsty; Simonson, Bridget; Kleber, Andre; Rosenzweig, Anthony; Das, Saumya] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Shah, Ravi; Lewis, Gregory D.; Lavender, Zachary; Truong, Quynh A.; Singh, Jagmeet P.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Xiao, Junjie] Shanghai Univ, Sch Life Sci, Expt Ctr Life Sci, Shanghai 200041, Peoples R China. [Xiao, Junjie] Shanghai Univ, Sch Life Sci, Regenerat Lab, Shanghai 200041, Peoples R China. [Barth, Andreas; Chakir, Khalid; Kass, David A.] Johns Hopkins Univ Med Inst, Baltimore, MD USA. [Das, Ranendra] Johns Hopkins Univ, Baltimore, MD USA. [Wang, Yaoyu] Dana Farber Canc Inst, Ctr Computat Biol, Boston, MA 02115 USA. RP Das, S (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave,CLS 907, Boston, MA 02215 USA. EM sdas@bidmc.harvard.edu FU Klarman Scholars Foundation; National Institutes of Health Common Funds through Office of Strategic Coordination/Office of the National Institutes of Health [UH2-TR000901]; NHLBI [PO1: HL077180] FX Dr Das is funded by the Klarman Scholars Foundation and a grant from National Institutes of Health Common Funds UH2-TR000901 through the Office of Strategic Coordination/Office of the National Institutes of Health Director. Dr Kass received funding from NHLBI PO1: HL077180. NR 35 TC 23 Z9 26 U1 10 U2 19 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 JUN 23 PY 2015 VL 131 IS 25 BP 2202 EP 2216 DI 10.1161/CIRCULATIONAHA.114.013220 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CQ3UG UT WOS:000360528400007 PM 25995320 ER PT J AU Pandarinath, C Gilja, V Blabe, CH Nuyujukian, P Sarma, AA Sorice, BL Eskandar, EN Hochberg, LR Henderson, JM Shenoy, KV AF Pandarinath, Chethan Gilja, Vikash Blabe, Christine H. Nuyujukian, Paul Sarma, Anish A. Sorice, Brittany L. Eskandar, Emad N. Hochberg, Leigh R. Henderson, Jaimie M. Shenoy, Krishna V. TI Neural population dynamics in human motor cortex during movements in people with ALS SO ELIFE LA English DT Article ID ARM MOVEMENTS; TETRAPLEGIA AB The prevailing view of motor cortex holds that motor cortical neural activity represents muscle or movement parameters. However, recent studies in non-human primates have shown that neural activity does not simply represent muscle or movement parameters; instead, its temporal structure is well-described by a dynamical system where activity during movement evolves lawfully from an initial pre-movement state. In this study, we analyze neuronal ensemble activity in motor cortex in two clinical trial participants diagnosed with Amyotrophic Lateral Sclerosis (ALS). We find that activity in human motor cortex has similar dynamical structure to that of non-human primates, indicating that human motor cortex contains a similar underlying dynamical system for movement generation. C1 [Pandarinath, Chethan; Gilja, Vikash; Blabe, Christine H.; Nuyujukian, Paul; Henderson, Jaimie M.] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Pandarinath, Chethan; Gilja, Vikash; Nuyujukian, Paul; Shenoy, Krishna V.] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Pandarinath, Chethan; Nuyujukian, Paul; Henderson, Jaimie M.; Shenoy, Krishna V.] Stanford Univ, Stanford Neurosci Inst, Stanford, CA 94305 USA. [Gilja, Vikash; Sarma, Anish A.; Hochberg, Leigh R.] Brown Univ, Sch Engn, Providence, RI 02912 USA. [Sarma, Anish A.; Hochberg, Leigh R.] Dept VA Med Ctr, Rehabil R&D Serv, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. [Sarma, Anish A.; Sorice, Brittany L.; Hochberg, Leigh R.] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. [Sarma, Anish A.; Hochberg, Leigh R.] Brown Univ, Inst Brain Sci, Providence, RI USA. [Eskandar, Emad N.] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Hochberg, Leigh R.] Harvard Univ, Sch Med, Neurol, Boston, MA USA. [Shenoy, Krishna V.] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA. [Shenoy, Krishna V.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Shenoy, Krishna V.] Stanford Univ, Neurosci Program, Stanford, CA 94305 USA. RP Shenoy, KV (reprint author), Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. EM shenoy@stanford.edu OI Hochberg, Leigh/0000-0003-0261-2273; Pandarinath, Chethan/0000-0003-1241-1432; Blabe, Christine/0000-0003-4623-4251; Henderson, Jaimie/0000-0002-3276-2267 FU National Institutes of Health (NIH) [R01DC009899, N01HD53403, N01HD10018, R01-NS066311]; U.S. Department of Veterans Affairs [B6453R, B6310N]; Garlick Foundation; Craig H. Neilsen Foundation; Massachusetts General Hospital Deane Institute for Integrated Research on Atrial Fibrillation and Stroke; Stanford University Institute for Neuro-Innovation and Translational Neuroscience; Stanford University Stanford BioX/Neuroventures; Stanford University Stanford Office of Postdoctoral Affairs FX National Institutes of Health (NIH) R01DC009899 Leigh R Hochberg; National Institutes of Health (NIH) N01HD53403 Leigh R Hochberg; National Institutes of Health (NIH) N01HD10018 Leigh R Hochberg; National Institutes of Health (NIH) R01-NS066311 Jaimie M Henderson, Krishna V Shenoy; U.S. Department of Veterans Affairs B6453R, B6310N Leigh R Hochberg; Garlick Foundation Jaimie M Henderson, Krishna V Shenoy; Craig H. Neilsen Foundation Chethan Pandarinath; Massachusetts General Hospital Deane Institute for Integrated Research on Atrial Fibrillation and Stroke Leigh R Hochberg; Stanford University Institute for Neuro-Innovation and Translational Neuroscience Jaimie M Henderson, Krishna V Shenoy; Stanford University Stanford BioX/Neuroventures Jaimie M Henderson, Krishna V Shenoy; Stanford University Stanford Office of Postdoctoral Affairs Chethan Pandarinath; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 17 TC 4 Z9 4 U1 0 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 23 PY 2015 VL 4 AR e07436 DI 10.7554/eLife.07436 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CL1QX UT WOS:000356720100001 PM 26099302 ER PT J AU Giugliano, RP Sabatine, MS AF Giugliano, Robert P. Sabatine, Marc S. TI Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cholesterol; lipids; low-density lipoprotein ID DENSITY-LIPOPROTEIN CHOLESTEROL; SUBTILISIN/KEXIN TYPE 9; HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; CORONARY-HEART-DISEASE; EVOLOCUMAB AMG 145; PLACEBO-CONTROLLED TRIAL; HIGH-RISK PATIENTS; RANDOMIZED CONTROLLED-TRIAL; STATIN-INTOLERANT PATIENTS AB Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor, escorting it to its destruction in the lysosome and thereby preventing the recirculation of the low-density lipoprotein receptor to the hepatocyte cell surface. Both gain-of-function mutations in PCSK9 (causing marked increases in low-density lipoprotein cholesterol [LDL-C] concentration and premature atherosclerosis) and loss-of-function mutations (causing modest LDL-C reduction with low rates of coronary heart disease) have been described. Several monoclonal antibodies to PCSK9 have achieved LDL-C reductions of 50% to 70% across various patient populations and background lipid therapies. Phase 2/3 trials have demonstrated good tolerability without clear drug-related toxicity, although the number and duration of patients treated to date is modest. Currently, 4 phase 3 trials involving >70,000 patients are testing whether these drugs reduce cardiovascular events. The U.S. Food and Drug Administration is currently reviewing the existing data to determine whether these agents could be made available prior to the completion of these cardiovascular endpoint trials expected in 2018. (C) 2015 by the American College of Cardiology Foundation. C1 [Giugliano, Robert P.; Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Giugliano, RP (reprint author), Brigham & Womens Hosp, TIMI Study Off, 350 Longwood Ave,First Floor Offices, Boston, MA 02115 USA. EM rgiugliano@partners.org RI 刘, 李陆/H-8469-2015 FU Merck; AstraZeneca; Amgen; Daiichi-Sankyo; Bristol-Myers Squibb; CVS Caremark; Pfizer; Sanofi; Abbott Laboratories; Accumetrics; Critical Diagnostics; Eisai; Genzyme; Nanosphere; Roche Diagnostics; Takeda; Gilead; GlaxoSmithKline; Intarcia; Aegerion; Alnylam; Cubist; MyoKardia; Quest Diagnostics; Vertex; Zeus Scientific FX Dr. Giugliano has received grant support from Merck and AstraZeneca; grant support and personal fees from Amgen and Daiichi-Sankyo; and personal fees from Bristol-Myers Squibb, CVS Caremark, Pfizer, and Sanofi outside the submitted work. Dr. Sabatine has received grant support from Abbott Laboratories, Accumetrics, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Nanosphere, Roche Diagnostics, Takeda, and Gilead; grant support and personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Intarcia, Merck, and Sanofi; and personal fees from Aegerion, Alnylam, Cubist, MyoKardia, Pfizer, Quest Diagnostics, Vertex, Zeus Scientific, and CVS Caremark outside of the submitted work. NR 78 TC 51 Z9 53 U1 6 U2 25 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 JUN 23 PY 2015 VL 65 IS 24 BP 2638 EP 2651 DI 10.1016/j.jacc.2015.05.001 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK6CK UT WOS:000356315200010 PM 26088304 ER PT J AU Jiang, P Freedman, ML Liu, JS Liu, XS AF Jiang, Peng Freedman, Matthew L. Liu, Jun S. Liu, Xiaole Shirley TI Inference of transcriptional regulation in cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE regulatory inference; tumor profiling; transcription factor; RNA-binding protein ID GENE-EXPRESSION; CHIP-SEQ; PROLIFERATION; REGRESSION; PROGNOSIS; PROFILES; DATABASE; REVEALS; SCREENS; PROJECT AB Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancer-associated TFs, we comprehensively integrated 686 ENCODE ChIP-seq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNA-binding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3'UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators. C1 [Jiang, Peng; Liu, Xiaole Shirley] Harvard Univ, TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Freedman, Matthew L.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Liu, Jun S.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. RP Liu, XS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. EM xsliu@jimmy.harvard.edu FU NIH [NHGRI U41 HG7000, NCI U01 CA180980, R01 GM113242-01]; NSF [DMS1208771] FX We thank Myles Brown, David Louis, Mario Suva, Jing Mi, Di Wu, Bo Li, and Eric Severson for helpful discussions. The work was supported by NIH Grants NHGRI U41 HG7000, NCI U01 CA180980, R01 GM113242-01, and NSF DMS1208771. NR 47 TC 13 Z9 13 U1 3 U2 8 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 JUN 23 PY 2015 VL 112 IS 25 BP 7731 EP 7736 DI 10.1073/pnas.1424272112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL1UV UT WOS:000356731300065 PM 26056275 ER PT J AU Ballal, SA Veiga, P Fenn, K Michaud, M Kim, JH Gallini, CA Glickman, JN Quere, G Garault, P Beal, C Derrien, M Courtin, P Kulakauskas, S Chapot-Chartier, MP Vlieg, JV Garrett, WS AF Ballal, Sonia A. Veiga, Patrick Fenn, Kathrin Michaud, Monia Kim, Jason H. Gallini, Carey Ann Glickman, Jonathan N. Quere, Gaelle Garault, Peggy Beal, Chloe Derrien, Muriel Courtin, Pascal Kulakauskas, Saulius Chapot-Chartier, Marie-Pierre Vlieg, Johan van Hylckama Garrett, Wendy S. TI Host lysozyme-mediated lysis of Lactococcus lactis facilitates delivery of colitis-attenuating superoxide dismutase to inflamed colons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Lactococcus lactis; oxidative stress; lysozyme; colitis; probiotics ID INFLAMMATORY-BOWEL-DISEASE; GRAM-POSITIVE BACTERIA; FERMENTED MILK PRODUCT; ULCERATIVE-COLITIS; ANTIMICROBIAL PEPTIDES; PROPHAGE INDUCTION; EPITHELIAL-CELLS; TEICHOIC-ACIDS; KAPPA-B; PEPTIDOGLYCAN AB Beneficial microbes that target molecules and pathways, such as oxidative stress, which can negatively affect both host and microbiota, may hold promise as an inflammatory bowel disease therapy. Prior work showed that a five-strain fermented milk product (FMP) improved colitis in T-bet(-/-) Rag2(-/-) mice. By varying the number of strains used in the FMP, we found that Lactococcus lactis I-1631 was sufficient to ameliorate colitis. Using comparative genomic analyses, we identified genes unique to L. lactis I-1631 involved in oxygen respiration. Respiration of oxygen results in reactive oxygen species (ROS) generation. Also, ROS are produced at high levels during intestinal inflammation and cause tissue damage. L. lactis I-1631 possesses genes encoding enzymes that detoxify ROS, such as superoxide dismutase (SodA). Thus, we hypothesized that lactococcal SodA played a role in attenuating colitis. Inactivation of the sodA gene abolished L. lactis I-1631' s beneficial effect in the T-bet(-/-) Rag2(-/-) model. Similar effects were obtained in two additional colonic inflammation models, Il10(-/-) mice and dextran sulfate sodium-treated mice. Efforts to understand how a lipophobic superoxide anion (O-2(-)) can be detoxified by cytoplasmic lactoccocal SodA led to the finding that host antimicrobial-mediated lysis is a prerequisite for SodA release and SodA's extracytoplasmic O-2(-) scavenging. L. lactis I-1631 may represent a promising vehicle to deliver antioxidant, colitis-attenuating SodA to the inflamed intestinal mucosa, and host antimicrobials may play a critical role in mediating SodA's bioaccessibility. C1 [Ballal, Sonia A.] Boston Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Boston, MA 02115 USA. [Ballal, Sonia A.; Veiga, Patrick; Fenn, Kathrin; Michaud, Monia; Kim, Jason H.; Gallini, Carey Ann; Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Ballal, Sonia A.; Veiga, Patrick; Fenn, Kathrin; Michaud, Monia; Kim, Jason H.; Gallini, Carey Ann; Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Veiga, Patrick; Quere, Gaelle; Garault, Peggy; Beal, Chloe; Derrien, Muriel; Vlieg, Johan van Hylckama] Danone Nutr Res, F-91767 Palaiseau, France. [Glickman, Jonathan N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Glickman, Jonathan N.] Miraca Life Sci, Newton, MA 02464 USA. [Courtin, Pascal; Kulakauskas, Saulius; Chapot-Chartier, Marie-Pierre] INRA, UMR Micalis 1319, F-78352 Jouy En Josas, France. [Courtin, Pascal; Kulakauskas, Saulius; Chapot-Chartier, Marie-Pierre] AgroParisTech, UMR Micalis, F-78352 Jouy En Josas, France. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Garrett, Wendy S.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Garrett, WS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu RI Veiga, Patrick/A-9862-2011; OI Veiga, Patrick/0000-0001-6318-8547; Derrien, Muriel/0000-0001-8841-9153 FU Danone Nutricia Research; Searle Scholars Award; National Cancer Institute [R01CA154426]; National Institute of Allergy and Infectious Diseases [K08AI078942]; Burroughs Wellcome Career in Medical Sciences Award FX We thank members of the W.S.G. laboratory for discussions and advice. This study was supported by a grant from Danone Nutricia Research, R01CA154426 (National Cancer Institute), K08AI078942 (National Institute of Allergy and Infectious Diseases), a Burroughs Wellcome Career in Medical Sciences Award, and a Searle Scholars Award. NR 46 TC 10 Z9 10 U1 1 U2 15 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 JUN 23 PY 2015 VL 112 IS 25 BP 7803 EP 7808 DI 10.1073/pnas.1501897112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL1UV UT WOS:000356731300077 PM 26056274 ER PT J AU Gordon, WR Zimmerman, B He, L Miles, LJ Huang, JH Tiyanont, K McArthur, DG Aster, JC Perrimon, N Loparo, JJ Blacklow, SC AF Gordon, Wendy R. Zimmerman, Brandon He, Li Miles, Laura J. Huang, Jiuhong Tiyanont, Kittichoat McArthur, Debbie G. Aster, Jon C. Perrimon, Norbert Loparo, Joseph J. Blacklow, Stephen C. TI Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch SO DEVELOPMENTAL CELL LA English DT Article ID LIGAND ENDOCYTOSIS; REGULATORY REGION; VINCULIN BINDING; CLEAVAGE; RECEPTOR; TENSION; MUTATIONS; MOLECULES; INTEGRIN; LEUKEMIA AB Ligands stimulate Notch receptors by inducing regulated intramembrane proteolysis (RIP) to produce a transcriptional effector. Notch activation requires unmasking of a metalloprotease cleavage site remote from the site of ligand binding, raising the question of how proteolytic sensitivity is achieved. Here, we show that application of physiologically relevant forces to the Notch1 regulatory switch results in sensitivity to metalloprotease cleavage, and bound ligands induce Notch signal transduction in cells only in the presence of applied mechanical force. Synthetic receptor-ligand systems that remove the native ligand-receptor interaction also activate Notch by inducing proteolysis of the regulatory switch. Together, these studies show that mechanical force exerted by signal-sending cells is required for ligand-induced Notch activation and establish that force-induced proteolysis can act as a mechanism of cellular mechanotransduction. C1 [Gordon, Wendy R.; Zimmerman, Brandon; Miles, Laura J.; Loparo, Joseph J.; Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Gordon, Wendy R.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Zimmerman, Brandon; Miles, Laura J.; Tiyanont, Kittichoat; McArthur, Debbie G.; Blacklow, Stephen C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [He, Li; Huang, Jiuhong; Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Aster, Jon C.; Blacklow, Stephen C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Perrimon, Norbert] Howard Hughes Med Inst, Boston, MA 02115 USA. [Huang, Jiuhong] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China. RP Loparo, JJ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM joseph_loparo@hms.harvard.edu; stephen_blacklow@hms.harvard.edu FU American Heart Association (AHA); Damon Runyon Postdoctoral Fellowship; NIH [P01 CA119070, R01 CA092433]; Howard Hughes Medical Institute (HHMI); NIH FX We thank Benedikt Bauer and Anthony Nguyen for help in optimizing single molecule experiments and Adam17 expression, Scott Ficarro for mass spectrometry, and Kelly Arnett and Brian McMillan for helpful discussions. W.R.G. was supported by an American Heart Association (AHA) SDG grant. L.H. was supported by a Damon Runyon Postdoctoral Fellowship. This work was supported by NIH grants P01 CA119070 (J.J.L., J.C.A., and S.C.B.) and R01 CA092433 (J.C.A. and S.C.B.), the Howard Hughes Medical Institute (HHMI), and the NIH (N.P.). NR 27 TC 33 Z9 34 U1 1 U2 6 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 JUN 22 PY 2015 VL 33 IS 6 BP 729 EP 736 DI 10.1016/j.devcel.2015.05.004 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CL2KY UT WOS:000356773900012 PM 26051539 ER PT J AU Chandler, PD Giovannucci, EL Scott, JB Bennett, GG Ng, K Chan, AT Hollis, BW Rifai, N Emmons, KM Fuchs, CS Drake, BF AF Chandler, Paulette D. Giovannucci, Edward L. Scott, Jamil B. Bennett, Gary G. Ng, Kimmie Chan, Andrew T. Hollis, Bruce W. Rifai, Nader Emmons, Karen M. Fuchs, Charles S. Drake, Bettina F. TI Effects of Vitamin D Supplementation on C-peptide and 25-hydroxyvitamin D Concentrations at 3 and 6 Months SO SCIENTIFIC REPORTS LA English DT Article ID PLACEBO-CONTROLLED TRIAL; INSULIN-RESISTANCE; GLUCOSE-INTOLERANCE; AFRICAN-AMERICANS; D INSUFFICIENCY; CELL FUNCTION; D DEFICIENCY; SECRETION; METAANALYSIS; WOMEN AB The link between African-Americans' disproportionate rates of diabetes, obesity and vitamin D deficiency may be marked by C-peptide as an indicator of insulin secretion. We hypothesize that vitamin D supplementation will increase C-peptide, a marker of insulin secretion. During 3 winters from 2007-2010, 328 healthy African-Americans (median age, 51 years) living in Boston, MA were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 IU of vitamin D3. The differences in non-fasting C-peptide between baseline and 3 months were -0.44 ng/mL for those receiving placebo, -0.10 ng/mL for those receiving 1000 IU/d, 0 ng/mL for those receiving 2000 IU/d, 1.24 ng/mL for those receiving 4000 IU/d (C-peptide increased 0.42 ng/mL for each additional 1000 IU/d of vitamin D3, p < 0.001). Vitamin D supplementation increased C-peptide in overweight African-Americans and may be compatible with other recommendations for diabetes prevention and management including weight loss and increased physical activity. C1 [Chandler, Paulette D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chandler, Paulette D.; Giovannucci, Edward L.; Ng, Kimmie; Chan, Andrew T.; Rifai, Nader; Emmons, Karen M.; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Scott, Jamil B.] Michigan State Univ, Coll Human Med, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Hollis, Bruce W.] Med Univ S Carolina, Div Pediat, Charleston, SC 29425 USA. [Rifai, Nader] Childrens Hosp, Div Lab Med, Boston, MA 02115 USA. [Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Drake, Bettina F.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. RP Chandler, PD (reprint author), Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. EM pchandler@partners.org OI Drake, Bettina/0000-0001-9340-5848 FU National Cancer Institute [U01CA138962]; Department of Defense Prostate Cancer Research Program [PC081669]; American Society of Clinical Oncology Career Development Award; Pharmavite LLC (Mission Hill, CA); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers; Office of Dietary Supplements [3P50 CA127003]; [K07CA148894]; [K22CA126992]; [5K05CA124415]; [K24DK098311] FX This trial was funded by the National Cancer Institute (U01CA138962 [Dr. Chandler]; Office of Dietary Supplements (3P50 CA127003 [Dr. Scott]); K07CA148894 [Dr Ng]; K22CA126992; 5K05CA124415 [Dr Emmons]; K24DK098311 [Dr. Chan]), the Department of Defense Prostate Cancer Research Program (PC081669 [Dr Drake]), the American Society of Clinical Oncology Career Development Award (Dr Ng), and Pharmavite LLC (Mission Hill, CA). These funding sources had no role in the conception or conduct of the study, took no part in the data collection or analysis, and had no role in the drafting, review, or approval of the article. Pharmavite LLC provided vitamin D and the placebo: We would like to thank Cara Marcus, MSLIS, AHIP, Director of Library Services, Brigham and Women's Faulkner Hospital for facilitating access to reference articles and Yiqing Song, MD, ScD for reviewing the manuscript and Camille A. Clarke, MD for assistance with editing manuscript. This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. 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 healthcare centers, or the National Institutes of Health. NR 39 TC 1 Z9 1 U1 1 U2 4 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 JUN 22 PY 2015 VL 5 AR 10411 DI 10.1038/srep10411 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9TI UT WOS:000356582000001 PM 26095242 ER PT J AU Preiss, D Campbell, RT Murray, HM Ford, I Packard, CJ Sattar, N Rahimi, K Colhoun, HM Waters, DD LaRosa, JC Amarenco, P Pedersen, TR Tikkanen, MJ Koren, MJ Poulter, NR Sever, PS Ridker, PM MacFadyen, JG Solomon, SD Davis, BR Simpson, LM Nakamura, H Mizuno, K Marfisi, RM Marchioli, R Tognoni, G Athyros, VG Ray, KK Gotto, AM Clearfield, MB Downs, JR McMurray, JJ AF Preiss, David Campbell, Ross T. Murray, Heather M. Ford, Ian Packard, Chris J. Sattar, Naveed Rahimi, Kazem Colhoun, Helen M. Waters, David D. LaRosa, John C. Amarenco, Pierre Pedersen, Terje R. Tikkanen, Matti J. Koren, Michael J. Poulter, Neil R. Sever, Peter S. Ridker, Paul M. MacFadyen, Jean G. Solomon, Scott D. Davis, Barry R. Simpson, Lara M. Nakamura, Haruo Mizuno, Kyoichi Marfisi, Rosa M. Marchioli, Roberto Tognoni, Gianni Athyros, Vasilios G. Ray, Kausik K. Gotto, Antonio M. Clearfield, Michael B. Downs, John R. McMurray, John J. TI The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials SO EUROPEAN HEART JOURNAL LA English DT Article DE Statin; Heart failure; Randomized trial; Prevention; Meta-analysis ID AVERAGE CHOLESTEROL LEVELS; PLACEBO-CONTROLLED TRIAL; ACUTE CORONARY SYNDROMES; HIGH-DOSE ATORVASTATIN; PRIMARY PREVENTION; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; HYPERTENSIVE PATIENTS; VASCULAR EVENTS; LDL CHOLESTEROL AB Aims The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. Methods and results We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first on-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR0.97,95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). Conclusion In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not. C1 [Preiss, David; Campbell, Ross T.; Sattar, Naveed; McMurray, John J.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Murray, Heather M.; Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8TA, Lanark, Scotland. [Packard, Chris J.] Univ Glasgow, Western Infirm, Glasgow Clin Res Facil, Glasgow G11 6NT, Lanark, Scotland. [Rahimi, Kazem] Univ Oxford, George Inst Global Hlth, Oxford, England. [Colhoun, Helen M.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Waters, David D.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [LaRosa, John C.] SUNY Hlth Sci Ctr Brooklyn, New York, NY USA. [Amarenco, Pierre] Hop Xavier Bichat, Dept Neurol, Paris, France. [Amarenco, Pierre] Hop Xavier Bichat, Stroke Ctr, Paris, France. [Pedersen, Terje R.] Univ Oslo, Oslo, Norway. [Pedersen, Terje R.] Oslo Univ Hosp, Ctr Preventat Med, Oslo, Norway. [Tikkanen, Matti J.] Univ Helsinki, Helsinki, Finland. [Tikkanen, Matti J.] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Helsinki, Finland. [Tikkanen, Matti J.] Folkhalsan Res Ctr, Helsinki, Finland. [Koren, Michael J.] Jacksonville Ctr Clin Res, Jacksonville, FL USA. [Poulter, Neil R.; Sever, Peter S.; Ray, Kausik K.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Int Ctr Circulatory Hlth, London, England. [Ridker, Paul M.; MacFadyen, Jean G.; Solomon, Scott D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA USA. [Davis, Barry R.; Simpson, Lara M.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Nakamura, Haruo] Mitsukoshi Hlth & Welf Fdn, Shinjuku Ku, Tokyo, Japan. [Mizuno, Kyoichi] Nippon Med Sch, Dept Med, Bunkyo Ku, Tokyo 113, Japan. [Marfisi, Rosa M.; Marchioli, Roberto; Tognoni, Gianni] Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy. [Athyros, Vasilios G.] Aristotle Univ Thessaloniki, Hippokrat Hosp, Propedeut Dept Internal Med 2, Sch Med, GR-54006 Thessaloniki, Greece. [Gotto, Antonio M.] Weill Cornell Med Coll, New York, NY USA. [Clearfield, Michael B.] Touro Univ, Coll Osteopath Med, Vallejo, CA USA. [Downs, John R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Downs, John R.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Preiss, D (reprint author), Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, 126 Univ Pl, Glasgow G12 8TA, Lanark, Scotland. EM david.preiss@glasgow.ac.uk RI Rahimi, Kazem/Q-1279-2015; OI Rahimi, Kazem/0000-0002-4807-4610; Preiss, David/0000-0003-3139-1836; Colhoun, Helen/0000-0002-8345-3288; Sattar, Naveed/0000-0002-1604-2593; mcmurray, john/0000-0002-6317-3975 FU BHF project [PG/13/17/30050]; National Institute for Health Research Senior Investigator Awards; Biomedical Research Centre; British Heart Foundation Research Centre Excellence Award; National Institute for Health Research Career Development Fellowship; Oxford Biomedical Research Centre; Oxford Martin School FX This project was not supported by external funding. R.T.C. is funded by a BHF project grant (PG/13/17/30050). N.R.P. is supported by the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. K.R. is supported by a National Institute for Health Research Career Development Fellowship and funding from the Oxford Biomedical Research Centre, and the Oxford Martin School. NR 38 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JUN 21 PY 2015 VL 36 IS 24 BP 1536 EP 1546 DI 10.1093/eurheartj/ehv072 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM7LZ UT WOS:000357876100015 PM 25802390 ER PT J AU Han, X Pearson, E Pelizzari, C Al-Hallaq, H Sidky, EY Bian, JG Pan, XC AF Han, Xiao Pearson, Erik Pelizzari, Charles Al-Hallaq, Hania Sidky, Emil Y. Bian, Junguo Pan, Xiaochuan TI Algorithm-enabled exploration of image-quality potential of cone-beam CT in image-guided radiation therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE cone-beam CT; image reconstruction; optimization; iterative algorithm ID INTENSITY-MODULATED RADIOTHERAPY; TOTAL VARIATION REGULARIZATION; COMPUTED-TOMOGRAPHY; ASSURANCE PROGRAM; PROSTATE-CANCER; MICRO-CT; RECONSTRUCTION; IMRT AB Kilo-voltage (KV) cone-beam computed tomography (CBCT) unit mounted onto a linear accelerator treatment system, often referred to as on-board imager (OBI), plays an increasingly important role in image-guided radiation therapy. While the FDK algorithm is currently used for reconstructing images from clinical OBI data, optimization-based reconstruction has also been investigated for OBI CBCT. An optimization-based reconstruction involves numerous parameters, which can significantly impact reconstruction properties (or utility). The success of an optimization-based reconstruction for a particular class of practical applications thus relies strongly on appropriate selection of parameter values. In the work, we focus on tailoring the constrained-TVminimization- based reconstruction, an optimization-based reconstruction previously shown of some potential for CBCT imaging conditions of practical interest, to OBI imaging through appropriate selection of parameter values. In particular, for given real data of phantoms and patient collected with OBI CBCT, we first devise utility metrics specific to OBI-quality-assurance tasks and then apply them to guiding the selection of parameter values in constrained-TV-minimization-based reconstruction. The study results show that the reconstructions are with improvement, relative to clinical FDK reconstruction, in both visualization and quantitative assessments in terms of the devised utility metrics. C1 [Han, Xiao; Sidky, Emil Y.; Pan, Xiaochuan] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Pearson, Erik; Pelizzari, Charles; Al-Hallaq, Hania; Pan, Xiaochuan] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. [Bian, Junguo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Han, X (reprint author), Univ Chicago, Dept Radiol, 5801 S Ellis Ave, Chicago, IL 60637 USA. EM xpan@uchicago.edu FU National Institutes of Health (NIH) [R01s EB000225, CA158446, CA182264, EB018102] FX This work was supported in part by the National Institutes of Health (NIH) under grants R01s EB000225, CA158446, CA182264, and EB018102. NR 43 TC 5 Z9 6 U1 2 U2 12 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 JUN 21 PY 2015 VL 60 IS 12 BP 4601 EP 4633 DI 10.1088/0031-9155/60/12/4601 PG 33 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CK3DA UT WOS:000356095200004 PM 26020490 ER PT J AU Xiao, G Sun, PZ Wu, RH AF Xiao, Gang Sun, Phillip Zhe Wu, Renhua TI Fast simulation and optimization of pulse-train chemical exchange saturation transfer (CEST) imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE Bloch-McConnell equations; chemical exchange saturation transfer (CEST); quantitative chemical exchange saturation transfer (qCEST); pulse-train ID PROTON FRACTION RATIO; PH-WEIGHTED MRI; RF IRRADIATION; IN-VIVO; CONTRAST AGENTS; CEREBRAL-ISCHEMIA; PARACEST AGENTS; HUMAN BRAIN; TISSUE PH; 7 T AB Chemical exchange saturation transfer (CEST) MRI has been increasingly applied to detect dilute solutes and physicochemical properties, with promising in vivo applications. Whereas CEST imaging has been implemented with continuous wave (CW) radio-frequency irradiation on preclinical scanners, pulse-train irradiation is often chosen on clinical systems. Therefore, it is necessary to optimize pulse-train CEST imaging, particularly important for translational studies. Because conventional Bloch-McConnell formulas are not in the form of homogeneous differential equations, the routine simulation approach simulates the evolving magnetization step by step, which is time consuming. Herein we developed a computationally efficient numerical solution using matrix iterative analysis of homogeneous Bloch-McConnell equations. The proposed algorithm requires simulation of pulse-train CEST MRI magnetization within one irradiation repeat, with 99% computation time reduction from that of conventional approach under typical experimental conditions. The proposed solution enables determination of labile proton ratio and exchange rate from pulse- train CEST MRI experiment, within 5% from those determined from quantitative CW-CEST MRI. In addition, the structural similarity index analysis shows that the dependence of CEST contrast on saturation pulse flip angle and duration between simulation and experiment was 0.98 +/- 0.01, indicating that the proposed simulation algorithm permits fast optimization and quantification of pulse-train CEST MRI. C1 [Xiao, Gang] Hanshan Normal Univ, Dept Math & Stat, Chaozhou, Guangdong, Peoples R China. [Sun, Phillip Zhe] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Dept Radiol, Biomarker & Metab Imaging Lab, Charlestown, MA 02129 USA. [Sun, Phillip Zhe] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Wu, Renhua] Shantou Univ, Affiliated Hosp 2, Coll Med, Dept Radiol, Shantou 515041, Guangdong, Peoples R China. RP Xiao, G (reprint author), Hanshan Normal Univ, Dept Math & Stat, Chaozhou, Guangdong, Peoples R China. EM pzhesun@mgh.harvard.edu; rhwu@stu.edu.cn FU NSFGD [S2013010013372]; NSFC [30930027]; NIH/NIBIB [1K01EB009771]; NIH/NINDS [1R01NS083654] FX This study was supported in part by grants from NSFGD S2013010013372 (Xiao G), NSFC 30930027 (Wu RH), NIH/NIBIB 1K01EB009771 (Sun PZ) and NIH/NINDS 1R01NS083654 (Sun PZ). NR 49 TC 3 Z9 3 U1 1 U2 14 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 JUN 21 PY 2015 VL 60 IS 12 BP 4719 EP 4730 DI 10.1088/0031-9155/60/12/4719 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CK3DA UT WOS:000356095200010 PM 26020414 ER PT J AU Kagan, VE Tyurina, YY Tyurin, VA Mohammadyani, D Angeli, JPF Baranov, SV Klein-Seetharaman, J Friedlander, RM Mallampalli, RK Conrad, M Bayir, H AF Kagan, Valerian E. Tyurina, Yulia Y. Tyurin, Vladimir A. Mohammadyani, Dariush Angeli, Jose Pedro Friedmann Baranov, Sergei V. Klein-Seetharaman, Judith Friedlander, Robert M. Mallampalli, Rama K. Conrad, Marcus Bayir, Huelya TI Cardiolipin Signaling Mechanisms: Collapse of Asymmetry and Oxidation SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID MASS-SPECTROMETRIC CHARACTERIZATION; HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; CYTOCHROME-C; BARTH-SYNDROME; CELL-DEATH; INDUCED APOPTOSIS; PHOSPHATIDYLSERINE PEROXIDATION; MITOCHONDRIAL CARDIOLIPIN; STRUCTURAL TRANSITIONS; ANIONIC PHOSPHOLIPIDS AB Significance: An ancient anionic phospholipid, cardiolipin (CL), ubiquitously present in prokaryotic and eukaryotic membranes, is essential for several structural and functional purposes. Recent Advances: The emerging role of CLs in signaling has become the focus of many studies. Critical Issues: In this work, we describe two major pathways through which mitochondrial CLs may fulfill the signaling functions via utilization of their (i) asymmetric distribution across membranes and translocations, leading to the surface externalization and (ii) ability to undergo oxidation reactions to yield the signature products recognizable by the executionary machinery of cells. Future Directions: We present a concept that CLs and their oxidation/hydrolysis products constitute a rich communication language utilized by mitochondria of eukaryotic cells for diversified regulation of cell physiology and metabolism as well as for inter-cellular interactions. Antioxid. Redox Signal. 22, 1667-1680. C1 [Kagan, Valerian E.; Tyurina, Yulia Y.; Tyurin, Vladimir A.] Univ Pittsburgh, Dept Environm & Occupat Hlth, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15219 USA. [Kagan, Valerian E.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15219 USA. [Kagan, Valerian E.] Univ Pittsburgh, Dept Radiat Oncol, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15219 USA. [Kagan, Valerian E.] Univ Pittsburgh, Dept Chem, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15219 USA. [Mohammadyani, Dariush] Univ Pittsburgh, Dept Chem, Dept Bioengn, Pittsburgh, PA 15219 USA. [Angeli, Jose Pedro Friedmann; Conrad, Marcus] German Res Ctr Environm Hlth, Inst Dev Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Baranov, Sergei V.; Friedlander, Robert M.] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA 15219 USA. [Klein-Seetharaman, Judith] Univ Warwick, Sch Med, Div Metab & Vasc Hlth, Coventry CV4 7AL, W Midlands, England. [Mallampalli, Rama K.] Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Dept Med, Pittsburgh, PA 15219 USA. [Mallampalli, Rama K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Bayir, Huelya] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15219 USA. RP Kagan, VE (reprint author), Univ Pittsburgh, Dept Environm & Occupat Hlth, Ctr Free Rad & Antioxidant Hlth, Bridgeside Point 100 Technol Dr, Pittsburgh, PA 15219 USA. EM kagan@pitt.edu RI Friedlander, Robert/A-2845-2016; Friedmann Angeli, Jose /C-9038-2014; OI Friedlander, Robert/0000-0003-4423-9219; Tyurin, Vladimir/0000-0002-3474-1697; Conrad, Marcus/0000-0003-1140-5612; Friedmann Angeli, Jose Pedro/0000-0001-7706-1379 FU NIH [PO1HL114453, CA165065, ES020693, U19AIO68021, NS076511, NS061817]; NIOSH [OH008282, HFSP-RGP0013/2014]; US Department of Veterans Affairs; Alexander von Humboldt Stiftung; Marie Curie Actions grant MPFP FP7-People-IIF [626470] FX This study was supported by NIH: PO1HL114453, CA165065, ES020693, U19AIO68021, NS076511, NS061817; NIOSH: OH008282, HFSP-RGP0013/2014, a Merit Review award from the US Department of Veterans Affairs and Alexander von Humboldt Stiftung (to AJPF) and Marie Curie Actions grant 626470 MPFP FP7-People-IIF. NR 104 TC 10 Z9 11 U1 1 U2 14 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN 20 PY 2015 VL 22 IS 18 BP 1667 EP 1680 DI 10.1089/ars.2014.6219 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CU9WA UT WOS:000363895900003 PM 25566681 ER PT J AU Awad, MM Hammerman, PS AF Awad, Mark M. Hammerman, Peter S. TI Durable Responses With PD-1 Inhibition in Lung and Kidney Cancer and the Ongoing Search for Predictive Biomarkers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID MELANOMA; SAFETY; NIVOLUMAB; ANTI-PD-1; BLOCKADE; ANTIBODY C1 [Awad, Mark M.; Hammerman, Peter S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Awad, MM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM peter_hammerman@dfci.harvard.edu NR 21 TC 8 Z9 8 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 JUN 20 PY 2015 VL 33 IS 18 BP 1993 EP U6 DI 10.1200/JCO.2015.61.4172 PG 3 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800002 PM 25918290 ER PT J AU Bellon, JR AF Bellon, Jennifer R. TI Personalized Radiation Oncology for Breast Cancer: The New Frontier SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID LOCOREGIONAL RECURRENCE; CONSERVING THERAPY; TUMOR RECURRENCE; TAMOXIFEN; NODE; RADIOTHERAPY; IRRADIATION; SURGERY; WOMEN; RISK C1 [Bellon, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellon, Jennifer R.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Bellon, JR (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM jbellon@lroc.harvard.edu NR 24 TC 7 Z9 7 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 JUN 20 PY 2015 VL 33 IS 18 BP 1998 EP U15 DI 10.1200/JCO.2015.61.2069 PG 5 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800004 PM 25964251 ER PT J AU Gettinger, SN Horn, L Gandhi, L Spigel, DR Antonia, SJ Rizvi, NA Powderly, JD Heist, RS Carvajal, RD Jackman, DM Sequist, LV Smith, DC Leming, P Carbone, DP Pinder-Schenck, MC Topalian, SL Hodi, FS Sosman, JA Sznol, M McDermott, DF Pardoll, DM Sankar, V Ahlers, CM Salvati, M Wigginton, JM Hellmann, MD Kollia, GD Gupta, AK Brahmer, JR AF Gettinger, Scott N. Horn, Leora Gandhi, Leena Spigel, David R. Antonia, Scott J. Rizvi, Naiyer A. Powderly, John D. Heist, Rebecca S. Carvajal, Richard D. Jackman, David M. Sequist, Lecia V. Smith, David C. Leming, Philip Carbone, David P. Pinder-Schenck, Mary C. Topalian, Suzanne L. Hodi, F. Stephen Sosman, Jeffrey A. Sznol, Mario McDermott, David F. Pardoll, Drew M. Sankar, Vindira Ahlers, Christoph M. Salvati, Mark Wigginton, Jon M. Hellmann, Matthew D. Kollia, Georgia D. Gupta, Ashok K. Brahmer, Julie R. TI Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PLATINUM-BASED CHEMOTHERAPY; RESPONSE CRITERIA; EGFR MUTATIONS; SOLID TUMORS; PHASE-III; B7 FAMILY; MELANOMA; GUIDELINES; DOCETAXEL; BLOCKADE AB Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. C1 [Gettinger, Scott N.; Sznol, Mario] Yale Canc Ctr, New Haven, CT 06510 USA. [Spigel, David R.; Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Nashville, TN 37235 USA. [Spigel, David R.] Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA. [Gandhi, Leena; Jackman, David M.; Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Heist, Rebecca S.; Sequist, Lecia V.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Antonia, Scott J.; Pinder-Schenck, Mary C.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Rizvi, Naiyer A.; Carvajal, Richard D.; Hellmann, Matthew D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Powderly, John D.] Carolina BioOncol Inst, Huntersville, NC USA. [Smith, David C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Leming, Philip] Christ Hosp Canc Ctr, Cincinnati, OH USA. [Topalian, Suzanne L.; Pardoll, Drew M.; Brahmer, Julie R.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Sankar, Vindira; Ahlers, Christoph M.; Salvati, Mark; Wigginton, Jon M.; Kollia, Georgia D.; Gupta, Ashok K.] Bristol Myers Squibb Co, Princeton, NJ USA. RP Gettinger, SN (reprint author), Yale Canc Ctr, 333 Cedar St,FMP127, New Haven, CT 06510 USA. EM scott.gettinger@yale.edu OI Gandhi, Leena/0000-0002-2398-9179 FU Bristol-Myers Squibb; Ono Pharmaceutical FX Supported by Bristol-Myers Squibb, which also funded medical writing assistance, and by Ono Pharmaceutical. NR 42 TC 201 Z9 216 U1 6 U2 26 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 JUN 20 PY 2015 VL 33 IS 18 BP 2004 EP U32 DI 10.1200/JCO.2014.58.3708 PG 12 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800006 PM 25897158 ER PT J AU McDermott, DF Drake, CG Sznol, M Choueiri, TK Powderly, JD Smith, DC Brahmer, JR Carvajal, RD Hammers, HJ Puzanov, I Hodi, FS Kluger, HM Topalian, SL Pardoll, DM Wigginton, JM Kollia, GD Gupta, A McDonald, D Sankar, V Sosman, JA Atkins, MB AF McDermott, David F. Drake, Charles G. Sznol, Mario Choueiri, Toni K. Powderly, John D. Smith, David C. Brahmer, Julie R. Carvajal, Richard D. Hammers, Hans J. Puzanov, Igor Hodi, F. Stephen Kluger, Harriet M. Topalian, Suzanne L. Pardoll, Drew M. Wigginton, Jon M. Kollia, Georgia D. Gupta, Ashok McDonald, Dan Sankar, Vindira Sosman, Jeffrey A. Atkins, Michael B. TI Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; SOLID TUMORS; PROGNOSTIC-FACTORS; ADVANCED MELANOMA; INTERFERON-ALPHA; IN-VITRO; CANCER; B7-H1; GUIDELINES; EVEROLIMUS AB Purpose Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts. Patients and Methods A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation. Results Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible. Conclusion Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC. C1 [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Choueiri, Toni K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Puzanov, Igor; Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Drake, Charles G.; Brahmer, Julie R.; Hammers, Hans J.; Topalian, Suzanne L.; Pardoll, Drew M.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Sznol, Mario] Yale Univ, Sch Med, New Haven, CT USA. [Sznol, Mario] Yale New Haven Med Ctr, Smilow Canc Ctr, New Haven, CT 06504 USA. [Powderly, John D.] Carolina BioOncol Inst, Huntersville, NC USA. [Smith, David C.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Carvajal, Richard D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wigginton, Jon M.; Kollia, Georgia D.; Gupta, Ashok; McDonald, Dan; Sankar, Vindira] Bristol Myers Squibb Co, Princeton, NJ USA. [Sosman, Jeffrey A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Atkins, Michael B.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. RP McDermott, DF (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave,Mailstop MASCO 428, Boston, MA 02215 USA. EM dmcdermo@bidmc.harvard.edu FU Bristol-Myers Squibb; StemScientific; Ono Pharmaceutical; National Cancer Institute of the National Institutes of Health; Specialized Programs of Research Excellence grant [P50CA101942] FX Supported by Bristol-Myers Squibb, which also funded writing assistance provided by StemScientific; by Ono Pharmaceutical; and by the National Cancer Institute of the National Institutes of Health, and a Specialized Programs of Research Excellence grant under award number P50CA101942 (D.F.M., T.K.C., M.B.A., and F.S.H). NR 38 TC 94 Z9 96 U1 3 U2 12 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 JUN 20 PY 2015 VL 33 IS 18 BP 2013 EP U42 DI 10.1200/JCO.2014.58.1041 PG 10 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800007 PM 25800770 ER PT J AU Menon, U Ryan, A Kalsi, J Gentry-Maharaj, A Dawnay, A Habib, M Apostolidou, S Singh, N Benjamin, E Burnell, M Davies, S Sharma, A Gunu, R Godfrey, K Lopes, A Oram, D Herod, J Williamson, K Seif, MW Jenkins, H Mould, T Woolas, R Murdoch, JB Dobbs, S Amso, NN Leeson, S Cruickshank, D Scott, I Fallowfield, L Widschwendter, M Reynolds, K McGuire, A Campbell, S Parmar, M Skates, SJ Jacobs, I AF Menon, Usha Ryan, Andy Kalsi, Jatinderpal Gentry-Maharaj, Aleksandra Dawnay, Anne Habib, Mariam Apostolidou, Sophia Singh, Naveena Benjamin, Elizabeth Burnell, Matthew Davies, Susan Sharma, Aarti Gunu, Richard Godfrey, Keith Lopes, Alberto Oram, David Herod, Jonathan Williamson, Karin Seif, Mourad W. Jenkins, Howard Mould, Tim Woolas, Robert Murdoch, John B. Dobbs, Stephen Amso, Nazar N. Leeson, Simon Cruickshank, Derek Scott, Ian Fallowfield, Lesley Widschwendter, Martin Reynolds, Karina McGuire, Alistair Campbell, Stuart Parmar, Mahesh Skates, Steven J. Jacobs, Ian TI Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANTIGEN VELOCITY; PROSTATE; MORTALITY; LUNG; MULTICENTER; RECRUITMENT; IMPACT; ROCA AB Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). Conclusion Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded. (C) 2015 American Society of Clinical Oncology. C1 [Menon, Usha; Ryan, Andy; Kalsi, Jatinderpal; Gentry-Maharaj, Aleksandra; Habib, Mariam; Apostolidou, Sophia; Benjamin, Elizabeth; Burnell, Matthew; Davies, Susan; Gunu, Richard; Widschwendter, Martin; Parmar, Mahesh; Jacobs, Ian] UCL, London W1T 7DN, England. [Dawnay, Anne; Mould, Tim] Univ Coll London Hosp, London, England. [Singh, Naveena] Barts & London Queen Marys Sch Med & Dent, London, England. [Oram, David; Reynolds, Karina] St Bartholomews Hosp, London, England. [McGuire, Alistair] London Sch Econ, London, England. [Campbell, Stuart] Create Hlth Clin, Waterloo, ON, Canada. [Sharma, Aarti] Univ Wales Hosp, Cardiff, S Glam, Wales. [Amso, Nazar N.] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales. [Godfrey, Keith] Queen Elizabeth Hosp, Gateshead, England. [Lopes, Alberto] Royal Cornwall Hosp, Truro, England. [Herod, Jonathan] Liverpool Womens Hosp, Liverpool, Merseyside, England. [Williamson, Karin] City Hosp Nottingham, Nottingham, England. [Seif, Mourad W.] St Marys Hosp, Manchester, England. [Jenkins, Howard; Jacobs, Ian] Royal Derby Hosp, Derby, England. [Woolas, Robert] Queen Alexandra Hosp, Portsmouth, Hants, England. [Murdoch, John B.] St Michaels Hosp, Bristol, Avon, England. [Dobbs, Stephen] Belfast City Hosp, Belfast BT9 7AD, Antrim, North Ireland. [Leeson, Simon] Llandudno Hosp, Ysbyty Gwynedd, England. [Cruickshank, Derek] James Cook Univ Hosp, Middlesbrough, Cleveland, England. [Fallowfield, Lesley] Univ Sussex, Falmer, England. [Skates, Steven J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Skates, Steven J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Jacobs, Ian] UNSW Australia, Sydney, NSW, Australia. RP Menon, U (reprint author), UCL, Inst Womens Hlth, Womens Canc, Maple House,149 Tottenham Court Rd, London W1T 7DN, England. EM u.menon@ucl.ac.uk OI de Barros Lopes, Alberto/0000-0002-8796-3891 FU Medical Research Council, Cancer Research United Kingdom; Department of Health; Eve Appeal; NIHR Senior Investigator Award; Special Trustees of Bart's; London and Special Trustees of UCLH; National Cancer Institute Early Detection Research Network [CA152990] FX Supported by the Medical Research Council, Cancer Research United Kingdom, and the Department of Health, with additional support from the Eve Appeal, and by researchers at the National Institute for Health Research (NIHR) University College London Hospital (UCLH) Biomedical Research Centre. I.J. held an NIHR Senior Investigator Award. The United Kingdom Collaborative Trial of Ovarian Cancer Screening Biobank was funded in part by the Special Trustees of Bart's and the London and Special Trustees of UCLH. S.J.S. is supported by Grant No. CA152990 from the National Cancer Institute Early Detection Research Network. NR 27 TC 38 Z9 38 U1 4 U2 14 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 JUN 20 PY 2015 VL 33 IS 18 BP 2062 EP U114 DI 10.1200/JCO.2014.59.4945 PG 14 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800013 PM 25964255 ER PT J AU Yuan, C Wolpin, BM AF Yuan, Chen Wolpin, Brian M. TI Diabetes Associated With Short Survival in Pancreatic Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Yuan, Chen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolpin, Brian M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wolpin, Brian M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Yuan, C (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 BP 2121 EP 2121 DI 10.1200/JCO.2015.61.4875 PG 1 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800023 PM 25940723 ER PT J AU Brown, PD Asher, AL Ballman, KV Farace, E Cerhan, JH Anderson, SK Carrero, XW Barker, FG Deming, RL Burri, S Menard, C Chung, C Stieber, VW Pollock, BE Galanis, E Buckner, JC Jaeckle, KA AF Brown, Paul D. Asher, Anthony L. Ballman, Karla V. Farace, Elana Cerhan, Jane H. Anderson, S. Keith Carrero, Xiomara W. Barker, Frederick G. Deming, Richard L. Burri, Stuart Menard, Cynthia Chung, Caroline Stieber, Volker W. Pollock, Bruce E. Galanis, Evanthia Buckner, Jan C. Jaeckle, Kurt A. TI NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Carolinas Healthcare Syst Neurosci Inst, Charlotte, NC USA. Mayo Clin, Rochester, MN USA. Penn State Hershey Med Ctr, Hershey, PA USA. Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mercy Canc Ctr, Des Moines, IA USA. Levine Canc Inst Radiat Oncol, Charlotte, NC USA. Princess Maraget Hosp, Toronto, ON, Canada. Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. Novant Hlth Forsyth Med Ctr, Winston Salem, NC USA. Mayo Clin Florida, Jacksonville, FL USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 SU S MA LBA4 PG 1 WC Oncology SC Oncology GA DO9HQ UT WOS:000378096500005 ER PT J AU Sandler, HM Hu, C Rosenthal, SA Sartor, O Gomella, LG Amin, M Purdy, J Michalski, JM Garzotto, M Pervez, N Balogh, AG Rodrigues, G Souhami, L Reaume, MN Williams, SG Hannan, R Horwitz, EM Raben, A Paulus, R Shipley, WU AF Sandler, Howard M. Hu, Chen Rosenthal, Seth A. Sartor, Oliver Gomella, Leonard G. Amin, Mahul Purdy, James Michalski, Jeff M. Garzotto, Mark Pervez, Nadeem Balogh, Alexander G. Rodrigues, George Souhami, Luis Reaume, M. Neil Williams, Scott G. Hannan, Raquibul Horwitz, Eric M. Raben, Adam Paulus, Rebecca Shipley, William U. TI A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Cedars Sinai Med Ctr, Dept Radiat Oncol, Los Angeles, CA 90048 USA. NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. Sutter Canc Ctr, Sacramento, CA USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Univ Calif Davis, Sacramento, CA USA. Washington Univ, St Louis, MO USA. Portland VA Med Ctr, Portland, OR USA. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Tom Baker Canc Clin, Calgary, AB, Canada. London Reg Canc Program, Dept Radiat Oncol, London, ON, Canada. McGill Univ, Dept Radiat Oncol, Ctr Hlth, Montreal, PQ H3A 2T5, Canada. Ottawa Hosp, Ctr Canc, Ottawa, ON, Canada. Peter MacCallum Canc Ctr, East Melbourne, Australia. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Helen F Graham Canc Ctr, Newark, DE USA. Ctr Stat, Radiat Therapy Oncol Grp, Philadelphia, PA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 SU S MA LBA5002 PG 1 WC Oncology SC Oncology GA DO9HQ UT WOS:000378096500011 ER PT J AU Schoffski, P Maki, RG Italiano, A Gelderblom, H Grignani, G De Camargo, VP Bauer, S Rha, SY Chawla, SP Blay, JY Hohenberger, P D'Adamo, DR Wang, B Chmielowski, B Le Cesne, A Demetri, GD Patel, S AF Schoffski, Patrick Maki, Robert G. Italiano, Antoine Gelderblom, Hans Grignani, Giovanni De Camargo, Veridiana Pires Bauer, Sebastian Rha, Sun Young Chawla, Sant P. Blay, Jean-Yves Hohenberger, Peter D'Adamo, David R. Wang, Benjamin Chmielowski, Bartosz Le Cesne, Axel Demetri, George D. Patel, Shreyaskumar TI Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Hosp Leuven, Leuven, Belgium. Mt Sinai Med Ctr, New York, NY 10029 USA. CLCC Inst Bergonie, Bordeaux, France. Leiden Univ, Med Ctr, Leiden, Netherlands. Fdn Piemonte Oncol IRCC, Candiolo, Italy. Hosp Sirio Libanes, Sao Paulo, Brazil. West German Canc Ctr, Essen, Germany. Severance Hosp, Seoul, South Korea. Sarcoma Oncol Ctr, Santa Monica, CA USA. Univ Lyon 1, F-69365 Lyon, France. Ctr Leon Berard, F-69373 Lyon, France. Univ Mannheim, Med Ctr, D-68131 Mannheim, Germany. Eisai Inc, Woodcliff Lake, NJ USA. Eisai, Woodcliff Lake, NJ USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Inst Gustave Roussy, Villejuif, France. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X NR 0 TC 2 Z9 2 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 JUN 20 PY 2015 VL 33 IS 18 SU S MA LBA10502 PG 1 WC Oncology SC Oncology GA DO9HQ UT WOS:000378096500018 ER PT J AU Seiwert, TY Haddad, RI Gupta, S Mehra, R Tahara, M Berger, R Lee, SH Burtness, B Le, DT Heath, K Blum, A Dolled-Filhart, M Emancipator, K Pathiraja, K Cheng, JD Chow, LQ AF Seiwert, Tanguy Y. Haddad, Robert I. Gupta, Shilpa Mehra, Ranee Tahara, Makoto Berger, Raanan Lee, Se-Hoon Burtness, Barbara Le, Dung T. Heath, Karl Blum, Amy Dolled-Filhart, Marisa Emancipator, Kenneth Pathiraja, Kumudu Cheng, Jonathan D. Chow, Laura Q. TI Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Chicago, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. Seoul Natl Univ Hosp, Seoul 110744, South Korea. Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT USA. JHU, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Merck & Co Inc, Kenilworth, NJ USA. Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 SU S MA LBA6008 PG 1 WC Oncology SC Oncology GA DO9HQ UT WOS:000378096500012 ER PT J AU Wolchok, JD Chiarion-Sileni, V Gonzalez, R Rutkowski, P Grob, JJ Cowey, CL Lao, CD Schadendorf, D Ferrucci, PF Smylie, M Dummer, R Hill, AG Haanen, JBAG Maio, M McArthur, GA Yang, A Rollin, L Horak, CE Larkin, JMG Hodi, FS AF Wolchok, Jedd D. Chiarion-Sileni, Vanna Gonzalez, Rene Rutkowski, Piotr Grob, Jean Jacques Cowey, Charles Lance Lao, Christopher D. Schadendorf, Dirk Ferrucci, Pier Francesco Smylie, Michael Dummer, Reinhard Hill, Andrew Graham Haanen, John B. A. G. Maio, Michele McArthur, Grant A. Yang, Arvin Rollin, Linda Horak, Christine E. Larkin, James M. G. Hodi, F. Stephen TI Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Weill Cornell Med Coll, New York, NY USA. IRCCS, Oncol Inst Veneto, Padua, Italy. Univ Colorado, Ctr Canc, Denver, CO 80202 USA. Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. Hosp Timone, Marseille, France. Texas Oncol Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Essen Gesamthsch, Dept Dermatol, Essen, Germany. European Inst Oncol, Milan, Italy. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Univ Spital, Zurich, Switzerland. Tasman Oncol Res, Brisbane, Qld, Australia. Netherlands Canc Inst, Amsterdam, Netherlands. Univ Hosp Siena, Siena, Italy. Peter MacCallum Canc Ctr, East Melbourne, Australia. Bristol Myers Squibb Co, Princeton, NJ USA. Bristol Myers Squibb Co, Wallingford, CT USA. Royal Marsden Hosp, London SW3 6JJ, England. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 SU S MA LBA1 PG 1 WC Oncology SC Oncology GA DO9HQ UT WOS:000378096500002 ER PT J AU Stary, G Olive, A Radovic-Moreno, AF Gondek, D Alvarez, D Basto, PA Perro, M Vrbanac, VD Tager, AM Shi, JJ Yethon, JA Farokhzad, OC Langer, R Starnbach, MN von Andrian, UH AF Stary, Georg Olive, Andrew Radovic-Moreno, Aleksandar F. Gondek, David Alvarez, David Basto, Pamela A. Perro, Mario Vrbanac, Vladimir D. Tager, Andrew M. Shi, Jinjun Yethon, Jeremy A. Farokhzad, Omid C. Langer, Robert Starnbach, Michael N. von Andrian, Ulrich H. TI A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells SO SCIENCE LA English DT Article ID CD103(+) DENDRITIC CELLS; ADAPTIVE IMMUNE-RESPONSES; MURINE GENITAL MUCOSA; 3 DOSAGE LEVELS; RESIDENT MEMORY; FIELD TRIAL; MEDIATED PROTECTION; ORAL TOLERANCE; SAUDI ARABIA; INFECTION AB Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-g-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b(+)CD103(-) dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b(-)CD103(+) DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (T-RM cells). Optimal Ct clearance required both TRM seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties. C1 [Stary, Georg; Olive, Andrew; Gondek, David; Alvarez, David; Perro, Mario; Starnbach, Michael N.; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. [Radovic-Moreno, Aleksandar F.; Basto, Pamela A.; Langer, Robert] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Radovic-Moreno, Aleksandar F.; Basto, Pamela A.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Vrbanac, Vladimir D.; Tager, Andrew M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Yethon, Jeremy A.] Sanofi Pasteur, Cambridge, MA 02139 USA. [Shi, Jinjun; Farokhzad, Omid C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Lab Nanomed & Biomat,Dept Anesthesiol, Boston, MA 02115 USA. [Farokhzad, Omid C.] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [von Andrian, Ulrich H.] MIT & Harvard, Ragon Inst MGH, Cambridge, MA 02139 USA. RP von Andrian, UH (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. EM georg_stary@hms.harvard.edu; uva@hms.harvard.edu OI Olive, Andrew/0000-0003-3441-3113 FU NIH [AI078897, AI069259, AI095261, AI111595, U54-CA119349, U54-CA151884, R37-EB000244, 1 R01-EB015419-01, R00 CA160350, T32 HL066987, P30-AI060354, R01 AI062827, R01 AI39558]; Harvard Innovation Award from Sanofi Pasteur; Ragon Institute of MGH, MIT and Harvard; David Koch Prostate Cancer Foundation; MGH Humanized Mouse Program by the Harvard University CFAR; Epidemiology and Prevention Interdisciplinary Center for Sexually Transmitted Diseases (NIH) [U19 AI113187]; Max Kade foundation; MIT Portugal Program; National Science Foundation (NSF-GRFP) FX We thank E. Nigro for secretarial assistance, L. B. Jones for technical support, and the members of the von Andrian laboratory for discussion. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Supported by NIH grants AI078897, AI069259, AI095261, and AI111595, a Harvard Innovation Award from Sanofi Pasteur, and the Ragon Institute of MGH, MIT and Harvard (U.H.v.A.); NIH grants U54-CA119349, U54-CA151884, and R37-EB000244 and the David Koch Prostate Cancer Foundation (R.L. and O.C.F.); NIH grant 1 R01-EB015419-01 (O.C.F.); NIH grant R00 CA160350 (J.S.); NIH grant T32 HL066987 (D.A.); NIH grant P30-AI060354 and the MGH Humanized Mouse Program by the Harvard University CFAR (A.M.T.); and NIH grant R01 AI062827, NIH grant R01 AI39558, and the Epidemiology and Prevention Interdisciplinary Center for Sexually Transmitted Diseases (NIH grant U19 AI113187) (M.N.S.). G.S. is a Max Kade foundation postdoctoral research exchange grant recipient. A.F.R.-M. acknowledges support from the MIT Portugal Program and the National Science Foundation (NSF-GRFP). G.S., A.R.F.-M., P.A.B., M.N.S., R.L., O.C.F., and U.H.v.A. are inventors on a patent application entitled "Nanoparticle-Based Compositions" (U.S. Application number PCT2014/029000; International Publication No. WO2014/153087) filed by Harvard University together with MIT and Brigham and Women's Hospital (BWH) that relates to the use of cSAP for mucosal vaccination. A.R.F.-M., R.L., and O.C.F. are inventors on a patent application entitled "pH Sensitive Biodegradable Polymeric Particles for Drug Delivery" (U.S. Application no. PCT2011/0065807) filed by BWH together with MIT that relates to the engineering of charge-switching particles. O.C.F., R.L., and U.H.v.A. disclose financial interests in BIND Therapeutics, Selecta Biosciences, and Blend Therapeutics, three biotechnology companies developing nanocarrier technologies for medical applications. BIND, Selecta, and Blend did not support the research in this study. Selecta and Blend have obtained licenses to a portion of the intellectual property described in this study. O.C.F., R.L., and U.H.v.A. are scientific founders and members of the Scientific Advisory Board and O.C.F. and R.L. are directors of Selecta Biosciences. O.C.F., R.L. and U.H.v.A. are members of the Scientific Advisory Board and O.C.F. and R.L. are scientific founders and directors of Blend Therapeutics. The following reagents used in the paper are subject to MTA: NR-1 transgenic mice, cSAP, cSP, and SAP. All reasonable requests for collaboration involving materials used in the research will be fulfilled, provided that a written agreement is executed in advance between BWH, MIT, or Harvard Medical School and the requester (and his or her affiliated institution). Such inquiries or requests for additional data should be directed to the corresponding author. NR 64 TC 34 Z9 35 U1 5 U2 17 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 JUN 19 PY 2015 VL 348 IS 6241 AR aaa8205 DI 10.1126/science.aaa8205 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK7XK UT WOS:000356449500042 PM 26089520 ER PT J AU Ciaranello, AL Doherty, K Penazzato, M Lindsey, JC Harrison, L Kelly, K Walensky, RP Essajee, S Losina, E Muhe, L Wools-Kaloustian, K Ayaya, S Weinstein, MC Palumbo, P Freedberg, KA AF Ciaranello, Andrea L. Doherty, Kathleen Penazzato, Martina Lindsey, Jane C. Harrison, Linda Kelly, Kathleen Walensky, Rochelle P. Essajee, Shaffiq Losina, Elena Muhe, Lulu Wools-Kaloustian, Kara Ayaya, Samuel Weinstein, Milton C. Palumbo, Paul Freedberg, Kenneth A. TI Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age SO AIDS LA English DT Article DE Africa; cost-effectiveness; first-line antiretroviral therapy; IMPAACT; P1060 trial; pediatric HIV AB Background:The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier.Design/methods:We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1x per-capita gross domestic product (South Africa: $7500)/YLS as very cost-effective,' interventions with ICERs below 3x gross domestic product/YLS as cost-effective,' and interventions leading to longer life expectancy and lower lifetime costs as cost-saving'.Results:Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective.Conclusions:On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used. C1 [Ciaranello, Andrea L.; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Doherty, Kathleen; Kelly, Kathleen; Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Ciaranello, Andrea L.; Doherty, Kathleen; Kelly, Kathleen; Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Penazzato, Martina] MRC, Clin Trials Unit, London, England. [Penazzato, Martina; Muhe, Lulu] WHO, CH-1211 Geneva, Switzerland. [Lindsey, Jane C.; Harrison, Linda] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Weinstein, Milton C.; Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.] Harvard Univ, Ctr AIDS Res, Cambridge, MA 02138 USA. [Essajee, Shaffiq] Clinton Hlth Access Initiat, New York, NY USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wools-Kaloustian, Kara] Indiana Univ Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46202 USA. [Ayaya, Samuel] Moi Univ, Dept Child Hlth & Pediat, Eldoret, Kenya. [Palumbo, Paul] Dartmouth Hitchcock Med Ctr, Dept Med, Lebanon, NH 03766 USA. [Palumbo, Paul] Dartmouth Hitchcock Med Ctr, Dept Pediat 16, Lebanon, NH 03766 USA. RP Ciaranello, AL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,Room 936, Boston, MA 02114 USA. EM aciaranello@partners.org FU WHO; National Institutes of Health through International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT); International Database to Evaluate AIDS (IeDEA); National Institute of Allergy and Infectious Diseases [K01 AI078754, R01 HD079214, K24 AI062476, R01 AI058736, R01 AI093269, U01 AI069911, U01AI09919]; Harvard Center for AIDS Research; March of Dimes Foundation; Massachusetts General Hospital Executive Committee on Research; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (IMPAACT LOC) [UM1AI068632]; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (IMPAACT SDMC) [UM1AI068616]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); National Institute of Allergy and Infectious Diseases (NIAID); NICHD [N01-DK-9-001/HHSN 267200800001C]; National Cancer Institute FX Supported by the WHO; the National Institutes of Health through the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), International Database to Evaluate AIDS (IeDEA), and National Institute of Allergy and Infectious Diseases (K01 AI078754, R01 HD079214, K24 AI062476, R01 AI058736, R01 AI093269, U01 AI069911, U01AI09919, and the Harvard Center for AIDS Research); the March of Dimes Foundation; and the Massachusetts General Hospital Executive Committee on Research. The funders had no role in study design, data analysis, interpretation of results, or decision to publish.; Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN 267200800001C).; Overall support for the IeDEA network is provided by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Cancer Institute. NR 0 TC 6 Z9 6 U1 1 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 JUN 19 PY 2015 VL 29 IS 10 BP 1247 EP 1259 DI 10.1097/QAD.0000000000000672 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB4KX UT WOS:000368483000002 PM 25870982 ER PT J AU Shah, S Bellows, BA Adedipe, AA Totten, JE Backlund, BH Sajed, D AF Shah, Sachita Bellows, Blaise A. Adedipe, Adeyinka A. Totten, Jodie E. Backlund, Brandon H. Sajed, Dana TI Perceived barriers in the use of ultrasound in developing countries SO CRITICAL ULTRASOUND JOURNAL LA English DT Article DE Ultrasound; Global health; Public health ID ULTRASONOGRAPHY AB Background: Access to ultrasound has increased significantly in resource-limited settings, including the developing world; however, there remains a lack of sonography education and ultrasound-trained physician support in developing countries. To further investigate this potential knowledge gap, our primary objective was to assess perceived barriers to ultrasound use in resource-limited settings by surveying care providers who practice in low-and middle-income settings. Methods: A 25-question online survey was made available to health care providers who work with an ultrasound machine in low-and middle-income countries (LMICs), including doctors, nurses, technicians, and clinical officers. This was a convenience sample obtained from list-serves of ultrasound and radiologic societies. The survey was analyzed, and descriptive results were obtained. Results: One hundred and thirty-eight respondents representing 44 LMICs including countries from the continents of Africa, South America, and Asia completed the survey, with a response rate of 9.6 %. Ninety-one percent of the respondents were doctors, and 9 % were nurses or other providers. Applications for ultrasound were diverse, including obstetrics (75 %), DVT evaluation (51 %), abscess evaluation (54 %), cardiac evaluation (64 %), inferior vena cava (IVC) assessment (49 %), Focused Assessment Sonography for Trauma (FAST) exam (64 %), biliary tree assessment (54 %), and other applications. The respondents identified the following barriers to use of ultrasound: lack of training (60 %), lack of equipment (45 %), ultrasound machine malfunction (37 %), and lack of ultrasound maintenance capability (47 %). Seventy-four percent of the respondents wished to have further training in ultrasound, and 82 % were open to receiving distance learning or telesonography training. Subjects used communication tools including Skype, Dropbox, emailed photos, and picture archiving and communication system (PACS) as ways to communicate and receive feedback on ultrasound images. Conclusions: Health care providers in the developing world identify lack of training as a primary barrier to regular use of ultrasound in their practice. While equipment requirements including maintenance and cost of machines are also important factors, future research is warranted on best practices for training methods, including telesonography and distance learning to enhance ultrasound use in low-resource settings. C1 [Shah, Sachita; Bellows, Blaise A.; Adedipe, Adeyinka A.; Totten, Jodie E.; Backlund, Brandon H.] Univ Washington, Div Emergency Med, Seattle, WA 98104 USA. [Sajed, Dana] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Totten, JE (reprint author), Univ Washington, Div Emergency Med, Box 359702,1CT89,325 9th Ave, Seattle, WA 98104 USA. EM jet25@uw.edu NR 8 TC 6 Z9 6 U1 1 U2 1 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 2036-3176 EI 2036-7902 J9 CRIT ULTRASOUND J JI Crit. Ultrasound J. PD JUN 19 PY 2015 VL 7 AR 11 DI 10.1186/s13089-015-0028-2 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS7FU UT WOS:000362250300001 ER PT J AU Andrews, JR Ryan, ET AF Andrews, Jason R. Ryan, Edward T. TI Diagnostics for invasive Salmonella infections: Current challenges and future directions SO VACCINE LA English DT Review DE Salmonella; Invasive; Enteric fever; Typhoid; Paratyphoid; Non-typhoidal; Diagnostics ID ENTERICA SEROVAR TYPHI; MEDIATED ISOTHERMAL AMPLIFICATION; LINKED-IMMUNOSORBENT-ASSAY; POLYMERASE-CHAIN-REACTION; NON-TYPHOIDAL SALMONELLA; TARGET PRODUCT PROFILES; CLINICAL-FEATURES; WIDAL TEST; FEBRILE ILLNESS; TROPICAL DISEASES AB Invasive Salmonellosis caused by Salmonella enterica serotype Typhi or Paratyphi A, B, C, or invasive non-typhoidal Salmonella serotypes, is an immensely important disease cluster for which reliable, rapid diagnostic tests are not available. Blood culture remains the gold standard but is insensitive, slow, and resource-intensive. Existing molecular diagnostics have poor sensitivity due to the low organism burden in bodily fluids. Commercially available serologic tests for typhoidal Salmonella have had limited sensitivity and specificity. In high burden, resource-limited settings, reliance on clinical diagnosis or inaccurate tests often results infrequent, unnecessary treatment, which contributes selective pressure for the emergence of antimicrobial resistance. This practice also results in inadequate therapy for other etiologies of acute febrile illnesses, including leptospirosis and rickettsial infections. A number of novel serologic, molecular, transcriptomic and metabolomic approaches to diagnostics are under development. Target product profiles that outline specific needs may focus development and investment, and establish benchmarks for accuracy, cost, speed, and portability of new diagnostics. Of note, a critical barrier to diagnostic assay rollout will be the low cost and low perceived harm of empiric therapy on behalf of providers and patients, which leaves few perceived incentives to utilize diagnostics. Approaches that align incentives with societal goals of limiting inappropriate antimicrobial use, such as subsidizing diagnostics, may be essential for stimulating development and uptake of such assays in resource-limited settings. New diagnostics for invasive Salmonellosis should be developed and deployed alongside diagnostics for alternative etiologies of acute febrile illnesses to improve targeted use of antibiotics. (C) 2015 Published by Elsevier Ltd. C1 [Andrews, Jason R.] Stanford Univ, Sch Med, Div Infect Dis & Geog Med, Stanford, CA 94305 USA. [Ryan, Edward T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Andrews, JR (reprint author), Stanford Univ, Sch Med, Div Infect Dis & Geog Med, 300 Pasteur Dr,Lane Bldg,L141, Stanford, CA 94305 USA. EM jandr@stanford.edu; etryan@mgh.harvard.edu FU Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene; U.S. National Institutes of Health [AI100023] FX This work was supported in part by awards from the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene (JRA), and the U.S. National Institutes of Health (AI100023; ETR). The funders had no role in decision to publish or preparation of the manuscript. NR 108 TC 11 Z9 12 U1 7 U2 34 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 19 PY 2015 VL 33 SU 3 BP C8 EP C15 DI 10.1016/j.vaccine.2015.02.030 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CM1KI UT WOS:000357439400003 PM 25937611 ER PT J AU Zhang, W Cho, SY Xiang, G Min, KJ Yu, Q Jin, JO AF Zhang, Wei Cho, Si-Young Xiang, Gao Min, Kyung-Jin Yu, Qing Jin, Jun-O TI Ginseng Berry Extract Promotes Maturation of Mouse Dendritic Cells SO PLOS ONE LA English DT Article ID IMMUNE-RESPONSES; DIABETIC MICE; T-CELLS; IN-VIVO; POLYSACCHARIDES; LIPOPOLYSACCHARIDES; PATHWAYS; ANTIGEN; VACCINE; RG1 AB Ginseng extract has been shown to possess certain anti-virus, anti-tumor and immune-activating effects. However, the immunostimulatory effect of ginseng berry extract (GB) has been less well characterized. In this study, we investigated the effect of GB on the activation of mouse dendritic cells (DCs) in vitro and in vivo. GB treatment induced up-regulation of co-stimulatory molecules in bone marrow-derived DCs (BMDCs). Interestingly, GB induced a higher degree of co-stimulatory molecule up-regulation than ginseng root extract (GR) at the same concentrations. Moreover, in vivo administration of GB promoted up-regulation of CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-alpha in spleen DCs. GB also promoted the generation of Th1 and Tc1 cells. Furthermore, Toll like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) signaling pathway were essential for DC activation induced by GB. In addition, GB strongly prompted the proliferation of ovalbumin (OVA)-specific CD4 and CD8 T cells. Finally, GB induced DC activation in tumor-bearing mice and the combination of OVA and GB treatment inhibited B16-OVA tumor cell growth in C57BL/6 mice. These results demonstrate that GB is a novel tumor therapeutic vaccine adjuvant by promoting DC and T cell activation. C1 [Zhang, Wei; Jin, Jun-O] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. [Cho, Si-Young] AmorePacific Corp, R&D Unit, Yongin, Gyeonggi Do, South Korea. [Xiang, Gao] Nanjing Univ, Model Anim Res Ctr, Nanjing 210008, Jiangsu, Peoples R China. [Min, Kyung-Jin] Inha Univ, Dept Biol Sci, Inchon, South Korea. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. EM Junojin1@gmail.com FU Research fund for International Young Scientists from National Natural Science Foundation of China [81450110090]; AmorePacific Corporation FX This study was supported by Research fund for International Young Scientists from National Natural Science Foundation of China (81450110090). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AmorePacific Corporation provided support in the form of salary for author Si-Young Cho and research materials, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the 'author contributions' section. NR 36 TC 5 Z9 5 U1 1 U2 13 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 JUN 19 PY 2015 VL 10 IS 6 AR e0130926 DI 10.1371/journal.pone.0130926 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3FE UT WOS:000356835000160 PM 26090808 ER PT J AU Winter, GE Buckley, DL Paulk, J Roberts, JM Souza, A Dhe-Paganon, S Bradner, JE AF Winter, Georg E. Buckley, Dennis L. Paulk, Joshiawa Roberts, Justin M. Souza, Amanda Dhe-Paganon, Sirano Bradner, James E. TI Phthalimide conjugation as a strategy for in vivo target protein degradation SO SCIENCE LA English DT Article ID BET BROMODOMAINS; SELECTIVE-INHIBITION; THALIDOMIDE; MOLECULES; COMPLEX; UBIQUITINATION; ACTIVATION; LEUKEMIA; CANCER; CELLS AB The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins. C1 [Winter, Georg E.; Buckley, Dennis L.; Paulk, Joshiawa; Roberts, Justin M.; Souza, Amanda; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dhe-Paganon, Sirano] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM james_bradner@dfci.harvard.edu FU EMBO long-term fellowship FX We thank W. Kaelin, S. Orkin, and R. Mazitschek for engaging discussions and W. Kaelin for cellular reagents; S.-H. Seo and S. Deangelo for assistance in the purification of BRD4; C. Ott for help with in vivo model studies; and N. Thoma for CRBN expression reagents. This research was supported by generous philanthropic gifts from Marc Cohen and Alain Cohen, the William Lawrence and Blanche Hughes Foundation, and the NIH (R01-CA176745 and P01-CA066996 to J.E.B.). G.E.W. is supported by an EMBO long-term fellowship. D.L.B. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). Atomic coordinates and structure factors have been deposited in the Protein Data Bank (accession code 4ZC9). Quantitative proteomics studies were performed by R. Kunz of the Thermo Fisher Scientific Center for Multiplexed Proteomics at Harvard Medical School. Dana-Farber Cancer Institute has filed patent applications (62/096,318; 62/128,457; 62/149,170) that include the dBET and dFKBP compositions described in this manuscript. J.E.B. is a Founder of Tensha Therapeutics, a biotechnology company that develops druglike derivatives of JQ1 as investigational cancer therapies. NR 29 TC 69 Z9 70 U1 30 U2 98 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 JUN 19 PY 2015 VL 348 IS 6241 BP 1376 EP 1381 DI 10.1126/science.aab1433 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK7XK UT WOS:000356449500055 PM 25999370 ER PT J AU Tacke, R Hilgendorf, I Garner, H Waterborg, C Park, K Nowyhed, H Hanna, RN Wu, RP Swirski, FK Geissmann, F Hedrick, CC AF Tacke, Robert Hilgendorf, Ingo Garner, Hannah Waterborg, Claire Park, Kiwon Nowyhed, Heba Hanna, Richard N. Wu, Runpei Swirski, Filip K. Geissmann, Frederic Hedrick, Catherine C. TI The transcription factor NR4A1 is essential for the development of a novel macrophage subset in the thymus SO SCIENTIFIC REPORTS LA English DT Article ID TISSUE MACROPHAGES; MONOCYTES; MOUSE; CELLS; HOMEOSTASIS; APOPTOSIS AB Tissue macrophages function to maintain homeostasis and regulate immune responses. While tissue macrophages derive from one of a small number of progenitor programs, the transcriptional requirements for site-specific macrophage subset development are more complex. We have identified a new tissue macrophage subset in the thymus and have discovered that its development is dependent on transcription factor NR4A1. Functionally, we find that NR4A1-dependent macrophages are critically important for clearance of apoptotic thymocytes. These macrophages are largely reduced or absent in mice lacking NR4A1, and Nr4a1-deficient mice have impaired thymocyte engulfment and clearance. Thus, NR4A1 functions as a master transcription factor for the development of this novel thymus-specific macrophage subset. C1 [Tacke, Robert; Waterborg, Claire; Park, Kiwon; Nowyhed, Heba; Hanna, Richard N.; Wu, Runpei; Hedrick, Catherine C.] La Jolla Inst Allergy & Immunol, Div Inflammat Biol, La Jolla, CA 92037 USA. [Garner, Hannah; Geissmann, Frederic] Kings Coll London, Ctr Mol & Cellular Biol Inflammat, London, England. [Hilgendorf, Ingo; Swirski, Filip K.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Hilgendorf, Ingo; Swirski, Filip K.] Harvard Univ, Sch Med, Boston, MA USA. RP Hedrick, CC (reprint author), La Jolla Inst Allergy & Immunol, Div Inflammat Biol, La Jolla, CA 92037 USA. EM hedrick@lji.org RI Waterborg, Claire/P-9245-2015 FU NIH [R01 HL118765, P01 HL055798]; American Heart Association [13POST16990029] FX We would like to thank D. Yoakum, A. Blatchley, and the LJI microscopy and flow cytometry cores for excellent technical assistance. This work was supported by funding from NIH R01 HL118765 (to C.C.H.), NIH P01 HL055798 (to C.C.H.) and the American Heart Association 13POST16990029 (to R.T.). NR 25 TC 6 Z9 6 U1 1 U2 3 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 JUN 19 PY 2015 VL 5 AR 10055 DI 10.1038/srep10055 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9AU UT WOS:000356532900001 PM 26091486 ER PT J AU Ray, JP Hacohen, N AF Ray, John P. Hacohen, Nir TI Impact of autoimmune risk alleles on the immune system SO GENOME MEDICINE LA English DT Editorial Material ID DISEASE AB Genetic analyses of autoimmune diseases have revealed hundreds of disease-associated DNA variants, but the identity and function of the causal variants are understudied and warrant deeper mechanistic studies. Here, we highlight methods for deciphering how alleles that are associated with autoimmune disease alter the human immune system, and suggest strategies for future autoimmune genetic research. C1 [Ray, John P.; Hacohen, Nir] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Hacohen, Nir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Ray, JP (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM johnray@broadinstitute.org; nhacohen@mgh.harvard.edu NR 10 TC 3 Z9 3 U1 0 U2 1 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 JUN 19 PY 2015 VL 7 AR 57 DI 10.1186/s13073-015-0182-y PG 3 WC Genetics & Heredity SC Genetics & Heredity GA CK8HN UT WOS:000356479200001 PM 26089985 ER PT J AU Vardy, E Sassano, MF Rennekamp, AJ Kroeze, WK Mosier, PD Westkaemper, RB Stevens, CW Katritch, V Stevens, RC Peterson, RT Roth, BL AF Vardy, Eyal Sassano, Maria F. Rennekamp, Andrew J. Kroeze, Wesley K. Mosier, Philip D. Westkaemper, Richard B. Stevens, Craig W. Katritch, Vsevolod Stevens, Raymond C. Peterson, Randall T. Roth, Bryan L. TI Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides SO CHEMISTRY & BIOLOGY LA English DT Article ID ZEBRAFISH DANIO-RERIO; PROTEIN-COUPLED RECEPTORS; NICOTINIC ACETYLCHOLINE-RECEPTOR; NEWT TARICHA-GRANULOSA; PHARMACOLOGICAL CHARACTERIZATION; BINDING-SITES; HETEROLOGOUS EXPRESSION; EXTRACELLULAR LOOPS; ANALGESIC POTENCY; ALPHA-NEUROTOXIN AB It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here, we test this idea by comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. The insensitivity of the delta OR (DOR) to deltorphin was due to variation of a single amino acid, Trp7.35, which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish, and amphibians. The deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides. C1 [Vardy, Eyal; Sassano, Maria F.; Kroeze, Wesley K.; Roth, Bryan L.] UNC Chapel Hill Med Sch, Dept Pharmacol, Chapel Hill, NC 27514 USA. [Sassano, Maria F.; Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr,Med Sch, Charlestown, MA 02129 USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Charlestown, MA 02129 USA. [Rennekamp, Andrew J.; Peterson, Randall T.] 7 Cambridge Ctr, Broad Inst, Cambridge, MA 02142 USA. [Mosier, Philip D.; Westkaemper, Richard B.] Virginia Commonwealth Univ, Dept Med Chem, Sch Pharm, Richmond, VA 23298 USA. [Stevens, Craig W.] Oklahoma State Univ, Ctr Hlth Sci, Dept Pharmacol & Physiol, Tulsa, OK 74107 USA. [Katritch, Vsevolod; Stevens, Raymond C.] Univ So Calif, Dept Biol Sci & Chem, Bridge Inst, Los Angeles, CA 90089 USA. RP Roth, BL (reprint author), UNC Chapel Hill Med Sch, Dept Pharmacol, 4072 Genet Med Bldg,120 Mason Farm Rd, Chapel Hill, NC 27514 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010; Katritch, Vsevolod/Q-8357-2016; OI Rennekamp , Andrew /0000-0001-6174-7253; Katritch, Vsevolod/0000-0003-3883-4505 FU NIDA NIH HHS [R21 DA038858, P01 DA035764, R01 DA017204]; NIMH NIH HHS [HHSN271201300017C, U01 MH104974] NR 66 TC 4 Z9 4 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD JUN 18 PY 2015 VL 22 IS 6 BP 764 EP 775 DI 10.1016/j.chembiol.2015.05.012 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN4PI UT WOS:000358411900010 PM 26091169 ER PT J AU Goettel, JA Biswas, S Lexmond, WS Yeste, A Passerini, L Patel, B Yang, SY Sun, JS Ouahed, J Shouval, DS McCann, KJ Horwitz, BH Mathis, D Milford, EL Notarangelo, LD Roncarolo, MG Fiebiger, E Marasco, WA Bacchetta, R Quintana, FJ Pai, SY Klein, C Muise, AM Snapper, SB AF Goettel, Jeremy A. Biswas, Subhabrata Lexmond, Willem S. Yeste, Ada Passerini, Laura Patel, Bonny Yang, Siyoung Sun, Jiusong Ouahed, Jodie Shouval, Dror S. McCann, Katelyn J. Horwitz, Bruce H. Mathis, Diane Milford, Edgar L. Notarangelo, Luigi D. Roncarolo, Maria-Grazia Fiebiger, Edda Marasco, Wayne A. Bacchetta, Rosa Quintana, Francisco J. Pai, Sung-Yun Klein, Christoph Muise, Aleixo M. Snapper, Scott B. TI Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3 SO BLOOD LA English DT Article ID REGULATORY T-CELLS; IMMUNE-RESPONSES; B-CELLS; SCURFY MICE; IPEX SYNDROME; MOUSE MODEL; BLT MICE; DISEASE; VIRUS; BLOOD AB Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics. C1 [Goettel, Jeremy A.; Lexmond, Willem S.; Ouahed, Jodie; Shouval, Dror S.; McCann, Katelyn J.; Fiebiger, Edda; Snapper, Scott B.] Boston Childrens Hosp, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Boston, MA USA. [Goettel, Jeremy A.; Biswas, Subhabrata; Lexmond, Willem S.; Yeste, Ada; Patel, Bonny; Sun, Jiusong; Ouahed, Jodie; Shouval, Dror S.; Horwitz, Bruce H.; Milford, Edgar L.; Notarangelo, Luigi D.; Fiebiger, Edda; Marasco, Wayne A.; Quintana, Francisco J.; Pai, Sung-Yun; Snapper, Scott B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Biswas, Subhabrata; Sun, Jiusong; Marasco, Wayne A.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Yeste, Ada; Patel, Bonny; Quintana, Francisco J.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Passerini, Laura; Roncarolo, Maria-Grazia; Bacchetta, Rosa] San Raffaele Telethon Inst Gene Therapy, San Raffaele Sci Inst, Div Regenerat Med Stem Cells & Gene Therapy, Milan, Italy. [Yang, Siyoung] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA USA. [Horwitz, Bruce H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Milford, Edgar L.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Milford, Edgar L.] Brigham & Womens Hosp, Tissue Typing Lab, Boston, MA 02115 USA. [Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Notarangelo, Luigi D.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA. [Roncarolo, Maria-Grazia] Univ Vita Salute San Raffaele, Milan, Italy. [Pai, Sung-Yun] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Pai, Sung-Yun] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Klein, Christoph] Univ Munich, Dept Pediat, Dr von Hauner Childrens Hosp, Munich, Germany. [Muise, Aleixo M.] Hosp Sick Children, Dept Paediat, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G 1X8, Canada. [Snapper, Scott B.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Snapper, SB (reprint author), 300 Longwood Ave,Enders 670, Boston, MA 02115 USA. EM scott.snapper@childrens.harvard.edu RI Notarangelo, Luigi/F-9718-2016; Passerini, Laura/J-7791-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Passerini, Laura/0000-0002-4020-7386; RONCAROLO, Maria Grazia/0000-0002-2193-9186 FU National Institutes of Health (NIH) National Research Service Award [F32DK097894]; NIH National Institute of Allergy and Infectious Diseases [AI075037, AI50950]; NIH National Heart, Lung, and Blood Institute [HL59561]; NIH National Institute of Diabetes and Digestive and Kidney Diseases [DK034854]; Helmsley Charitable Trust; Wolpow Family Chair in IBD Treatment and Research; Fondazione Telethon FX This work was supported by the National Institutes of Health (NIH) National Research Service Award (F32DK097894) (J.A.G.); grants from the NIH National Institute of Allergy and Infectious Diseases (AI075037) (E.F.) and (AI50950), the NIH National Heart, Lung, and Blood Institute (HL59561), and the NIH National Institute of Diabetes and Digestive and Kidney Diseases (DK034854); the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research (S.B.S.). NR 58 TC 8 Z9 8 U1 1 U2 3 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 JUN 18 PY 2015 VL 125 IS 25 BP 3886 EP 3895 DI 10.1182/blood-2014-12-618363 PG 10 WC Hematology SC Hematology GA CL9FZ UT WOS:000357283300011 PM 25833964 ER PT J AU Counter, SA Buchanan, LH Ortega, F AF Counter, S. Allen Buchanan, Leo H. Ortega, Fernando TI BLOOD LEAD LEVELS IN ANDEAN INFANTS AND YOUNG CHILDREN IN ECUADOR: AN INTERNATIONAL COMPARISON SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID ZINC PROTOPORPHYRIN LEVELS; RISK-FACTORS; BREAST-MILK; CONTAMINATED ENVIRONMENT; IRON-DEFICIENCY; EXPOSURE; GASOLINE; ADOLESCENTS; ASSOCIATION; IMPAIRMENT AB Lead (Pb) exposure in infants and children remains an international health concern. Blood lead (PbB) levels of a cohort of 130 Ecuadorian infants and young children aged 0.33 to 5.8 yr were compared to values reported for similar age groups in Africa, Asia, Europe, Latin America, and the United States. The mean PbB level for the total group of 130 Ecuadorian infants and young children in this study was 29.4 g/dl (SD: 24.3; range: 3.0-128.2; median: 21.7; geometric mean: 20.7 g/dl). The mean PbB level for the 0-2 yr age group (infants) was 33.6 g/dl (SD: 28.9; median: 22.0; range: 3.9-119.7; geometric mean: 23.6 g/dl), while the average PbB level for the 3-5 yr age group (young children) was 27.9 g/dl (SD: 22.5: median: 22; range: 3-128.2; geometric mean: 19.8 g/dl). The difference between the mean PbB levels for the infants and young children was not statistically significant. The average PbB level of 32.6 g/dl for males was not statistically different from the mean PbB level of 26.3 g/dl for females. The PbB levels observed in Ecuadorian infants and young children in this investigation were elevated above the World Health Organization (WHO) level of concern of 10 g/dl and Centers for Disease Control and Prevention (CDC) current reference value of 5 g/dl. Values were comparable to concentrations found in Pakistan, where occupational use of Pb is prevalent. These findings further indicate that infants and young children exposed to Pb from Pb glazing of ceramics in Andean Ecuadorian villages exhibit greater potential metal-mediated poisoning than children of similar ages in Asia, Europe, other Latin American countries, and the United States. C1 [Counter, S. Allen] Harvard Univ, Sch Med, Dept Neurol, Biol Labs, Cambridge, MA 02138 USA. [Counter, S. Allen] Massachusetts Gen Hosp, Dept Neurophysiol, Boston, MA 02114 USA. [Buchanan, Leo H.] Univ Massachusetts, Sch Med, Dept Pediat, Eunice Kennedy Shriver Ctr, Worcester, MA USA. [Buchanan, Leo H.] Harvard Univ Hlth Serv, Dept Otolaryngol, Cambridge, MA USA. [Ortega, Fernando] Univ San Francisco Quito, Colegio Artes Liberales, Escuela Salud Publ, Colegio Ciencias Salud,Escuela Med, Quito, Ecuador. [Ortega, Fernando] Univ San Francisco Quito, Galapagos Inst Arts & Sci GAIAS, Quito, Ecuador. RP Counter, SA (reprint author), Harvard Univ, Sch Med, Dept Neurol, Biol Labs, 16 Divin Ave, Cambridge, MA 02138 USA. EM allen_counter@harvard.edu FU David Rockefeller Center for Latin American Studies at Harvard University; Harvard Biological Laboratories; Harvard University Health Services; Eunice Kennedy Shriver Center/University of Massachusetts Medical School; National Institutes of Health (NIH) [P30 HD04147] FX The authors thank Universidad San Francisco de Quito Colegio Ciencias de la Salud, Escuela de Medicina in Quito, Ecuador for continued support of the Ecuadorian Lead and Mercury Exposure project. We thank Dr. Gonzalo Mantilla, Dean, Colegio Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, for ongoing support and advice. We thank Anthony B. Jacobs for excellent technical assistance. We appreciate the support of the physicians and nurses of the Subcentro de Salud, including Roberto Chiriboga, Rommy Correa, Maria Angela Collaguaso, Rosa Mercedes Cruz, Fabiola Herrera, Erika Herrera, and Jenny Bonifaz. The authors are grateful to the David Rockefeller Center for Latin American Studies at Harvard University for funds to support this project. We thank Dr. Jeremy Bloxham, Dean of Science at Harvard University. We also thank Harvard Biological Laboratories, Harvard University Health Services, and the Eunice Kennedy Shriver Center/University of Massachusetts Medical School for support. L. H. Buchanan is supported in part by National Institutes of Health (NIH) grant P30 HD04147. NR 60 TC 4 Z9 4 U1 1 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1528-7394 EI 1087-2620 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PD JUN 18 PY 2015 VL 78 IS 12 BP 778 EP 787 DI 10.1080/15287394.2015.1031050 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CK8NS UT WOS:000356495600005 ER PT J AU Yehia, BR Stephens-Shields, AJ Fleishman, JA Berry, SA Agwu, AL Metlay, JP Moore, RD Mathews, WC Nijhawan, A Rutstein, R Gaur, AH Gebo, KA AF Yehia, Baligh R. Stephens-Shields, Alisa J. Fleishman, John A. Berry, Stephen A. Agwu, Allison L. Metlay, Joshua P. Moore, Richard D. Mathews, W. Christopher Nijhawan, Ank Rutstein, Richard Gaur, Aditya H. Gebo, Kelly A. CA HIV Res Network TI The HIV Care Continuum: Changes over Time in Retention in Care and Viral Suppressionqs SO PLOS ONE LA English DT Article ID ANTIRETROVIRAL THERAPY; SELF-MANAGEMENT; CHRONIC DISEASE; UNITED-STATES; BEHAVIORAL-MODEL; OUTCOMES; PREVENTION; ADHERENCE; CASCADE; CLINICS AB Background The HIV care continuum (diagnosis, linkage to care, retention in care, receipt of antiretroviral therapy (ART), viral suppression) has been used to identify opportunities for improving the delivery of HIV care. Continuum steps are typically calculated in a conditional manner, with the number of persons completing the prior step serving as the base population for the next step. This approach may underestimate the prevalence of viral suppression by excluding patients who are suppressed but do not meet standard definitions of retention in care. Understanding how retention in care and viral suppression interact and change over time may improve our ability to intervene on these steps in the continuum. Methods We followed 17,140 patients at 11 U.S. HIV clinics between 2010-2012. For each calendar year, patients were classified into one of five categories: (1) retained/suppressed, (2) retained/not-suppressed, (3) not-retained/suppressed, (4) not-retained/not-suppressed, and (5) lost to follow-up (for calendar years 2011 and 2012 only). Retained individuals were those completing >= 2 HIV medical visits separated by >= 90 days in the year. Persons not retained completed >= 1 HIV medical visit during the year, but did not meet the retention definition. Persons lost to follow-up had no HIV medical visits in the year. HIV viral suppression was defined as HIV-1 RNA <= 200 copies/mL at the last measure in the year. Multinomial logistic regression was used to determine the probability of patients' transitioning between retention/suppression categories from 2010 to 2011 and 2010 to 2012, adjusting for age, sex, race/ethnicity, HIV risk factor, insurance status, CD4 count, and use of ART. Results Overall, 65.8% of patients were retained/suppressed, 17.4% retained/not-suppressed, 10.0% not-retained/suppressed, and 6.8% not-retained/not-suppressed in 2010. 59.5% of patients maintained the same status in 2011 (kappa=0.458) and 53.3% maintained the same status in 2012 (kappa=0.437). Conclusions Not counting patients not-retained/suppressed as virally suppressed, as is commonly done in the HIV care continuum, underestimated the proportion suppressed by 13%. Applying the care continuum in a longitudinal manner will enhance its utility. C1 [Yehia, Baligh R.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Yehia, Baligh R.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Yehia, Baligh R.; Stephens-Shields, Alisa J.] Univ Penn, Perelman Sch Med, Ctr Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Fleishman, John A.] Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Rockville, MD USA. [Berry, Stephen A.; Agwu, Allison L.; Moore, Richard D.; Gebo, Kelly A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Mathews, W. Christopher] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Nijhawan, Ank] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Rutstein, Richard] Childrens Hosp Philadelphia, Div Gen Pediat, Philadelphia, PA 19104 USA. [Gaur, Aditya H.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN USA. RP Yehia, BR (reprint author), Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM byehia@upenn.edu FU Agency for Healthcare Research and Quality [HHSA290201100007C]; National Institutes of Health [K23-MH097647, K23-AI084854] FX This work was supported by the Agency for Healthcare Research and Quality [HHSA290201100007C] and the National Institutes of Health [K23-MH097647 to BRY; K23-AI084854 to SAB]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 8 Z9 8 U1 1 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 JUN 18 PY 2015 VL 10 IS 6 AR e0129376 DI 10.1371/journal.pone.0129376 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9NT UT WOS:000356567500046 PM 26086089 ER PT J AU Garris, CS Pittet, MJ AF Garris, Christopher S. Pittet, Mikael J. TI ER Stress in Dendritic Cells Promotes Cancer SO CELL LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM STRESS; TRANSCRIPTION FACTOR; XBP1; IMMUNITY AB XBP1 is part of the ER stress response, and when activated in cancer cells, it fosters tumor growth. In this issue of Cell, Cubillos-Ruiz et al. demonstrate that XBP1 in tumor-infiltrating dendritic cells blunts anti-tumor immunity. These findings further imply XBP1 as a relevant target for cancer therapy. C1 [Garris, Christopher S.; Pittet, Mikael J.] Massachusetts Gen Hosp, Ctr Syst Biol, Res Inst, Boston, MA 02114 USA. [Garris, Christopher S.; Pittet, Mikael J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Garris, Christopher S.] Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA 02115 USA. RP Pittet, MJ (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Res Inst, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu NR 9 TC 1 Z9 1 U1 3 U2 15 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 JUN 18 PY 2015 VL 161 IS 7 BP 1492 EP 1493 DI 10.1016/j.cell.2015.06.006 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL0GG UT WOS:000356618200003 PM 26091029 ER PT J AU Mantel, CR O'Leary, HA Chitteti, BR Huang, XX Cooper, S Hangoc, G Brustovetsky, N Srour, EF Lee, MR Messina-Graham, S Haas, DM Falah, N Kapur, R Pelus, LM Bardeesy, N Fitamant, J Ivan, M Kim, KS Broxmeyer, HE AF Mantel, Charlie R. O'Leary, Heather A. Chitteti, Brahmananda R. Huang, XinXin Cooper, Scott Hangoc, Giao Brustovetsky, Nickolay Srour, Edward F. Lee, Man Ryul Messina-Graham, Steven Haas, David M. Falah, Nadia Kapur, Reuben Pelus, Louis M. Bardeesy, Nabeel Fitamant, Julien Ivan, Mircea Kim, Kye-Seong Broxmeyer, Hal E. TI Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock SO CELL LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; ADENINE-NUCLEOTIDE TRANSLOCASE; UMBILICAL-CORD BLOOD; CYCLOSPORINE-A; OXIDATIVE STRESS; PROGENITOR CELLS; BONE-MARROW; INNER-MEMBRANE; CYCLOPHILIN-D; ISCHEMIA/REPERFUSION INJURY AB Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation. C1 [Mantel, Charlie R.; O'Leary, Heather A.; Huang, XinXin; Cooper, Scott; Hangoc, Giao; Srour, Edward F.; Lee, Man Ryul; Messina-Graham, Steven; Kapur, Reuben; Pelus, Louis M.; Ivan, Mircea; Broxmeyer, Hal E.] Indiana Univ Sch Med, Dept Microbiol Immunol, Indianapolis, IN 46202 USA. [Chitteti, Brahmananda R.; Srour, Edward F.; Ivan, Mircea] Indiana Univ Sch Med, Dept Med Hematol Oncol, Indianapolis, IN 46202 USA. [Brustovetsky, Nickolay] Indiana Univ Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. [Srour, Edward F.; Kapur, Reuben] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Haas, David M.; Falah, Nadia] Indiana Univ Sch Med, Dept Obstet & Gynecol, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Kapur, Reuben] Indiana Univ Sch Med, Dept Biochem Mol Biol, Indianapolis, IN 46202 USA. [Lee, Man Ryul] Soonchunhyang Inst Medi Bio Sci, Chungcheongnam Do 336745, South Korea. [Bardeesy, Nabeel; Fitamant, Julien] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Kim, Kye-Seong] Hanyang Univ, Grad Sch Biomed Sci & Engn, Seoul 133791, South Korea. RP Broxmeyer, HE (reprint author), Indiana Univ Sch Med, Dept Microbiol Immunol, Indianapolis, IN 46202 USA. EM hbroxmey@iupui.edu RI Ivan, Mircea/A-8109-2012 FU US Public Health Service Grants from the NIH [R01 HL67384, R01 HL056416, R01 HL112669, P30 DK090948]; National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [2012M3A9B4028738]; Korea Health technology RD Project; Ministry of Health Welfare [A120262]; Republic of Korea; NIH [T32, DK07519, R01 NS078008] FX Research was supported by US Public Health Service Grants from the NIH (R01 HL67384, R01 HL056416, R01 HL112669, and P30 DK090948 to H.E.B.), the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2012M3A9B4028738), and a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare (A120262), Republic of Korea (to K.-S.K.). H.A.O. and S.M-G. were supported by NIH T32 training grant DK07519 (to H.E.B.). N. Brustovetsky was supported by NIH grant R01 NS078008. We thank P.L. Mantel for editorial assistance. We would like to dedicate this paper to Dr. Donald Metcalf, a pioneer in the field of hematopoiesis, who recently passed away. NR 75 TC 33 Z9 36 U1 9 U2 25 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 JUN 18 PY 2015 VL 161 IS 7 BP 1553 EP 1565 DI 10.1016/j.cell.2015.04.054 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL0GG UT WOS:000356618200013 PM 26073944 ER PT J AU Ghosh, S Fujita, D Bandyopadhyay, A AF Ghosh, Subrata Fujita, Daisuke Bandyopadhyay, Anirban TI An organic jelly made fractal logic gate with an infinite truth table SO SCIENTIFIC REPORTS LA English DT Article ID CHAOS; COMPUTATION; TIME AB Widely varying logic gates invented over a century are all finite. As data deluge problem looms large on the information processing and communication industry, the thrust to explore radical concepts is increasing rapidly. Here, we design and synthesis a molecule, wherein, the input energy transmits in a cycle inside the molecular system, just like an oscillator, then, we use the molecule to make a jelly that acts as chain of oscillators with a fractal like resonance band. Hence, with the increasing detection resolution, in the vacant space between two energy levels of a given resonance band, a new band appears, due to fractal nature, generation of newer energy levels never stops. This is natural property of a linear chain oscillator. As we correlate each energy level of the resonance band of organic jelly, as a function of pH and density of the jelly, we realize a logic gate, whose truth table is finite, but if we zoom any small part, a new truth table appears. In principle, zooming of truth table would continue forever. Thus, we invent a new class of infinite logic gate for the first time. C1 [Ghosh, Subrata; Fujita, Daisuke; Bandyopadhyay, Anirban] Natl Inst Mat Sci, Adv Key Technol Div, Tsukuba, Ibaraki, Japan. [Ghosh, Subrata] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Ghosh, S (reprint author), Natl Inst Mat Sci, Adv Key Technol Div, 1-2-1 Sengen, Tsukuba, Ibaraki, Japan. EM ocsgin@gmail.com; anirban.bandyo@gmail.com FU AFSOR FX This work was financially supported by the AFSOR. NR 38 TC 1 Z9 1 U1 0 U2 18 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 JUN 18 PY 2015 VL 5 AR 11265 DI 10.1038/srep11265 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK8YZ UT WOS:000356527700001 PM 26086417 ER PT J AU Cannon, CP Blazing, MA Giugliano, RP McCagg, A White, JA Theroux, P Darius, H Lewis, BS Ophuis, TO Jukema, JW De Ferrari, GM Ruzyllo, W De Lucca, P Im, K Bohula, EA Reist, C Wiviott, SD Tershakovec, AM Musliner, TA Braunwald, E Califf, RM AF Cannon, Christopher P. Blazing, Michael A. Giugliano, Robert P. McCagg, Amy White, Jennifer A. Theroux, Pierre Darius, Harald Lewis, Basil S. Ophuis, Ton Oude Jukema, J. Wouter De Ferrari, Gaetano M. Ruzyllo, Witold De Lucca, Paul Im, KyungAh Bohula, Erin A. Reist, Craig Wiviott, Stephen D. Tershakovec, Andrew M. Musliner, Thomas A. Braunwald, Eugene Califf, Robert M. CA IMPROVW-IT Investigators TI Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; AVERAGE CHOLESTEROL LEVELS; PLACEBO-CONTROLLED TRIAL; CLINICAL-TRIALS; HEART-DISEASE; CARDIOVASCULAR OUTCOMES; MYOCARDIAL-INFARCTION; HYPERTENSIVE PATIENTS; PRIMARY PREVENTION; LOWERING TREATMENT AB BACKGROUND Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (>= 30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P< 0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of pre-specified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. C1 [Cannon, Christopher P.; Giugliano, Robert P.; McCagg, Amy; Im, KyungAh; Bohula, Erin A.; Wiviott, Stephen D.; Braunwald, Eugene] Brigham & Womens Hosp, Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA 02115 USA. [Cannon, Christopher P.; Giugliano, Robert P.; McCagg, Amy; Im, KyungAh; Bohula, Erin A.; Wiviott, Stephen D.; Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. [Blazing, Michael A.; White, Jennifer A.; Reist, Craig; Califf, Robert M.] DCRI, Durham, NC USA. [Theroux, Pierre] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Darius, Harald] Vivantes Neukolln Med Ctr, Berlin, Germany. [Lewis, Basil S.] Lady Davis Carmel Med Ctr, Haifa, Israel. [Ophuis, Ton Oude] Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands. [Jukema, J. Wouter] Netherlands Leiden Univ, Med Ctr, Leiden, Netherlands. [De Ferrari, Gaetano M.] Fdn IRCCS Policlin San Matteo, Pavia, Italy. [De Ferrari, Gaetano M.] Univ Pavia, I-27100 Pavia, Italy. [Ruzyllo, Witold] Natl Inst Cardiol, Warsaw, Poland. [De Lucca, Paul; Tershakovec, Andrew M.; Musliner, Thomas A.] Merck, Kenilworth, NJ USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 350 Long Wood Ave,1st Fl, Boston, MA 02115 USA. EM cpcannon@partners.org RI Kobayashi, Junjiro/J-8547-2015; De Caterina, Raffaele/K-3857-2016; De Ferrari, Gaetano/K-5188-2016; Ponikowski, Piotr/O-6454-2015; Nicolau, Jose/E-1487-2012; Marin-Neto, Jose Antonio/F-6099-2012; Hradec, Jaromir/S-2388-2016; Prunier, Fabrice/A-5210-2011; Henrion, Daniel/J-8141-2015; Miranda, Luisa/N-6353-2013; Nagy, Ivan/I-7419-2013 OI Rider, Jennifer/0000-0002-2637-6036; Ciuti, Gabriele/0000-0001-6957-5919; Volpe, Massimo/0000-0002-9642-8380; Zingarelli, Antonio/0000-0002-8240-2622; De Caterina, Raffaele/0000-0003-1637-574X; De Ferrari, Gaetano/0000-0003-4940-0876; Ponikowski, Piotr/0000-0002-3391-7064; Hradec, Jaromir/0000-0001-7597-8239; Gavina, Cristina/0000-0003-2553-8264; tavano, davide/0000-0002-0938-0076; Henrion, Daniel/0000-0003-1094-0285; Miranda, Luisa/0000-0002-7553-6059; FU Merck FX Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878. NR 40 TC 545 Z9 562 U1 55 U2 119 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 JUN 18 PY 2015 VL 372 IS 25 BP 2387 EP 2397 DI 10.1056/NEJMoa1410489 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CK6RF UT WOS:000356354600005 PM 26039521 ER PT J AU Dobbs, K Conde, CD Zhang, SY Parolini, S Audry, M Chou, J Haapaniemi, E Keles, S Bilic, I Okada, S Massaad, MJ Rounioja, S Alwahadneh, AM Serwas, NK Capuder, K Ciftci, E Felgentreff, K Ohsumi, TK Pedergnana, V Boisson, B Haskologlu, S Ensari, A Schuster, M Moretta, A Itan, Y Patrizi, O Rozenberg, F Lebon, P Saarela, J Knip, M Petrovski, S Goldstein, DB Parrott, RE Savas, B Schambach, A Tabellini, G Bock, C Chatila, TA Comeau, AM Geha, RS Abel, L Buckley, RH Ikinciogullari, A Al-Herz, W Helminen, M Dogu, F Casanova, JL Boztug, K Notarangelo, LD AF Dobbs, K. Conde, C. Dominguez Zhang, S. -Y. Parolini, S. Audry, M. Chou, J. Haapaniemi, E. Keles, S. Bilic, I. Okada, S. Massaad, M. J. Rounioja, S. Alwahadneh, A. M. Serwas, N. K. Capuder, K. Ciftci, E. Felgentreff, K. Ohsumi, T. K. Pedergnana, V. Boisson, B. Haskologlu, S. Ensari, A. Schuster, M. Moretta, A. Itan, Y. Patrizi, O. Rozenberg, F. Lebon, P. Saarela, J. Knip, M. Petrovski, S. Goldstein, D. B. Parrott, R. E. Savas, B. Schambach, A. Tabellini, G. Bock, C. Chatila, T. A. Comeau, A. M. Geha, R. S. Abel, L. Buckley, R. H. Ikinciogullari, A. Al-Herz, W. Helminen, M. Dogu, F. Casanova, J. -L. Boztug, K. Notarangelo, L. D. TI Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; RAC ACTIVATOR DOCK2; T-CELLS; PRIMARY IMMUNODEFICIENCY; INBORN-ERRORS; IMMUNITY; MUTATIONS; LYMPHOCYTE; TOLERANCE; DEDICATOR AB BACKGROUND Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, auto-immunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. METHODS We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. RESULTS We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-a and interferon-lambda production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. CONCLUSIONS Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. C1 [Dobbs, K.; Chou, J.; Keles, S.; Massaad, M. J.; Capuder, K.; Felgentreff, K.; Chatila, T. A.; Geha, R. S.; Notarangelo, L. D.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Notarangelo, L. D.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Ohsumi, T. K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Notarangelo, L. D.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Comeau, A. M.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Conde, C. Dominguez; Bilic, I.; Serwas, N. K.; Schuster, M.; Bock, C.; Boztug, K.] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria. [Boztug, K.] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria. [Boztug, K.] CeRUD Vienna Ctr Rare & Undiagnosed Dis, Vienna, Austria. [Zhang, S. -Y.; Audry, M.; Okada, S.; Boisson, B.; Itan, Y.; Abel, L.; Casanova, J. -L.] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, New York, NY 10021 USA. [Petrovski, S.; Goldstein, D. B.] Columbia Univ, Inst Genom Med, New York, NY USA. [Zhang, S. -Y.; Pedergnana, V.; Abel, L.; Casanova, J. -L.] INSERM, U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France. [Zhang, S. -Y.; Rozenberg, F.; Lebon, P.; Abel, L.; Casanova, J. -L.] Paris Descartes Univ, Sorbonne Paris Cite, Imagine Inst, Paris, France. [Casanova, J. -L.] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris, France. [Casanova, J. -L.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Parolini, S.; Patrizi, O.; Tabellini, G.] Univ Brescia, Dept Mol & Translat Med, Brescia, Italy. [Moretta, A.] Univ Genoa, Dept Expt Med, Genoa, Italy. [Haapaniemi, E.] Univ Helsinki, Folkhalsan Inst Genet, Helsinki, Finland. [Haapaniemi, E.] Univ Helsinki, Res Programs Unit, Mol Neurol, Helsinki, Finland. [Saarela, J.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Knip, M.] Univ Helsinki, Childrens Hosp, Helsinki, Finland. [Knip, M.] Univ Helsinki, Res Programs Unit, Diabet & Obes Res Program, Helsinki, Finland. [Knip, M.] Univ Helsinki, Folkhalsan Res Ctr, Helsinki, Finland. Helsinki Univ Cent Hosp, Helsinki, Finland. [Rounioja, S.; Knip, M.; Helminen, M.] Tampere Univ Hosp, Tampere Ctr Child Hlth Res, Tampere, Finland. [Rounioja, S.] Tampere Univ Hosp, Fimlab Labs, Tampere, Finland. [Keles, S.] Necmettin Erbakan Univ, Meram Fac Med, Div Pediat Immunol & Allergy, Konya, Turkey. [Ciftci, E.] Ankara Univ, Sch Med, Dept Pediat Infect Dis, TR-06100 Ankara, Turkey. [Haskologlu, S.; Ikinciogullari, A.; Dogu, F.] Ankara Univ, Sch Med, Dept Immunol & Allergy, TR-06100 Ankara, Turkey. [Ensari, A.; Savas, B.] Ankara Univ, Sch Med, Dept Pathol, TR-06100 Ankara, Turkey. [Alwahadneh, A. M.] Queen Rania Pediat Hosp, King Hussein Med Ctr, Pediat Allergy Immunol & Rheumatol Sect, Amman, Jordan. [Schambach, A.] Hannover Med Sch, Inst Expt Hematol, Hannover, Germany. [Petrovski, S.; Goldstein, D. B.] Duke Univ, Sch Med, Duke Ctr Human Genome Variat, Durham, NC USA. [Parrott, R. E.; Buckley, R. H.] Duke Univ, Dept Pediat, Sch Med, Div Allergy & Immunol, Durham, NC 27706 USA. [Buckley, R. H.] Duke Univ, Sch Med, Dept Immunol, Durham, NC USA. [Al-Herz, W.] Kuwait Univ, Fac Med, Dept Pediat, Safat, Kuwait. RP Notarangelo, LD (reprint author), Boston Childrens Hosp, Div Immunol, Karp Res Bldg,Rm 10217,1 Blackfan Circle, Boston, MA 02115 USA. EM shzh289@mail.rockefeller.edu; casanova@rockefeller.edu; kboztug@cemm.oeaw.ac.at; luigi.notarangelo@childrens.harvard.edu RI Bock, Christoph/B-6723-2008; Okada, Satoshi/B-8901-2011; Notarangelo, Luigi/F-9718-2016; OI Bock, Christoph/0000-0001-6091-3088; Okada, Satoshi/0000-0002-4622-5657; Notarangelo, Luigi/0000-0002-8335-0262; Petrovski, Slave/0000-0002-1527-961X; Schuster, Michael/0000-0003-2975-8969; Saarela, Janna/0000-0002-0853-6219 FU National Institutes of Health FX Supported by the National Institutes of Health and others. NR 42 TC 20 Z9 21 U1 2 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 18 PY 2015 VL 372 IS 25 BP 2409 EP 2422 DI 10.1056/NEJMoa1413462 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA CK6RF UT WOS:000356354600007 PM 26083206 ER PT J AU Dudzinski, DM Prabhakar, AM Ptaszek, LM Vlahakes, GJ AF Dudzinski, David M. Prabhakar, Anand M. Ptaszek, Leon M. Vlahakes, Gus J. TI Case 19-2015: A 71-Year-Old Man with Chest Pain and Shortness of Breath SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CARDIOVERTER-DEFIBRILLATOR REGISTRY; CARDIOVASCULAR DATA REGISTRY; COMPUTED-TOMOGRAPHY; LEAD PERFORATION; INSIGHTS; COMPLICATIONS; MORTALITY C1 [Dudzinski, David M.; Ptaszek, Leon M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Prabhakar, Anand M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Vlahakes, Gus J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Dudzinski, David M.; Ptaszek, Leon M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Prabhakar, Anand M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Vlahakes, Gus J.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 15 TC 1 Z9 1 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 18 PY 2015 VL 372 IS 25 BP 2438 EP 2446 DI 10.1056/NEJMcpc1415757 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CK6RF UT WOS:000356354600011 PM 26083209 ER PT J AU Hickman, TT Liberman, MC Jacob, MH AF Hickman, Tyler T. Liberman, M. Charles Jacob, Michele H. TI Adenomatous Polyposis Coli Protein Deletion in Efferent Olivocochlear Neurons Perturbs Afferent Synaptic Maturation and Reduces the Dynamic Range of Hearing SO JOURNAL OF NEUROSCIENCE LA English DT Article DE adenomatous polyposis coli protein (APC); hair cell; hearing; olivocochlear efferent; ribbon; synapse ID INNER HAIR-CELLS; AUDITORY-NERVE RESPONSE; NEUROTROPHIC FACTOR; NICOTINIC SYNAPSES; MAMMALIAN COCHLEA; CA2+ DEPENDENCE; CHROMOSOME 5Q; SK2 CHANNELS; RIBBON SIZE; IN-VIVO AB Normal hearing requires proper differentiation of afferent ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) that carry acoustic information to the brain. Within individual IHCs, presynaptic ribbons show a size gradient with larger ribbons on the modiolar face and smaller ribbons on the pillar face. This structural gradient is associated with a gradient of spontaneous rates and threshold sensitivity, which is essential for a wide dynamic range of hearing. Despite their importance for hearing, mechanisms that direct ribbon differentiation are poorly defined. We recently identified adenomatous polyposis coli protein (APC) as a key regulator of interneuronal synapse maturation. Here, we show that APC is required for ribbon size heterogeneity and normal cochlear function. Compared with wild-type littermates, APC conditional knock-out (cKO) mice exhibit decreased auditory brainstem responses. The IHC ribbon size gradient is also perturbed. Whereas the normal-developing IHCs display ribbon size gradients before hearing onset, ribbon sizes are aberrant in APC cKOs from neonatal ages on. Reporter expression studies show that the CaMKII-Cre used to delete the floxed APC gene is present in efferent olivocochlear (OC) neurons, not IHCs or SGNs. APC loss led to increased volumes and numbers of OC inhibitory dopaminergic boutons on neonatal SGN fibers. Our findings identify APC in efferent OC neurons as essential for regulating ribbon heterogeneity, dopaminergic terminal differentiation, and cochlear sensitivity. ThisAPCeffect on auditory epithelial cell synapses resembles interneuronal and nerve-muscle synapses, thereby defining a global role for APC in synaptic maturation in diverse cell types. C1 [Hickman, Tyler T.; Jacob, Michele H.] Tufts Univ, Dept Neurosci, Sackler Biomed Grad Sch, Sch Med, Boston, MA 02111 USA. [Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02111 USA. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02111 USA. RP Jacob, MH (reprint author), Tufts Univ, Dept Neurosci, 136 Harrison Ave, Boston, MA 02111 USA. EM Michele.Jacob@Tufts.edu FU National Institutes of Health [NIDCD R01 DC008802, NINDS T32 NS061764, NINDS P30 NS047243, NIDCD R01 DC00188, P30 DC 05209] FX This work was supported by National Institutes of Health Grants NIDCD R01 DC008802 (M.H.J.), NINDS T32 NS061764 (M.H.J.; T.H., predoctoral trainee), NINDS P30 NS047243 (F.R. Jackson), NIDCD R01 DC00188 (M.C.L.), and P30 DC 05209 (M.C.L.). NR 70 TC 0 Z9 0 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 17 PY 2015 VL 35 IS 24 BP 9236 EP 9245 DI 10.1523/JNEUROSCI.4384-14.2015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CN2KU UT WOS:000358250700025 PM 26085645 ER PT J AU Goncalves, OF Sousa, S Maia, L Carvalho, S Leite, J Ganho, A Fernandes-Goncalves, A Frank, B Pocinho, F Carracedo, A Sampaio, A AF Goncalves, Oscar F. Sousa, Sonia Maia, Liliana Carvalho, Sandra Leite, Jorge Ganho, Ana Fernandes-Goncalves, Ana Frank, Brandon Pocinho, Fernando Carracedo, Angel Sampaio, Adriana TI Inferior frontal gyrus white matter abnormalities in obsessive-compulsive disorder SO NEUROREPORT LA English DT Article DE connectivity; inferior frontal gyrus; obsessive-compulsive disorder; pars opercularis; pars orbitalis; pars triangularis ID VOXEL-BASED MORPHOMETRY; RESPONSE-INHIBITION; BRAIN; METAANALYSIS; INVENTORY; OCD AB The aim of the present study is to explore obsessive-compulsive disorder (OCD)-related abnormalities in white matter connectivity in OCD for a core region associated with inhibitory control [i.e. inferior frontal gyrus (IFG)]. Fifteen patients with OCD (11 men) and 15 healthy controls (nine men) underwent diffusion tensor imaging scanning to study four diffusivity indexes of white matter integrity [fractional anisotropy, mean diffusivity (MD), axial diffusivity and radial diffusivity (RD)]. The results showed that persons with OCD manifested significantly lower fractional anisotropy levels in the bilateral IFG as well as its parcellations in the pars opercularis, pars triangularis, and pars orbitalis. Significantly higher levels of MD, RD were evident for the OCD group in the IFG as a whole as well as in the bilateral subregions of the pars triangularis and pars opercularis (for MD and RD), the right side of the pars orbitalis (for RD), and the left side of the pars triangularis and right side pars opercularis (for axial diffusivity). Overall, the results suggest significant alterations in structural connectivity, probably associated with myelination and axonal abnormalities in the IFG of OCD patients. NeuroReport 26:495-500 Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Goncalves, Oscar F.; Carvalho, Sandra; Leite, Jorge] Spaulding Rehabil Hosp, Spaulding Ctr Neuromodulat, Dept Phys Med & Rehabil, Boston, MA USA. [Goncalves, Oscar F.; Carvalho, Sandra; Leite, Jorge] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Goncalves, Oscar F.; Frank, Brandon] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Goncalves, Oscar F.; Sousa, Sonia; Maia, Liliana; Carvalho, Sandra; Leite, Jorge; Ganho, Ana; Sampaio, Adriana] Univ Minho, Sch Psychol, Neuropsychophysiol Lab, CIPsi, Braga, Portugal. [Fernandes-Goncalves, Ana] CUF Porto Hosp, Dept Psychiat, Oporto, Portugal. [Pocinho, Fernando] Univ Coimbra Hosp, Dept Psychiat, Coimbra, Portugal. [Carracedo, Angel] Univ Santiago de Compostela, Forens Genet Unit, Santiago De Compostela, Spain. RP Goncalves, OF (reprint author), Spaulding Rehabil Hosp, Spaulding Neuromodulat Ctr, Charlestown Campus 79-96,13th St, Charlestown, MA 02129 USA. EM ocoelhonevesgoncalves@partners.org RI Goncalves, Oscar/G-5278-2010; Sampaio, Adriana/C-8361-2011; Leite, Jorge/E-4404-2013; OI Goncalves, Oscar/0000-0003-2735-9155; Sampaio, Adriana/0000-0001-7347-1282; Leite, Jorge/0000-0002-0323-9012; Carvalho, Sandra/0000-0003-1759-5146 FU Brain Imaging Network Grid/FCT (Portugal); Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/86041/2012, SFRH/BPD/86027/2012]; European Union (FSE-POPH) [SFRH/BPD/86041/2012, SFRH/BPD/86027/2012] FX This work was partially supported by a research award to the first author (O.F.G.) from the Brain Imaging Network Grid/FCT (Portugal). Jorge Leite (SFRH/BPD/86027/2012) and Sandra Carvalho (SFRH/BPD/86041/2012) are supported by grants from the Portuguese Foundation for Science and Technology (FCT) and European Union (FSE-POPH). NR 25 TC 2 Z9 2 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-4965 EI 1473-558X J9 NEUROREPORT JI Neuroreport PD JUN 17 PY 2015 VL 26 IS 9 BP 495 EP 500 DI 10.1097/WNR.0000000000000377 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CJ2OG UT WOS:000355323700002 PM 25945482 ER PT J AU Tawakol, A Hara, T Truelove, J Wojtkiewicz, GR Hucker, WJ MacNabb, MH Brownell, AL Jokivarsi, K Kessinger, CW Jaff, MR Henke, PK Weissleder, R Jaffer, FA AF Tawakol, Ahmed Hara, Tetsuya Truelove, Jessica Wojtkiewicz, Gregory R. Hucker, William J. MacNabb, Megan H. Brownell, Anna-Liisa Jokivarsi, Kimmo Kessinger, Chase W. Jaff, Michael R. Henke, Peter K. Weissleder, Ralph Jaffer, Farouc A. TI F-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Enables the Detection of Recurrent Same-Site Deep Vein Thrombosis by Illuminating Recently Formed, Neutrophil-Rich Thrombus Response SO CIRCULATION LA English DT Letter C1 [Tawakol, Ahmed; Hucker, William J.; MacNabb, Megan H.; Jaff, Michael R.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Hara, Tetsuya; Kessinger, Chase W.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Wojtkiewicz, Gregory R.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Brownell, Anna-Liisa; Jokivarsi, Kimmo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Biomed Imaging Ctr, Boston, MA USA. [Henke, Peter K.] Univ Michigan, Dept Surg, Vasc Surg Sect, Ann Arbor, MI 48109 USA. RP Tawakol, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. 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 JUN 16 PY 2015 VL 131 IS 24 BP E531 EP E532 DI 10.1161/CIRCULATIONAHA.115.014802 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IK UT WOS:000369254500003 PM 26078375 ER PT J AU Vodopivec, I Shah, CP Prasad, S Cohen, AB AF Vodopivec, Ivana Shah, Chirag P. Prasad, Sashank Cohen, Adam B. TI Teaching NeuroImages: Cat-scratch optic neuropathy without neuroretinitis SO NEUROLOGY LA English DT Editorial Material C1 [Vodopivec, Ivana; Cohen, Adam B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Shah, Chirag P.] Brigham & Womens Hosp, Ophthalm Consultants Boston, 75 Francis St, Boston, MA 02115 USA. [Prasad, Sashank] Brigham & Womens Hosp, Dept Neurol, Div Neuroophthalmol, 75 Francis St, Boston, MA 02115 USA. RP Vodopivec, I (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM ivodopivec@partners.org NR 2 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 16 PY 2015 VL 84 IS 24 BP E204 EP E205 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DC2VX UT WOS:000369077700001 PM 26078406 ER PT J AU Suchankova, P Yan, J Schwandt, ML Stangl, BL Caparelli, EC Momenan, R Jerlhag, E Engel, JA Hodgkinson, CA Egli, M Lopez, MF Becker, HC Goldman, D Heilig, M Ramchandani, VA Leggio, L AF Suchankova, P. Yan, J. Schwandt, M. L. Stangl, B. L. Caparelli, E. C. Momenan, R. Jerlhag, E. Engel, J. A. Hodgkinson, C. A. Egli, M. Lopez, M. F. Becker, H. C. Goldman, D. Heilig, M. Ramchandani, V. A. Leggio, L. TI The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID POPULATION-BASED SAMPLE; VENTRAL TEGMENTAL AREA; FOOD-INTAKE; REWARD ANTICIPATION; GLP-1; POLYMORPHISM; EXENDIN-4; CORRELATE; SMOKING; ANALOG AB The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD. C1 [Suchankova, P.; Leggio, L.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Suchankova, P.; Jerlhag, E.; Engel, J. A.] Univ Gothenburg, Sahlgrenska Acad, Dept Pharmacol, Gothenburg, Sweden. [Yan, J.; Stangl, B. L.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Yan, J.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Schwandt, M. L.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Caparelli, E. C.; Leggio, L.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Momenan, R.] NIAAA, Sect Brain Electrophysiol & Imaging, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Hodgkinson, C. A.; Goldman, D.] NIAAA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Egli, M.] NIAAA, Div Neurosci & Behav, Bethesda, MD 20892 USA. [Lopez, M. F.; Becker, H. C.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston Alcohol Res Ctr, Charleston, SC 29425 USA. [Becker, H. C.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Becker, H. C.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Leggio, L.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, 10 Ctr Dr 10CRC 15330 MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016; Leggio, Lorenzo/M-2972-2016 OI Goldman, David/0000-0002-1724-5405; FU Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIAAA Extramural Division of Neuroscience and Behavior via the NIH/NIAAA contract 'Preclinical Medications Screening in Alcohol Dependence and Anxiety Models' [HHSN267200700038C]; Swedish Brain Foundation; LUA/ALF grant from the Sahlgrenska University Hospital [148251]; Indiana Alcohol Research Center [NIH P60 AA007611]; NIH Genes, Environment and Health Initiative (GEI) [U01HG004422]; Gene Environment Association Studies under GEI; NIH GEI [U01HG004438]; NIAAA; NIDA; NIH [HHSN268200782096C] FX This work was supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA; PS, JY, MLS, BLS, RM, CAH, DG, MH, VAR, LL), the Intramural Research Program of the National Institute on Drug Abuse (NIDA; PS, ECC, LL). This work was also supported by the NIAAA Extramural Division of Neuroscience and Behavior via the NIH/NIAAA contract 'Preclinical Medications Screening in Alcohol Dependence and Anxiety Models' (HHSN267200700038C; ME, MFL, HCB), under which the compound AC3174 was provided to NIAAA for testing by Medical University of South Carolina (MUSC). AC3174 was manufactured by Amylin Pharmaceuticals and is now owned by MedImmune, LLC (a wholly owned subsidiary of AstraZeneca), whose staff reviewed and authorized the use of the data described in the 'Study 5'. In addition, this work was supported by the Swedish Brain Foundation (PS), and a LUA/ALF grant (no. 148251) from the Sahlgrenska University Hospital (PS, EJ, JAE). Development of the Computerized Alcohol Infusion System (CAIS) software used in the IV-ASA study was supported by the Indiana Alcohol Research Center (NIH P60 AA007611). Finally, funding support for the Study of Addiction: Genetics and Environment (SAGE; Study 2) was provided through the NIH Genes, Environment and Health Initiative (GEI; U01HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), NIAAA, NIDA and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. NR 50 TC 10 Z9 10 U1 0 U2 7 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 JUN 16 PY 2015 VL 5 AR e583 DI 10.1038/tp.2015.68 PG 11 WC Psychiatry SC Psychiatry GA DA2WW UT WOS:000367658900004 PM 26080318 ER PT J AU Corrick, KL Stec, MJ Merritt, EK Windham, ST Thomas, SJ Cross, JM Bamman, MM AF Corrick, Katie L. Stec, Michael J. Merritt, Edward K. Windham, Samuel T. Thomas, Steven J. Cross, James M. Bamman, Marcas M. TI Serum from human burn victims impairs myogenesis and protein synthesis in primary myoblasts SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE burn; inflammation; myogenesis; myoblast; myotube; muscle protein synthesis ID HUMAN SKELETAL-MUSCLE; INJURY; ACTIVATION; GROWTH; DIFFERENTIATION; REGENERATION; INFLAMMATION; CATABOLISM; EXPRESSION; CASPASE-3 AB The pathophysiological response to a severe burn injury involves a robust increase in circulating inflammatory/endocrine factors and a hypermetabolic state, both of which contribute to prolonged skeletal muscle atrophy. In order to characterize the role of circulating factors in muscle atrophy following a burn injury, human skeletal muscle satellite cells were grown in culture and differentiated to myoblasts/myotubes in media containing serum from burn patients or healthy, age, and sex-matched controls. While incubation in burn serum did not affect NF kappa B signaling, cells incubated in burn serum displayed a transient increase in STAT3 phosphorlyation (Tyr705) after 48 h of treatment with burn serum (approximate to + 70%; P < 0.01), with these levels returning to normal by 96 h. Muscle cells differentiated in burn serum displayed reduced myogenic fusion signaling (phospho-STAT6 (Tyr641), approximate to-75% ADAM12, approximate to-20% both P < 0.01), and reduced levels of myogenin (approximate to-75% P < 0.05). Concomitantly, myotubes differentiated in burn serum demonstrated impaired myogenesis (assessed by number of nuclei/myotube). Incubation in burn serum for 96 h did not increase proteolytic signaling (assessed via caspase-3 and ubiquitin levels), but reduced anabolic signaling [p-p70S6k (Ser421/Thr424), -30%; p-rpS6 (Ser240/244), approximate to -50%] and impaired protein synthesis (-24%) (P < 0.05). This resulted in a loss of total protein content (-18%) and reduced cell size (-33%) (P < 0.05). Overall, incubation of human muscle cells in serum from burn patients results in impaired myogenesis and reduced myotube size, indicating that circulating factors may play a significant role in muscle loss and impaired muscle recovery following burn injury. C1 [Corrick, Katie L.; Stec, Michael J.; Merritt, Edward K.; Bamman, Marcas M.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. [Stec, Michael J.; Merritt, Edward K.; Windham, Samuel T.; Bamman, Marcas M.] Univ Alabama Birmingham, UAB Ctr Exercise Med, Birmingham, AL 35294 USA. [Windham, Samuel T.; Thomas, Steven J.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Cross, James M.] Univ Texas Hlth Sci Ctr Houston, Dept Surg, Houston, TX 77030 USA. [Bamman, Marcas M.] Birmingham VA Med Ctr, Ctr Geriatr Res Educ & Clin, Birmingham, AL USA. RP Bamman, MM (reprint author), Univ Alabama Birmingham, UAB Ctr Exercise Med, Dept Cell Dev & Integrat Biol, MCLM 966,1720 2nd Ave South, Birmingham, AL 35294 USA. EM mbamman@uab.edu FU VA Merit Review Grant [R01AG017896, F32AR060670, F31AG044109]; UAB Burn Center FX We are indebted to the subjects for their efforts and dedication. This work was supported by a VA Merit Review Grant (MB), R01AG017896 (MB), F32AR060670 (EM), F31AG044109 (MS), and the UAB Burn Center. NR 33 TC 5 Z9 5 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD JUN 16 PY 2015 VL 6 AR 184 DI 10.3389/fphys.2015.00184 PG 8 WC Physiology SC Physiology GA CM4UZ UT WOS:000357681800001 PM 26136691 ER PT J AU Marcsisin, SR Liptak, C Marineau, J Bradner, JE Engen, JR AF Marcsisin, Sean R. Liptak, Cary Marineau, Jason Bradner, James E. Engen, John R. TI Tag and Capture Flow Hydrogen Exchange Mass Spectrometry with a Fluorous-Immobilized Probe SO ANALYTICAL CHEMISTRY LA English DT Article ID 4-ALPHA-HELIX BUNDLE PROTEIN; HEXAFLUOROLEUCINE; MICROARRAYS; SEPARATION; REGIONS; BINDING; MEDIA; MS AB Analysis of complex mixtures of proteins by hydrogen exchange (HX) mass spectrometry (MS) is limited by one's ability to resolve the protein(s) of interest from the proteins that are not of interest. One strategy for overcoming this problem is to tag the target protein(s) to allow for rapid removal from the mixture for subsequent analysis. Here we illustrate a new solution involving fluorous conjugation of a retrievable probe. The appended fluorous tag allows for facile immobilization on a fluorous surface. When a target protein is passed over the immobilized probe molecule, it can be efficiently captured and then exposed to a flowing stream of deuterated buffer for hydrogen exchange. The utility of this method is illustrated for a model system of the Elongin BC protein complex bound to a peptide from HIV Vif. Efficient capture is demonstrated, and deuteration when immobilized was identical to deuteration in conventional solution-phase hydrogen exchange MS. Protein captured from a crude bacterial cell lysate could also be deuterated without the need for separate purification steps before HX MS. The advantages and disadvantages of the method are discussed in light of miniaturization and automation. C1 [Marcsisin, Sean R.; Liptak, Cary; Engen, John R.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Marineau, Jason; Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Engen, JR (reprint author), Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. EM j.engen@neu.edu FU National Institutes of Health [R01-GM101135]; Waters Corp.; Leukemia & Lymphoma Society FX This work was supported by funding from the National Institutes of Health (R01-GM101135) to J.R.E. and a research collaboration with Waters Corp. (J.R.E.). J.E.B. and J.M. are supported by the Leukemia & Lymphoma Society (to J.E.B.). This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. NR 27 TC 0 Z9 0 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD JUN 16 PY 2015 VL 87 IS 12 BP 6349 EP 6356 DI 10.1021/acs.analchem.5b01220 PG 8 WC Chemistry, Analytical SC Chemistry GA CL2DZ UT WOS:000356755100067 PM 26023704 ER PT J AU Katz, IT Shapiro, DE Tuomala, R AF Katz, Ingrid T. Shapiro, David E. Tuomala, Ruth TI Factors Associated With Lack of Viral Suppression at Delivery RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Katz, Ingrid T.] Brigham & Womens Hosp, Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02115 USA. [Katz, Ingrid T.] Harvard Univ, Sch Med, Boston, MA USA. [Shapiro, David E.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Tuomala, Ruth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Tuomala, Ruth] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. RP Katz, IT (reprint author), Brigham & Womens Hosp, Massachusetts Gen Hosp, Ctr Global Hlth, 75 Francis St, Boston, MA 02115 USA. NR 4 TC 1 Z9 1 U1 0 U2 1 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 JUN 16 PY 2015 VL 162 IS 12 BP 874 EP 875 DI 10.7326/L15-5059-2 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CK8VC UT WOS:000356516300027 PM 26075762 ER PT J AU Driscoll, TP Cosgrove, BD Heo, SJ Shurden, ZE Mauck, RL AF Driscoll, Tristan P. Cosgrove, Brian D. Heo, Su-Jin Shurden, Zach E. Mauck, Robert L. TI Cytoskeletal to Nuclear Strain Transfer Regulates YAP Signaling in Mesenchymal Stem Cells SO BIOPHYSICAL JOURNAL LA English DT Article ID FOCAL ADHESION KINASE; MECHANICAL-PROPERTIES; VINCULIN RECRUITMENT; LOADING IMPROVES; DEPENDENT MANNER; ANNULUS FIBROSUS; K+ CHANNELS; TALIN ROD; MECHANOTRANSDUCTION; MECHANOSENSITIVITY AB Mechanical forces transduced to cells through the extracellular matrix are critical regulators of tissue development, growth, and homeostasis, and can play important roles in directing stem cell differentiation. In addition to force-sensing mechanisms that reside at the cell surface, there is growing evidence that forces transmitted through the cytoskeleton and to the nuclear envelope are important for mechanosensing, including activation of the Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathway. Moreover, nuclear shape, mechanics, and deformability change with differentiation state and have been likewise implicated in force sensing and differentiation. However, the significance of force transfer to the nucleus through the mechanosensing cytoskeletal machinery in the regulation of mesenchymal stem cell mechanobiologic response remains unclear. Here we report that actomyosin-generated cytoskeletal tension regulates nuclear shape and force transmission through the cytoskeleton and demonstrate the differential short- and long-term response of mesenchymal stem cells to dynamic tensile loading based on the contractility state, the patency of the actin cytoskeleton, and the connections it makes with the nucleus. Specifically, we show that while some mechanoactive signaling pathways (e.g., ERK signaling) can be activated in the absence of nuclear strain transfer, cytoskeletal strain transfer to the nucleus is essential for activation of the YAP/TAZ pathway with stretch. C1 [Driscoll, Tristan P.; Cosgrove, Brian D.; Heo, Su-Jin; Shurden, Zach E.; Mauck, Robert L.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [Driscoll, Tristan P.; Cosgrove, Brian D.; Heo, Su-Jin; Shurden, Zach E.; Mauck, Robert L.] Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA. [Mauck, Robert L.] Univ Penn, Sch Engn & Appl Sci, Dept Mech Engn & Appl Mech, Philadelphia, PA 19104 USA. [Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. 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 OI Driscoll, Tristan/0000-0002-2426-5551 FU National Institutes of Health [R01 EB02425, R01 AR056624, T32 AR007132]; University of Pennsylvania University Research Foundation Award; Montague Research Award at the Perelman School of Medicine; Penn Center for Musculoskeletal Disorders [P30 AR050950] FX This work was supported by the National Institutes of Health (grants No. R01 EB02425 and No. R01 AR056624). Additional support was provided from a University of Pennsylvania University Research Foundation Award, the Montague Research Award at the Perelman School of Medicine, a grant from the Penn Center for Musculoskeletal Disorders (No. P30 AR050950), and a training grant from the National Institutes of Health (No. T32 AR007132). NR 44 TC 17 Z9 18 U1 4 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUN 16 PY 2015 VL 108 IS 12 BP 2783 EP 2793 DI 10.1016/j.bpj.2015.05.010 PG 11 WC Biophysics SC Biophysics GA CK6UO UT WOS:000356364000010 PM 26083918 ER PT J AU Su, Y Subedee, A Bloushtain-Qimron, N Savova, V Krzystanek, M Li, L Marusyk, A Tabassum, DP Zak, A Flacker, MJ Li, M Lin, JJ Sukumar, S Suzuki, H Long, H Szallasi, Z Gimelbrant, A Maruyama, R Polyak, K AF Su, Ying Subedee, Ashim Bloushtain-Qimron, Noga Savova, Virginia Krzystanek, Marcin Li, Lewyn Marusyk, Andriy Tabassum, Doris P. Zak, Alexander Flacker, Mary Jo Li, Mei Lin, Jessica J. Sukumar, Saraswati Suzuki, Hiromu Long, Henry Szallasi, Zoltan Gimelbrant, Alexander Maruyama, Reo Polyak, Kornelia TI Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer SO CELL REPORTS LA English DT Article ID TRANSCRIPTION FACTORS; TUMOR SUBTYPE; IDENTIFICATION; GENES; PROGENITORS; POPULATION; EXTINCTION; EXPRESSION; PHENOTYPE; EVOLUTION AB Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. C1 [Su, Ying; Subedee, Ashim; Bloushtain-Qimron, Noga; Marusyk, Andriy; Tabassum, Doris P.; Li, Mei; Lin, Jessica J.; Maruyama, Reo; Polyak, Kornelia] Dana Farber Canc Inst Boston, Dept Med Oncol, Boston, MA 02215 USA. [Savova, Virginia; Zak, Alexander; Gimelbrant, Alexander] Dana Farber Canc Inst Boston, Dept Canc Biol, Boston, MA 02215 USA. [Li, Lewyn; Long, Henry] Dana Farber Canc Inst Boston, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Su, Ying; Marusyk, Andriy; Lin, Jessica J.; Maruyama, Reo; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Su, Ying; Marusyk, Andriy; Lin, Jessica J.; Maruyama, Reo; Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Savova, Virginia; Gimelbrant, Alexander] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Subedee, Ashim; Tabassum, Doris P.; Polyak, Kornelia] Harvard Univ, Sch Med, BBS Program, Boston, MA 02115 USA. [Krzystanek, Marcin; Szallasi, Zoltan] Tech Univ Denmark, Dept Syst Biol, DK-2800 Kongens Lyngby, Denmark. [Flacker, Mary Jo; Sukumar, Saraswati] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA. [Suzuki, Hiromu; Maruyama, Reo] Sapporo Med Univ, Sch Med,Sapporo, Dept Mol Biol, Sapporo, Hokkaido 0608556, Japan. [Szallasi, Zoltan] Childrens Hosp, Boston, MA 02115 USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Polyak, Kornelia] Broad Inst, Cambridge, MA 02138 USA. RP Maruyama, R (reprint author), Dana Farber Canc Inst Boston, Dept Med Oncol, Boston, MA 02215 USA. EM reomaru@sapmed.ac.jp; kornelia_polyak@dfci.harvard.edu OI Szallasi, Zoltan/0000-0001-5395-7509; Krzystanek, Marcin/0000-0002-5920-2147 FU US Army Congressionally Directed Research Program [BC084006, BC134001, BC087579]; Danish Cancer Society; Susan G. Komen Foundation; Kraeftens Bekaempelse FX We thank members of our laboratories for their critical reading of this manuscript and useful discussions and the Cytogenetics Core of Dana-Farber Harvard Cancer Center (P30 CA006516) for the SKY studies. This work was supported by the US Army Congressionally Directed Research Program BC084006 and BC134001 (K.P.) and BC087579 (A.M.), Kraeftens Bekaempelse, the Danish Cancer Society (M.K.), and the Susan G. Komen Foundation (R.M. and Y.S.). NR 39 TC 14 Z9 14 U1 0 U2 8 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 JUN 16 PY 2015 VL 11 IS 10 BP 1549 EP 1563 DI 10.1016/j.celrep.2015.05.011 PG 15 WC Cell Biology SC Cell Biology GA CK6XM UT WOS:000356372100007 PM 26051943 ER PT J AU Pritchard, LK Vasiljevic, S Ozorowski, G Seabright, GE Cupo, A Ringe, R Kim, HJ Sanders, RW Doores, KJ Burton, DR Wilson, IA Ward, AB Moore, JP Crispin, M AF Pritchard, Laura K. Vasiljevic, Snezana Ozorowski, Gabriel Seabright, Gemma E. Cupo, Albert Ringe, Rajesh Kim, Helen J. Sanders, Rogier W. Doores, Katie J. Burton, Dennis R. Wilson, Ian A. Ward, Andrew B. Moore, John P. Crispin, Max TI Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers SO CELL REPORTS LA English DT Article ID N-GLYCAN RECOGNITION; NEUTRALIZING ANTIBODIES; GLYCOPROTEIN GP120; DEPENDENT EPITOPE; ENV TRIMERS; GP41-GP120 INTERFACE; GP140 TRIMERS; DC-SIGN; POTENT; BROAD AB A highly glycosylated, trimeric envelope glycoprotein (Env) mediates HIV-1 cell entry. The high density and heterogeneity of the glycans shield Env from recognition by the immune system, but paradoxically, many potent broadly neutralizing antibodies (bNAbs) recognize epitopes involving this glycan shield. To better understand Env glycosylation and its role in bNAb recognition, we characterized a soluble, cleaved recombinant trimer (BG505 SOSIP.664) that is a close structural and antigenic mimic of native Env. Large, unprocessed oligomannose-type structures (Man(8-9)GlcNAc(2)) are notably prevalent on the gp120 components of the trimer, irrespective of the mammalian cell expression system or the bNAb used for affinity purification. In contrast, gp41 subunits carry more highly processed glycans. The glycans on uncleaved, non-native oligomeric gp140 proteins are also highly processed. A homogeneous, oligomannose-dominated glycan profile is therefore a hallmark of a native Env conformation and a potential Achilles' heel that can be exploited for bNAb recognition and vaccine design. C1 [Pritchard, Laura K.; Vasiljevic, Snezana; Seabright, Gemma E.; Crispin, Max] Univ Oxford, Oxford Glycobiol Inst, Dept Biochem, Oxford OX1 3QU, England. [Ozorowski, Gabriel; Kim, Helen J.; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, IAVI Neutralizing Antibody Ctr & Collaborat AIDS, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Cupo, Albert; Ringe, Rajesh; Sanders, Rogier W.; Moore, John P.] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA. [Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Lab Expt Virol,Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Doores, Katie J.] Guys Hosp, Kings & St Thomas Hosp, Kings Coll London, Sch Med, London SE1 9RT, England. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] MIT, Ragon Inst Massachusetts Gen Hosp, Boston, MA 02142 USA. [Burton, Dennis R.] Harvard Univ, Boston, MA 02142 USA. RP Crispin, M (reprint author), Univ Oxford, Oxford Glycobiol Inst, Dept Biochem, South Pk Rd, Oxford OX1 3QU, England. EM max.crispin@bioch.ox.ac.uk RI Ward, Andrew/F-9203-2014; OI Ward, Andrew/0000-0001-7153-3769; Doores, Katie/0000-0002-5507-1725 FU Department of Biochemistry, University of Oxford; NIH HIVRAD grant [P01 AI082362]; International AIDS Vaccine Initiative Neutralizing Antibody Center CAVD grant (Glycan characterization and Outer Domain glycoform design); Scripps CHAVI-ID [1UM1AI100663]; Medical Research Council [MR/K024426/1]; Netherlands Organization for Scientific Research (NWO); European Research Council [ERC-StG-2011-280829-SHEV] FX We dedicate this article in memory of our good friend and greatly admired colleague, Dr. Chris Scanlan. The CN54 gp140 and UG37 gp140 proteins were kindly provided by Professor Quentin Sattentau (University of Oxford). We thank Professor Raymond A. Dwek FRS for constant unwavering support and insightful discussions. L.K.P. was supported by a Scholarship from the Department of Biochemistry, University of Oxford. M.C. is a Fellow of Oriel College, Oxford. This work was supported by NIH HIVRAD grant P01 AI082362, an International AIDS Vaccine Initiative Neutralizing Antibody Center CAVD grant (Glycan characterization and Outer Domain glycoform design), the Scripps CHAVI-ID (1UM1AI100663), and the Medical Research Council MR/K024426/1. R.W.S. is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). J.P.M., R.W.S., A.B.W., I.A.W., and A.C. are listed as inventors on patent applications relating to the general use of BG505 SOSIP.664 trimers and/or their production in stable CHO and 293T cell lines. NR 53 TC 30 Z9 30 U1 2 U2 19 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 JUN 16 PY 2015 VL 11 IS 10 BP 1604 EP 1613 DI 10.1016/j.celrep.2015.05.017 PG 10 WC Cell Biology SC Cell Biology GA CK6XM UT WOS:000356372100011 PM 26051934 ER PT J AU Gursoy-Yuzugullu, O Ayrapetov, MK Price, BD AF Gursoy-Yuzugullu, Ozge Ayrapetov, Marina K. Price, Brendan D. TI Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NHEJ; DSB repair; H2A.Z; Anp32e; genome instability ID REGULATES CHROMATIN COMPACTION; HOMOLOGOUS RECOMBINATION; DAMAGED CHROMATIN; PATHWAY CHOICE; ACETYLATION; SURFACE; METHYLATION; ACTIVATION; VARIANT; H3 AB The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4-Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative non-homologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair. C1 [Gursoy-Yuzugullu, Ozge; Ayrapetov, Marina K.; Price, Brendan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. RP Price, BD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. EM brendan_price@dfci.harvard.edu FU NIH [CA93602, CA64585, CA177884] FX We thank Ali Hamiche for Anp32e cDNA, Ken Kaye for LANA constructs, and Sangamo Biosciences for p84-ZFN. We also thank Jessica Tyler for sharing unpublished data and for insightful discussions and Timur Yusufzai for advice. This work was supported by NIH Grants CA93602, CA64585, and CA177884. NR 51 TC 14 Z9 14 U1 0 U2 11 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 JUN 16 PY 2015 VL 112 IS 24 BP 7507 EP 7512 DI 10.1073/pnas.1504868112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK5GS UT WOS:000356251800053 PM 26034280 ER PT J AU Nunes, P Roth, I Meda, P Feraille, E Brown, D Hasler, U AF Nunes, Paula Roth, Isabelle Meda, Paolo Feraille, Eric Brown, Dennis Hasler, Udo TI Ionic imbalance, in addition to molecular crowding, abates cytoskeletal dynamics and vesicle motility during hypertonic stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE electrolyte; cell volume; hypertonicity; membrane trafficking; mitochondria ID COATED PIT FORMATION; ACTIN-BASED MOTILITY; IN-VITRO; VESICULAR TRAFFICKING; POTASSIUM-DEPLETION; CHLORIDE TRANSPORT; INSULIN-SECRETION; PROTEIN STABILITY; SODIUM-TRANSPORT; MATRIX VOLUME AB Cell volume homeostasis is vital for the maintenance of optimal protein density and cellular function. Numerous mammalian cell types are routinely exposed to acute hypertonic challenge and shrink. Molecular crowding modifies biochemical reaction rates and decreases macromolecule diffusion. Cell volume is restored rapidly by ion influx but at the expense of elevated intracellular sodium and chloride levels that persist long after challenge. Although recent studies have highlighted the role of molecular crowding on the effects of hypertonicity, the effects of ionic imbalance on cellular trafficking dynamics in living cells are largely unexplored. By tracking distinct fluorescently labeled endosome/vesicle populations by live-cell imaging, we show that vesicle motility is reduced dramatically in a variety of cell types at the onset of hypertonic challenge. Live-cell imaging of actin and tubulin revealed similar arrested microfilament motility upon challenge. Vesicle motility recovered long after cell volume, a process that required functional regulatory volume increase and was accelerated by a return of extracellular osmolality to isosmotic levels. This delay suggests that, although volume-induced molecular crowding contributes to trafficking defects, it alone cannot explain the observed effects. Using fluorescent indicators and FRET-based probes, we found that intracellular ATP abundance and mitochondrial potential were reduced by hypertonicity and recovered after longer periods of time. Similar to the effects of osmotic challenge, isovolumetric elevation of intracellular chloride concentration by ionophores transiently decreased ATP production by mitochondria and abated microfilament and vesicle motility. These data illustrate how perturbed ionic balance, in addition to molecular crowding, affects membrane trafficking. C1 [Nunes, Paula; Roth, Isabelle; Meda, Paolo; Feraille, Eric; Hasler, Udo] Univ Geneva Univ Med Ctr, Dept Cellular Physiol & Metab, CH-1211 Geneva 4, Switzerland. [Brown, Dennis] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Brown, Dennis] Harvard Univ, Sch Med, Program Membrane Biol, Boston, MA 02114 USA. [Brown, Dennis] Harvard Univ, Sch Med, Div Nephrol, Boston, MA 02114 USA. RP Nunes, P (reprint author), Univ Geneva Univ Med Ctr, Dept Cellular Physiol & Metab, CH-1211 Geneva 4, Switzerland. EM Paula.Nunes@unige.ch RI Nunes-Hasler, Paula/N-4337-2015 OI Nunes-Hasler, Paula/0000-0002-4598-685X FU Swiss National Science Foundation [31003A_138408/1]; Fondation Schmidheiny; Sir Jules Thorn Charitable Overseas Trust FX This work was supported by Swiss National Science Foundation Grant 31003A_138408/1 and a grant from the Fondation Schmidheiny (to U.H.), as well as a Young Researcher Subsidy from The Sir Jules Thorn Charitable Overseas Trust (to P.N.). NR 83 TC 7 Z9 8 U1 3 U2 17 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 JUN 16 PY 2015 VL 112 IS 24 BP E3104 EP E3113 DI 10.1073/pnas.1421290112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK5GS UT WOS:000356251800006 PM 26045497 ER PT J AU Gao, Y Feng, Y Shen, JK Lin, M Choy, E Cote, GM Harmon, DC Mankin, HJ Hornicek, FJ Duan, ZF AF Gao, Yan Feng, Yong Shen, Jacson K. Lin, Min Choy, Edwin Cote, Gregory M. Harmon, David C. Mankin, Henry J. Hornicek, Francis J. Duan, Zhenfeng TI CD44 is a direct target of miR-199a-3p and contributes to aggressive progression in osteosarcoma SO SCIENTIFIC REPORTS LA English DT Article ID COLON-CANCER CELLS; EPITHELIAL OVARIAN-CANCER; LUNG METASTASIS; EXPRESSION; RESISTANCE; CHEMORESISTANCE; PROLIFERATION; EPIDEMIOLOGY; HYALURONAN; PREDICTOR AB Osteosarcoma is the most common primary bone malignancy in children and adolescents. Herein, we investigated the role of cluster of differentiation 44 (CD44), a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration in osteosarcoma. We constructed a human osteosarcoma tissue microarray with 114 patient tumor specimens, including tumor tissues from primary, metastatic, and recurrent stages, and determined the expression of CD44 by immunohistochemistry. Results showed that CD44 was overexpressed in metastatic and recurrent osteosarcoma as compared with primary tumors. Higher expression of CD44 was found in both patients with shorter survival and patients who exhibited unfavorable response to chemotherapy before surgical resection. Additionally, the 3'-untranslated region of CD44 mRNA was the direct target of microRNA-199a-3p (miR-199a-3p). Overexpression of miR-199a-3p significantly inhibited CD44 expression in osteosarcoma cells. miR-199a-3p is one of the most dramatically decreased miRs in osteosarcoma cells and tumor tissues as compared with normal osteoblast cells. Transfection of miR-199a-3p significantly increased the drug sensitivity through down-regulation of CD44 in osteosarcoma cells. Taken together, these results suggest that the CD44-miR-199a-3p axis plays an important role in the development of metastasis, recurrence, and drug resistance of osteosarcoma. Developing strategies to target CD44 may improve the clinical outcome of osteosarcoma. C1 [Gao, Yan; Feng, Yong; Shen, Jacson K.; Lin, Min; Choy, Edwin; Cote, Gregory M.; Harmon, David C.; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [Gao, Yan; Feng, Yong; Shen, Jacson K.; Lin, Min; Choy, Edwin; Cote, Gregory M.; Harmon, David C.; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Gao, Yan] Zhengzhou Univ, Affiliated Hosp 3, Dept Clin Lab, Zhengzhou 450052, Henan Province, Peoples R China. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Gattegno and Wechsler funds; Kenneth Stanton Fund; Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH) [UO1, CA 151452-01]; Sarcoma SPORE/NIH; Academic Enrichment Fund of MGH Orthopaedics; China Scholarship Council; Excellent Doctorial Dissertations Grant of Zhengzhou University FX This work was supported, in part, by the Gattegno and Wechsler funds, the Kenneth Stanton Fund. Dr. Duan is supported, in part, through a grant from Sarcoma Foundation of America (SFA), a grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA 151452-01, a pilot grant from Sarcoma SPORE/NIH, and a grant from an Academic Enrichment Fund of MGH Orthopaedics. Dr. Gao is supported by scholarship from the China Scholarship Council and Excellent Doctorial Dissertations Grant of Zhengzhou University. The authors also want thank Chungdak Namgyal in the Tissue Microarray and Imaging Core at the Dana-Farber/Harvard Cancer Center for help with the construction of osteosarcoma TMA. NR 39 TC 7 Z9 7 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 16 PY 2015 VL 5 AR 11365 DI 10.1038/srep11365 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK8SY UT WOS:000356509800001 PM 26079799 ER PT J AU Conde, P Rodriguez, M van der Touw, W Jimenez, A Burns, M Miller, J Brahmachary, M Chen, HM Boros, P Rausell-Palamos, F Yun, TJ Riquelme, P Rastrojo, A Aguado, B Stein-Streilein, J Tanaka, M Zhou, L Zhang, JF Lowary, TL Ginhoux, F Park, CG Cheong, C Brody, J Turley, SJ Lira, SA Bronte, V Gordon, S Heeger, PS Merad, M Hutchinson, J Chen, SH Ochando, J AF Conde, Patricia Rodriguez, Mercedes van der Touw, William Jimenez, Ana Burns, Matthew Miller, Jennifer Brahmachary, Manisha Chen, Hui-ming Boros, Peter Rausell-Palamos, Francisco Yun, Tae Jin Riquelme, Paloma Rastrojo, Alberto Aguado, Begona Stein-Streilein, Joan Tanaka, Masato Zhou, Lan Zhang, Junfeng Lowary, Todd L. Ginhoux, Florent Park, Chae Gyu Cheong, Cheolho Brody, Joshua Turley, Shannon J. Lira, Sergio A. Bronte, Vincenzo Gordon, Siamon Heeger, Peter S. Merad, Miriam Hutchinson, James Chen, Shu-Hsia Ochando, Jordi TI DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance SO IMMUNITY LA English DT Article ID COLONY-STIMULATING FACTOR; ADHESION MOLECULE-3-GRABBING NONINTEGRIN; DENDRITIC CELL-FUNCTION; REGULATORY T-CELLS; C-TYPE LECTINS; MOUSE DC-SIGN; SUPPRESSOR-CELLS; IMMUNE-RESPONSES; INFLAMMATORY MONOCYTES; ALLOGRAFT-REJECTION AB Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic. C1 [Conde, Patricia; Burns, Matthew; Heeger, Peter S.; Ochando, Jordi] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10129 USA. [Rodriguez, Mercedes] Inst Salud Carlos III, Ctr Nacl Microbiol, Immunol Trasplantes, Madrid 28220, Spain. [van der Touw, William; Jimenez, Ana; Miller, Jennifer; Chen, Hui-ming; Brody, Joshua; Merad, Miriam; Chen, Shu-Hsia] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10129 USA. [Brahmachary, Manisha] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10129 USA. [Boros, Peter] Icahn Sch Med Mt Sinai, Dept Surg, New York, NY 10129 USA. [Rausell-Palamos, Francisco] Icahn Sch Med Mt Sinai, Diabet Obes & Metab Inst, New York, NY 10129 USA. [Yun, Tae Jin; Cheong, Cheolho] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Riquelme, Paloma; Hutchinson, James] Univ Hosp Regensburg, Dept Surg, D-93053 Regensburg, Germany. [Rastrojo, Alberto; Aguado, Begona] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, E-28049 Madrid, Spain. [Stein-Streilein, Joan] Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst, Boston, MA 02114 USA. [Tanaka, Masato] Tokyo Univ Pharm & Life Sci, Lab Immune Regulat, Tokyo 1920392, Japan. [Zhou, Lan] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Zhang, Junfeng; Lowary, Todd L.] Univ Alberta, Alberta Glyc Ctr, Edmonton, AB T6G 2G2, Canada. [Zhang, Junfeng; Lowary, Todd L.] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada. [Ginhoux, Florent] Agcy Sci Technol & Res, Singapore Immunol Network, Singapore 138648, Singapore. [Park, Chae Gyu] Yonsei Univ, Coll Med, Immunol Lab, Seoul 120752, South Korea. [Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02284 USA. [Lira, Sergio A.] Icahn Sch Med Mt Sinai, Inst Immunol, New York, NY 10129 USA. [Bronte, Vincenzo] Verona Univ Hosp, I-37129 Verona, Italy. [Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 2JD, England. RP Ochando, J (reprint author), Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10129 USA. EM jordi.ochando@mssm.edu RI Rastrojo, Alberto/N-4607-2014; Bronte, Vincenzo/K-7902-2016 OI Rastrojo, Alberto/0000-0003-4381-7267; Bronte, Vincenzo/0000-0002-3741-5141 FU COST Action: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT) [BM1305]; Mount Sinai Recanati/Miller Transplantation Institute developmental funds; AST/Pfizer Basic Science Faculty Development Grant; Ministerio de Educacion y Ciencia [SAF2010-15062, SAF2013-48834-R]; Fundacion Mutua Madrilena grant FX We thank Andres Hidalgo (Centro Nacional de Investigaciones Cardiovasculares, ISCIII) and Emmanuel Gautier (Department of Pathology & Immunology, Washington University) for critical review of the manuscript. We acknowledge the technical contributions of the Flow Cytometry, Microsurgery, and the Biorepository/Pathology Centers of Research Excellence at Mount Sinai, and the Alberta Glycomics Centre for their help on the LNFPIII synthesis. Acknowledgments to Marcy Kuentzel and Sridar Chittur at the University of Albany Center for Functional Genomics Microarray Core facility for their assistance in generating the microarray data. This work was supported by the COST Action BM1305: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT), the Mount Sinai Recanati/Miller Transplantation Institute developmental funds, AST/Pfizer Basic Science Faculty Development Grant, Ministerio de Educacion y Ciencia SAF2010-15062, SAF2013-48834-R, and Fundacion Mutua Madrilena grants to J.O. A portion of this work appears as part of the doctoral thesis of P.C. NR 54 TC 19 Z9 20 U1 5 U2 16 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 JUN 16 PY 2015 VL 42 IS 6 BP 1143 EP 1158 DI 10.1016/j.immuni.2015.05.009 PG 16 WC Immunology SC Immunology GA CK6UC UT WOS:000356362800018 PM 26070485 ER PT J AU Ganda, OP AF Ganda, Om P. TI Clinician Understanding of Cholesterol Treatment Guidelines Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Harvard Univ, Joslin Diabet Ctr, Sch Med, Boston, MA 02215 USA. RP Ganda, OP (reprint author), Harvard Univ, Joslin Diabet Ctr, Sch Med, 1 Joslin Pl, Boston, MA 02215 USA. EM om.ganda@joslin.harvard.edu NR 2 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 JUN 16 PY 2015 VL 313 IS 23 BP 2382 EP 2382 DI 10.1001/jama.2015.5526 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CK5XE UT WOS:000356300200032 PM 26080351 ER PT J AU Costine, B Smith, C Price, G Taylor, S Duhaime, AC AF Costine, Beth Smith, Colin Price, George Taylor, Sabrina Duhaime, Ann-Christine TI FIX THE LESION OR KEEP BRAIN DEVELOPMENT GOING? NEUROBLAST PATTERNS AFTER TBI IN THE IMMATURE GYRENCEPHALIC BRAIN SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Pediatric TBI; Neurogenesis; Cortical Impact; Swine C1 [Costine, Beth; Smith, Colin; Price, George; Taylor, Sabrina; Duhaime, Ann-Christine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA A8-04 BP A39 EP A40 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000104 ER PT J AU Costine, B Smith, C Shifman, M McGuone, D Dodge, C Duhaime, AC AF Costine, Beth Smith, Colin Shifman, Monica McGuone, Declan Dodge, Carter Duhaime, Ann-Christine TI LARGE-ANIMAL COMBINED INSULT MODEL FOR INFLICTED BRAIN INJURY IN INFANCY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Abusive Head Trauma; Seizures; Brain Pathology; Swine C1 [Costine, Beth; Smith, Colin; Shifman, Monica; McGuone, Declan; Dodge, Carter; Duhaime, Ann-Christine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA A4-04 BP A28 EP A28 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000071 ER PT J AU Duhaime, AC AF Duhaime, Ann-Christine TI LONG TERM FUNCTIONAL OUTCOMES AFTER HEMICRANIECTOMY FOR TRAUMA SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Surgery; Decompression; Craniotomy; Outcome C1 [Duhaime, Ann-Christine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Neurosurg, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA AANS04-01 BP A129 EP A129 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000353 ER PT J AU Harris, J Browne, KD Wolf, JA Smith, DH Duda, JE Cullen, DK AF Harris, James Browne, Kevin D. Wolf, John A. Smith, Douglas H. Duda, John E. Cullen, D. Kacy TI NEURONAL PLASMALEMMAL PERMEABILITY/DENDRITIC BEADING IN THE HIPPOCAMPUS FOLLOWING DIFFUSE BRAIN INJURY IN SWINE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE traumatic brain injury; biomechanics; plasma membrane; cell permeability C1 [Harris, James; Browne, Kevin D.; Wolf, John A.; Duda, John E.; Cullen, D. Kacy] Philadelphia Vet Affairs Med Ctr, Ctr Neurotrauma Neurodegenerat & Restorat, Philadelphia, PA USA. [Harris, James; Browne, Kevin D.; Wolf, John A.; Smith, Douglas H.; Cullen, D. Kacy] Univ Penn, Ctr Brain Injury & Repair, Dept Neurosurg, Philadelphia, PA 19104 USA. [Duda, John E.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA T1-13 BP A6 EP A6 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000014 ER PT J AU Koch, P Tekriwal, A Ulyanova, A Grovola, M Cullen, DK Wolf, J AF Koch, Paul Tekriwal, Anand Ulyanova, Alexandra Grovola, Micheal Cullen, D. Kacy Wolf, John TI CHRONIC NEUROPHYSIOLOGICAL RECORDING OF THE HIPPOCAMPUS IN AWAKE BEHAVING SWINE AFTER DIFFUSE BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE electrophysiology; behavior; rotational injury; mild TBI C1 [Koch, Paul; Tekriwal, Anand; Ulyanova, Alexandra; Grovola, Micheal; Cullen, D. Kacy; Wolf, John] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Grovola, Micheal; Cullen, D. Kacy; Wolf, John] Philadelphia VA Med Ctr, Dept Neurosurg, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA S10-02 BP A10 EP A10 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000023 ER PT J AU Osier, N Yan, HQ Ma, XC Mondello, S Empey, P Poloyac, S Feldman, K Wang, K Hayes, R Kochanek, PM Dixon, CE AF Osier, Nicole Yan, Hong Q. Ma, Xiecheng Mondello, Stefania Empey, Philip Poloyac, Samuel Feldman, Keri Wang, Kevin Hayes, Ronald Kochanek, Patrick M. Dixon, C. Edward TI EVALUATION OF KOLLIDON VA-64 IN THE CONTROLLED CORTICAL IMPACT MODEL OF TRAUMATIC BRAIN INJURY: AN OBTT CONSORTIUM STUDY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE traumatic brain injury; neuroprotection; consortium; rat C1 [Yan, Hong Q.; Ma, Xiecheng; Dixon, C. Edward] UPitt, Neurosurg, Pittsburgh, PA USA. [Osier, Nicole] UPitt, SON, Pittsburgh, PA USA. [Osier, Nicole; Yan, Hong Q.; Ma, Xiecheng; Feldman, Keri; Kochanek, Patrick M.] UPitt, SCRR, Pittsburgh, PA USA. [Empey, Philip; Poloyac, Samuel] UPitt, Pharm, Pittsburgh, PA USA. [Mondello, Stefania; Hayes, Ronald] Banyan Biomarker LLC, Alachua, FL USA. [Feldman, Keri; Kochanek, Patrick M.] UPitt, CCM, Pittsburgh, PA USA. [Dixon, C. Edward] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Wang, Kevin] Univ Florida, Med, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA D8-19 BP A120 EP A120 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000326 ER PT J AU Rabiei, K Murphy, S Costine, B Caruso, P Shifman, M Duhaime, AC AF Rabiei, Katrin Murphy, Sarah Costine, Beth Caruso, Paul Shifman, Monica Duhaime, Ann-Christine TI MRI FINDINGS IN ACUTE TBI: INTER-RATER RELIABILITY USING NIH COMMON DATA ELEMENTS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Concussion; diffuse correlation spectroscopy; cerebral blood flow; mice C1 [Rabiei, Katrin; Murphy, Sarah; Costine, Beth; Caruso, Paul; Shifman, Monica; Duhaime, Ann-Christine] Harvard Univ, Massachusetts Gen Hosp, Pediat Neurosurg, Boston, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-09 BP A61 EP A61 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000163 ER PT J AU Schwarzschild, M AF Schwarzschild, Michael TI URATE - A NOVEL POTENTIAL THERAPY IN CNS INJURY AND NEURODEGENERATION SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Urate; Inosine; Nrf-2; Parkinson's disease; TBI; stroke C1 [Schwarzschild, Michael] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA S14-03 BP A150 EP A150 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000424 ER PT J AU Smith, DH Hicks, RR Johnson, VE Cummings, DM Bergstrom, DA Noble, LJ Hovda, D Whalen, M Ahlers, ST LaPlaca, M Tortella, FC Duhaime, AC Dixon, CE AF Smith, Douglas H. Hicks, Ramona R. Johnson, Victoria E. Cummings, Diana M. Bergstrom, Debra A. Noble, Linda J. Hovda, David Whalen, Michael Ahlers, Stephen T. LaPlaca, Michelle Tortella, Frank C. Duhaime, Ann-Christine Dixon, C. Edward TI PRECLINICAL TRAUMATIC BRAIN INJURY COMMON DATA ELEMENTS: TOWARDS A COMMON LANGUAGE ACROSS LABORATORIES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Modeling C1 [Smith, Douglas H.; Johnson, Victoria E.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Hicks, Ramona R.; Cummings, Diana M.; Bergstrom, Debra A.] NINDS, NIH, Bethesda, MD 20892 USA. [Hicks, Ramona R.] One Mind, Leadership Team, Seattle, WA USA. [Noble, Linda J.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Hovda, David] Univ Calif Los Angeles, Neurosurg, Los Angeles, CA USA. [Whalen, Michael] Massachusetts Gen Hosp, Neurosci Ctr, Charlestown, MA USA. [Ahlers, Stephen T.] Naval Med Res Ctr, Operat & Undersea Med, Silver Spring, MD USA. [LaPlaca, Michelle] Georgia Tech, Atlanta, GA USA. [LaPlaca, Michelle] Emory Univ, Biomed Engn, Atlanta, GA 30322 USA. [Tortella, Frank C.] Walter Reed Army Inst Res, Brain Trauma Neuroprotect & Neurorestorat, Silver Spring, MD USA. [Duhaime, Ann-Christine] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Dixon, C. Edward] Univ Pittsburgh, Dept Neurol Surg, Pittsburg, KS USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA PL07-03 BP A135 EP A135 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000375 ER PT J AU Ulyanova, A Lee, JH Brem, S Lucas, T O'Rourke, D Grovola, M Wang, JH Na, YJ Singh, J Smith, D Kim, J Eberwine, J Sul, JY Grady, S Wolf, J AF Ulyanova, Alexandra Lee, Jae-Hee Brem, Steven Lucas, Timothy O'Rourke, Donald Grovola, Michael Wang, Jinhui Na, Youngji Singh, Jennifer Smith, Douglas Kim, Junhyong Eberwine, James Sul, Jai-Yoon Grady, Sean Wolf, John TI ELECTROPHYSIOLOGICAL PHENOTYPING OF HUMAN NEURONS IN SLICES AND DISSOCIATED CULTURE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE TBI; adult human neurons; electrophysiology; single cell mRNA analysis C1 [Ulyanova, Alexandra; Brem, Steven; Lucas, Timothy; O'Rourke, Donald; Grovola, Michael; Smith, Douglas; Grady, Sean; Wolf, John] Univ Penn, Neurosurg, Philadelphia, PA 19104 USA. [Wolf, John] Philadelphia VA Med Ctr, Neurosurg, Philadelphia, PA USA. [Lee, Jae-Hee; Wang, Jinhui; Singh, Jennifer; Eberwine, James; Sul, Jai-Yoon] Univ Penn, Pharmacol, Philadelphia, PA 19104 USA. [Na, Youngji; Kim, Junhyong] Univ Penn, Biol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA C6-03 BP A85 EP A86 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000231 ER PT J AU Whalen, M Buckley, E Sadeghian, H Golinski, J McAllister, L Franceschini, M AF Whalen, Michael Buckley, Erin Sadeghian, Homa Golinski, Julianne McAllister, Lauren Franceschini, Maria TI DECREASED CEREBRAL BLOOD FLOW IS ASSOCIATED WITH WORSE COGNITIVE OUTCOME AFTER REPETITIVE CONCUSSIONS IN MICE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Concussion; diffuse correlation spectroscopy; cerebral blood flow; mice C1 [Whalen, Michael; Buckley, Erin; Sadeghian, Homa; Golinski, Julianne; McAllister, Lauren; Franceschini, Maria] Massachusetts Gen Hosp, Pediat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-08 BP A61 EP A61 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000162 ER PT J AU Malik, N Vollmer, S Nanda, SK Lopez-Pelaez, M Prescott, A Gray, N Cohen, P AF Malik, Nazma Vollmer, Stefan Nanda, Sambit Kumar Lopez-Pelaez, Marta Prescott, Alan Gray, Nathanael Cohen, Philip TI Suppression of interferon beta gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members SO BIOCHEMICAL JOURNAL LA English DT Article DE BI-2536; bromodomain and extra-terminal; histone; interferon; Polo-like kinase; Toll-like receptor ID DOUBLE-STRANDED-RNA; HERPES-SIMPLEX ENCEPHALITIS; KAPPA-B; KINASE 1; P-TEFB; ESSENTIAL COMPONENTS; REGULATORY FACTOR-7; POSITIVE FEEDBACK; SOLID TUMORS; IKK-EPSILON AB PLK (Polo-like kinase) inhibitors, such as BI-2536, have been reported to suppress IFNB (encoding IFN beta, interferon beta) gene transcription induced by ligands that activate TLR3 (Toll-like receptor 3) and TLR4. In the present study, we found that BI-2536 is likely to exert this effect by preventing the interaction of the transcription factors IRF3 (interferon-regulatory factor 3) and c-Jun with the IFNB promoter, but without affecting the TBK1 {TANK [ TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor kappa B activator]-binding kinase 1}-catalysed phosphorylation of IRF3 at Ser(396), the dimerization and nuclear translocation of IRF3 or the phosphorylation of c-Jun andATF2 (activating transcription factor 2). Although BI-2536 inhibits few other kinases tested, it interacts with BET (bromodomain and extra-terminal) family members and displaces them from acetylated lysine residues on histones. We found that BET inhibitors that do not inhibit PLKs phenocopied the effect of BI-2536 on IFNB gene transcription. Similarly, BET inhibitors blocked the interaction of IRF5 with the IFNB promoter and the secretion of IFN beta induced by TLR7 or TLR9 ligands in the human plasmacytoid dendritic cell line GEN2.2, but without affecting the nuclear translocation of IRF5. We found that the BET family member BRD4 (bromodomain-containing protein 4) was associated with the IFNB promoter and that this interaction was enhanced by TLR3-or TLR4-ligation and prevented by BI2536 and other BET inhibitors. Our results establish that BET family members are essential for TLR-stimulated IFNB gene transcription by permitting transcription factors to interact with the IFNB promoter. They also show that the interaction of the IFNB promoter with BRD4 is regulated by TLR ligation and that BI-2536 is likely to suppress IFNB gene transcription by targeting BET family members. C1 [Malik, Nazma; Vollmer, Stefan; Nanda, Sambit Kumar; Lopez-Pelaez, Marta; Cohen, Philip] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. [Prescott, Alan] Univ Dundee, Coll Life Sci, Div Cell Signalling & Immunol, Dundee DD1 5EH, Scotland. [Gray, Nathanael] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. RP Cohen, P (reprint author), Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dow St, Dundee DD1 5EH, Scotland. EM p.cohen@dundee.ac.uk FU Wellcome Trust [WT100294]; Medical Research Council [MRC_MR/K000985/1]; AstraZeneca; Boehringer Ingelheim; GlaxoSmithKline; Janssen Pharmaceutica; Merck-Serono; Pfizer; MRC Protein Phosphorylation and Ubiquitylation Unit FX This research was supported by the Wellcome Trust [grant number WT100294], the Medical Research Council [grant number MRC_MR/K000985/1], AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck-Serono and Pfizer. N.M. is the recipient of a Prize Studentship from the MRC Protein Phosphorylation and Ubiquitylation Unit. NR 52 TC 1 Z9 1 U1 2 U2 6 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUN 15 PY 2015 VL 468 BP 363 EP 372 DI 10.1042/BJ20141523 PN 3 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CQ9WS UT WOS:000360966500002 PM 25891802 ER PT J AU Steere, AC Arvikar, SL AF Steere, Allen C. Arvikar, Sheila L. TI What Constitutes Appropriate Treatment of Post-Lyme Disease Symptoms and Other Pain and Fatigue Syndromes? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE Lyme disease; post-Lyme disease symptoms; pain and fatigue syndromes; treatment ID ERYTHEMA MIGRANS; CONTROLLED-TRIAL; TAI CHI; FIBROMYALGIA; THERAPY; TARGET C1 [Steere, Allen C.; Arvikar, Sheila L.] Harvard Univ, Sch Med, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis,Massachusetts Gen, Boston, MA USA. RP Steere, AC (reprint author), Massachusetts Gen Hosp, CNY 149-8301,55 Fruit St, Boston, MA 02114 USA. EM asteere@mgh.harvard.edu FU NIAID NIH HHS [AI-101175] NR 20 TC 1 Z9 1 U1 4 U2 12 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 JUN 15 PY 2015 VL 60 IS 12 BP 1783 EP 1785 DI 10.1093/cid/civ187 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CN0BC UT WOS:000358075800009 PM 25852123 ER PT J AU Yuh, B Tate, J Butt, AA Crothers, K Freiberg, M Leaf, D Logeais, M Rimland, D Rodriguez-Barradas, MC Ruser, C Justice, AC AF Yuh, Bianca Tate, Janet Butt, Adeel A. Crothers, Kristina Freiberg, Matthew Leaf, David Logeais, Mary Rimland, David Rodriguez-Barradas, Maria C. Ruser, Christopher Justice, Amy C. TI Weight Change After Antiretroviral Therapy and Mortality SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; veterans; weight; antiretroviral therapy; BMI ID BODY-MASS INDEX; CORONARY-ARTERY-DISEASE; HIV-INFECTED PATIENTS; OBESITY PARADOX; MITOCHONDRIAL TOXICITY; HEART-FAILURE; COHORT; OUTCOMES; IMPACT; GAIN AB Background. Weight gain after antiretroviral therapy (ART) initiation is common, but its implication for mortality is unknown. We evaluated weight change in the first year after ART initiation and its association with subsequent mortality. Methods. Human immunodeficiency virus-infected patients from the Veterans Aging Cohort Study (VACS) who initiated ART between 2000 and 2008, with weight recorded at baseline and 1 year later, were followed another 5 years for mortality. Baseline body mass index (BMI) was classified as underweight (<18.5 kg/m(2)), normal (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (>= 30 kg/m(2)). We used multivariable Cox models to assess mortality risk with adjustment for disease severity using the VACS Index. Results. The sample consisted of 4184 men and 127 women with a mean age of 47.9 +/- 10.0 years. After 1 year of ART, median weight change was 5.9 pounds (2.7 kg) (interquartile range, -2.9 to 17.0 pounds, -1.3 to 7.7 kg). Weight gain after ART initiation was associated with lower mortality among underweight and normal-weight patients. A minimum threshold of 10- to 19.9-pound (4.5 to 9.0 kg) weight gain was beneficial for normal-weight patients (hazard ratio, 0.56; 95% confidence interval, .41-.78), but there was no clear benefit to weight gain for overweight/obese patients. Baseline weight, CD4 cell count status, and hemoglobin level were strongly associated with weight gain. Risk for weight gain was higher among those with greater disease severity, regardless of weight at initiation. Conclusions. The survival benefits of weight gain after ART initiation are dependent on starting BMI. Weight gain after ART is associated with lower mortality for those who are not initially overweight. C1 [Yuh, Bianca; Tate, Janet; Ruser, Christopher; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Tate, Janet; Ruser, Christopher; Justice, Amy C.] Vet Affairs VA Connecticut Healthcare Syst, West Haven, CT USA. [Butt, Adeel A.; Freiberg, Matthew] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Butt, Adeel A.; Freiberg, Matthew] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Crothers, Kristina] Univ Washington, Sch Med, Seattle, WA USA. [Leaf, David] UCLA Sch Med, San Francisco, CA USA. [Leaf, David] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. [Logeais, Mary] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Rimland, David] Atlanta VA Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Rodriguez-Barradas, Maria C.] Michael E Debakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. RP Tate, J (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06416 USA. EM janet.tate2@va.gov OI Butt, Adeel/0000-0002-1118-1826; Justice, Amy/0000-0003-0139-5502 FU National Institutes of Health (NIH): National Institute on Alcohol Abuse and Alcoholism [U10-AA13566]; National Heart, Lung, and Blood Institute [R01-HL095136, R01-HL090342, RCI-HL100347]; National Institute on Aging [R01-AG029154, K23 AG024896]; National Center for Advancing Translational Sciences of the NIH [TL1TR000141] FX This work was supported by the National Institutes of Health (NIH): National Institute on Alcohol Abuse and Alcoholism (grant number U10-AA13566), National Heart, Lung, and Blood Institute (grant number R01-HL095136, R01-HL090342, and RCI-HL100347), and National Institute on Aging (grant number R01-AG029154, K23 AG024896). Additional funding for this work includes the National Center for Advancing Translational Sciences of the NIH (grant number TL1TR000141 to B. Y.). NR 41 TC 11 Z9 12 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2015 VL 60 IS 12 BP 1852 EP 1859 DI 10.1093/cid/civ192 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CN0BC UT WOS:000358075800021 PM 25761868 ER PT J AU Maheswaran, S Haber, DA AF Maheswaran, Shyamala Haber, Daniel A. TI Ex Vivo Culture of CTCs: An Emerging Resource to Guide Cancer Therapy SO CANCER RESEARCH LA English DT Review ID CIRCULATING TUMOR-CELLS; BREAST-CANCER; LUNG-CANCER; ORGANOID CULTURES; PROSTATE-CANCER; BLOOD; CULTIVATION; METASTASIS; MUTATIONS; MODEL AB With increasing application of targeted therapies and the development of acquired resistance, much attention is being focused on developing in vitro and in vivo patient-specific tumor models for individualized therapeutic evaluation of cancers. Circulating tumor cells provide a source of noninvasively and sequentially sampled invasive cancer cells suitable for propagation in vitro. We review the advantages and challenges associated with ex vivo culture of tumor cells circulating in the blood of patients with cancer. (C) 2015 AACR. C1 [Maheswaran, Shyamala; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Maheswaran, Shyamala; Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Maheswaran, S (reprint author), Massachusetts Gen Hosp, Bldg 149,13th St, Charlestown, MA 02129 USA. EM maheswaran@helix.mgh.harvard.edu; haber@helix.mgh.harvard.edu FU Breast Cancer Research Foundation; Stand Up to Cancer; Wellcome Trust; National Foundation for Cancer Research; NIH [CA129933]; NIBIB [EB008047]; Susan G. Komen for the Cure [KG09042]; NCI-MGH Proton Federal Share Program; Howard Hughes Medical Institute; Stand Up To Cancer Dream Team Translational Research Grant [SU2C-AACR-DT0309] FX This work was supported by grants from the Breast Cancer Research Foundation (D.A. Haber), Stand Up to Cancer (D.A. Haber, Mehmet Toner, S. Maheswaran), the Wellcome Trust (D.A. Haber), the National Foundation for Cancer Research (D.A. Haber), NIH CA129933 (D.A. Haber), NIBIB EB008047 (Mehmet Toner, D.A. Haber), Susan G. Komen for the Cure KG09042 (S. Maheswaran), NCI-MGH Proton Federal Share Program (S. Maheswaran), and the Howard Hughes Medical Institute (D.A. Haber). Research was also supported by a Stand Up To Cancer Dream Team Translational Research Grant SU2C-AACR-DT0309 (D.A. Haber, Mehmet Toner, S. Maheswaran). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. NR 39 TC 14 Z9 14 U1 2 U2 26 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 JUN 15 PY 2015 VL 75 IS 12 BP 2411 EP 2415 DI 10.1158/0008-5472.CAN-15-0145 PG 5 WC Oncology SC Oncology GA CL9YG UT WOS:000357334400002 PM 25998619 ER PT J AU Gainor, JF Tan, DSW De Pas, T Solomon, BJ Ahmad, A Lazzari, C de Marinis, F Spitaleri, G Schultz, K Friboulet, L Yeap, BY Engelman, JA Shaw, AT AF Gainor, Justin F. Tan, Daniel S. W. De Pas, Tomasso Solomon, Benjamin J. Ahmad, Aziah Lazzari, Chiara de Marinis, Filippo Spitaleri, Gianluca Schultz, Katherine Friboulet, Luc Yeap, Beow Y. Engelman, Jeffrey A. Shaw, Alice T. TI Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; CHRONIC MYELOID-LEUKEMIA; IMATINIB; RESISTANCE; CHEMOTHERAPY; INHIBITION; CH5424802; EML4-ALK; SAFETY AB Purpose: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents. Experimental Design: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib. Results: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4-10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1-694). The mPFS on ceritinib was 7.8 months (6.5-9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4-9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5-19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5-63.1). Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC-even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. (C) 2015 AACR. C1 [Gainor, Justin F.; Schultz, Katherine; Friboulet, Luc; Yeap, Beow Y.; Engelman, Jeffrey A.; Shaw, Alice T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tan, Daniel S. W.; Ahmad, Aziah] Natl Canc Ctr, Div Med Oncol, Singapore, Singapore. [Tan, Daniel S. W.; Ahmad, Aziah] Genome Inst Singapore, Singapore, Singapore. [De Pas, Tomasso; Lazzari, Chiara; de Marinis, Filippo; Spitaleri, Gianluca] Ist Europeo Oncol, Dept Med, Milan, Italy. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Dept Med Oncol, East Melbourne, Australia. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM ashaw1@partners.org RI friboulet, luc/N-7276-2015 OI friboulet, luc/0000-0002-1129-4978 FU U.S. National Institutes of Health [5R01CA164273, 5P50CA090578-10, C06CA059267] FX This work was supported by grants from the U.S. National Institutes of Health 5R01CA164273, 5P50CA090578-10, and C06CA059267. NR 25 TC 42 Z9 45 U1 0 U2 11 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 JUN 15 PY 2015 VL 21 IS 12 BP 2745 EP 2752 DI 10.1158/1078-0432.CCR-14-3009 PG 8 WC Oncology SC Oncology GA CL9YZ UT WOS:000357336600014 PM 25724526 ER PT J AU Roqueiro, D Witteveen, MJ Anttila, V Terwindt, GM van den Maagdenberg, AMJM Borgwardt, K AF Roqueiro, Damian Witteveen, Menno J. Anttila, Verneri Terwindt, Gisela M. van den Maagdenberg, Arn M. J. M. Borgwardt, Karsten TI In silico phenotyping via co-training for improved phenotype prediction from genotype SO BIOINFORMATICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MIGRAINE AB Motivation: Predicting disease phenotypes from genotypes is a key challenge in medical applications in the postgenomic era. Large training datasets of patients that have been both genotyped and phenotyped are the key requisite when aiming for high prediction accuracy. With current genotyping projects producing genetic data for hundreds of thousands of patients, large-scale phenotyping has become the bottleneck in disease phenotype prediction. Results: Here we present an approach for imputing missing disease phenotypes given the genotype of a patient. Our approach is based on co-training, which predicts the phenotype of unlabeled patients based on a second class of information, e.g. clinical health record information. Augmenting training datasets by this type of in silico phenotyping can lead to significant improvements in prediction accuracy. We demonstrate this on a dataset of patients with two diagnostic types of migraine, termed migraine with aura and migraine without aura, from the International Headache Genetics Consortium. Conclusions: Imputing missing disease phenotypes for patients via co-training leads to larger training datasets and improved prediction accuracy in phenotype prediction. C1 [Roqueiro, Damian; Witteveen, Menno J.; Borgwardt, Karsten] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Machine Learning & Computat Biol Lab, Zurich, Switzerland. [Anttila, Verneri] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Anttila, Verneri] Harvard Univ, Sch Med, Boston, MA USA. [Anttila, Verneri] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Anttila, Verneri] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Terwindt, Gisela M.; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [van den Maagdenberg, Arn M. J. M.] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. RP Witteveen, MJ (reprint author), Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Machine Learning & Computat Biol Lab, Zurich, Switzerland. EM menno.witteveen@bsse.ethz.ch; karsten.borgwardt@bsse.ethz.ch OI Anttila, Verneri/0000-0002-0073-4675 FU Alfried Krupp von Bohlen und HalbachStiftung; Marie Curie Initial Training Network MLPM [316861]; EU FP-7 EUROHEADPAIN [602633]; Netherlands Organization for Scientific Research [VIDI 917.11.319] FX This work was funded in part by the Alfried Krupp von Bohlen und HalbachStiftung (K.B.), and the Marie Curie Initial Training Network MLPM2012, Grant No. 316861 (M.J.W., K.B.). Additional funding was obtained from EU FP-7 EUROHEADPAIN (Grant No. 602633) (A.v.d.M.) and by the Netherlands Organization for Scientific Research [VIDI 917.11.319] (G.M.T.) NR 25 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2015 VL 31 IS 12 BP 303 EP 310 DI 10.1093/bioinformatics/btv254 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CL0IO UT WOS:000356625700035 ER PT J AU Rudolf, J Douglass, J Baron, J Lewandrowski, K AF Rudolf, Joseph Douglass, Joseph Baron, Jason Lewandrowski, Kent TI Evaluation of the i-STAT point-of-care capillary whole blood hematocrit and hemoglobin: Comparison to the Siemens RAPIDLab 1200, Sysmex XE5000, and manual spun hematocrit SO CLINICA CHIMICA ACTA LA English DT Article DE Hematocrit; Hemoglobin; Point-of-care; Near patient testing; Method comparison ID CARDIOPULMONARY BYPASS; PROTEIN; BIAS AB Background: Conductivity based point-of-care hematocrit with calculated hemoglobin devices serves an important role in clinical scenarios where time sensitive transfusion decisions are necessary. However, questions about the appropriateness of conductivity based assays in certain patient populations (patients on cardiopulmonary bypass and those receiving high volumes of intravenous fluids or autologous blood transfusions) have been raised. The clinical suitability of POC devices for these applications necessitates that they be accurate and that the results are interchangeable with central laboratory methods. Methods: We performed hematocrit and hemoglobin analysis on 225 clinical samples using the i-STAT instrument, a standard reference method for hematocrit (manual spun) and other common methods on both cardiopulmonary bypass and non-cardiopulmonary bypass patients. Results: The i-STAT hematocrit and hemoglobin showed close agreement to comparison methods with minimal bias Median test results were not clinically or statistically different between those measured on the i-STAT and those measured using the manual spun hematocrit reference method (p = 0.4085, Wilcoxon signed rank test) or the Sysmex photometric hemoglobin method (p = 0.2728, Wilcoxon signed rank test). The results on the i-STAT were statistically different from those obtained on the Sysmex for hematocrit (p < 0.0001) and the Siemens RAPIDLab co-oximeter for hemoglobin (p < 0.0001). Conclusion: The i-STAT hematocrit and hemoglobin performs well when compared to the hematocrit reference method and other common methods for both hematocrit and hemoglobin. Some differences between non-reference methods may be observed, but these were not considered clinically significant (C) 2015 Elsevier B.V. All rights reserved. C1 [Rudolf, Joseph; Douglass, Joseph; Baron, Jason; Lewandrowski, Kent] Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, Boston, MA 02114 USA. [Rudolf, Joseph; Baron, Jason; Lewandrowski, Kent] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lewandrowski, K (reprint author), Massachusetts Gen Hosp, Gray 5 Chem,Fruit St, Boston, MA 02114 USA. EM klewandrowski@partners.org FU Abbott Point-of-Care Inc., Princeton, NJ FX This study was supported by a grant from the Abbott Point-of-Care Inc., Princeton, NJ. NR 17 TC 0 Z9 0 U1 2 U2 5 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 JUN 15 PY 2015 VL 446 BP 37 EP 42 DI 10.1016/j.cca.2015.03.035 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CL2AI UT WOS:000356745600007 PM 25861846 ER PT J AU Arjomandi, M Wong, H Donde, A Frelinger, J Dalton, S Ching, W Power, K Balmes, JR AF Arjomandi, Mehrdad Wong, Hofer Donde, Aneesh Frelinger, Jessica Dalton, Sarah Ching, Wendy Power, Karron Balmes, John R. TI Exposure to medium and high ambient levels of ozone causes adverse systemic inflammatory and cardiac autonomic effects SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE ozone; inhalational exposure; heart rate variability; systemic inflammation; airway inflammation ID HEART-RATE-VARIABILITY; C-REACTIVE PROTEIN; AIR-POLLUTION; METABOLIC SYNDROME; VASCULAR DYSFUNCTION; MEXICO-CITY; EXERCISE; INHALATION; ASTHMA; HYPERRESPONSIVENESS AB Epidemiological evidence suggests that exposure to ozone increases cardiovascular morbidity. However, the specific biological mechanisms mediating ozone-associated cardiovascular effects are unknown. To determine whether short-term exposure to ambient levels of ozone causes changes in biomarkers of cardiovascular disease including heart rate variability (HRV), systemic inflammation, and coagulability, 26 subjects were exposed to 0, 100, and 200 ppb ozone in random order for 4 h with intermittent exercise. HRV was measured and blood samples were obtained immediately before (0 h), immediately after (4 h), and 20 h after (24 h) each exposure. Bronchoscopy with bronchoalveolar lavage (BAL) was performed 20 h after exposure. Regression modeling was used to examine dose-response trends between the endpoints and ozone exposure. Inhalation of ozone induced dose-dependent adverse changes in the frequency domains of HRV across exposures consistent with increased sympathetic tone [increase of (parameter estimate +/- SE) 0.4 +/- 0.2 and 0.3 +/- 0.1 in low-to high-frequency domain HRV ratio per 100 ppb increase in ozone at 4 h and 24 h, respectively (P = 0.02 and P = 0.01)] and a dosedependent increase in serum C-reactive protein (CRP) across exposures at 24 h [increase of 0.61 +/- 0.24 mg/l in CRP per 100 ppb increase in ozone (P = 0.01)]. Changes in HRV and CRP did not correlate with ozone-induced local lung inflammatory responses (BAL granulocytes, IL-6, or IL-8), but changes in HRV and CRP were associated with each other after adjustment for age and ozone level. Inhalation of ozone causes adverse systemic inflammatory and cardiac autonomic effects that may contribute to the cardiovascular mortality associated with short-term exposure. C1 [Arjomandi, Mehrdad; Wong, Hofer; Donde, Aneesh; Frelinger, Jessica; Power, Karron; Balmes, John R.] San Francisco Gen Hosp Med Ctr, Div Occupat & Environm Med, Human Exposure Lab, San Francisco, CA USA. [Arjomandi, Mehrdad; Frelinger, Jessica; Balmes, John R.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Arjomandi, Mehrdad; Frelinger, Jessica; Dalton, Sarah; Ching, Wendy] San Francisco VA Med Ctr, Pulm Res Grp, San Francisco, CA USA. [Balmes, John R.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Arjomandi, M (reprint author), Univ Calif San Francisco Corresponding, San Francisco Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Bldg 203,Rm 3A-128,Mailstop 111-D,4150 Clement St, San Francisco, CA 94121 USA. EM mehrdad.arjomandi@ucsf.edu FU California Air Resources Board (CARB) [04-322]; National Institutes of Health [NIH/NHLBI K23 HL-083099]; Northern California Institute for Research and Education; University of California San Francisco Cardiovascular Research Institute Faculty Development Funds; NIH/NCRR/OD UCSF-CTSI [KL2 RR-024130, UL1 RR-024131] FX This work was supported by California Air Resources Board (CARB Contract No. 04-322); National Institutes of Health Grants NIH/NHLBI K23 HL-083099, NIH/NCRR/OD UCSF-CTSI Grant Number KL2 RR-024130, and UL1 RR-024131; Northern California Institute for Research and Education; and University of California San Francisco Cardiovascular Research Institute Faculty Development Funds. NR 51 TC 6 Z9 6 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN 15 PY 2015 VL 308 IS 12 BP H1499 EP H1509 DI 10.1152/ajpheart.00849.2014 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA CK5NZ UT WOS:000356273200005 PM 25862833 ER PT J AU Pfister, NT Fomin, V Regunath, K Zhou, JY Zhou, W Silwal-Pandit, L Freed-Pastor, WA Laptenko, O Neo, SP Bargonetti, J Bin Tian, MH Gunaratne, J Engebraaten, O Manley, JL Borresen-Dale, AL Neilsen, PM Prives, C AF Pfister, Neil T. Fomin, Vitalay Regunath, Kausik Zhou, Jeffrey Y. Zhou, Wen Silwal-Pandit, Laxmi Freed-Pastor, William A. Laptenko, Oleg Neo, Suat Peng Bargonetti, Jill Bin Tian, Mainul Hoque Gunaratne, Jayantha Engebraaten, Olav Manley, James L. Borresen-Dale, Anne-Lise Neilsen, Paul M. Prives, Carol TI Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells SO GENES & DEVELOPMENT LA English DT Article DE mutant p53; VEGFR2; SWI/SNF; chromatin; transcription; breast cancer; 3D culture ID ENDOTHELIAL GROWTH-FACTOR; LI-FRAUMENI-SYNDROME; PROMOTER IN-VIVO; TUMOR-SUPPRESSOR; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVATION; NUCLEOSOME OCCUPANCY; MOUSE MODELS; WILD-TYPE; GAIN AB Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential. C1 [Pfister, Neil T.; Fomin, Vitalay; Regunath, Kausik; Zhou, Jeffrey Y.; Zhou, Wen; Freed-Pastor, William A.; Laptenko, Oleg; Manley, James L.; Prives, Carol] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Silwal-Pandit, Laxmi; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Inst Canc Res, Dept Genet, Norwegian Radiumhosp, N-0310 Oslo, Norway. [Silwal-Pandit, Laxmi; Engebraaten, Olav; Borresen-Dale, Anne-Lise] Univ Oslo, Inst Clin Med, Fac Med, KG Jebsen Ctr Breast Canc Res, N-0450 Oslo, Norway. [Freed-Pastor, William A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Neo, Suat Peng; Gunaratne, Jayantha] Agcy Sci Technol & Res, Inst Mol & Cell Biol, Quantitat Prote Grp, Singapore 138673, Singapore. [Bargonetti, Jill] CUNY Hunter Coll, Dept Biol Sci, New York, NY 10065 USA. [Bin Tian, Mainul Hoque; Gunaratne, Jayantha] Rutgers New Jersey Med Sch, Dept Microbiol Biochem & Mol Genet, Newark, NJ 07103 USA. [Gunaratne, Jayantha] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore 117597, Singapore. [Engebraaten, Olav] Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway. [Neilsen, Paul M.] Swinburne Univ Technol, Kuching 93350, Sarawak, Malaysia. RP Prives, C (reprint author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. EM clp3@columbia.edu RI Zhou, Wen/A-5763-2010; ASTAR, IMCB/E-2320-2012 OI Zhou, Wen/0000-0002-5496-5815; FU National Institutes of Health grant [CA87497]; National Institutes of Health Medical Scientist Training Program through Columbia University Medical School; Roche Norway FX We thank Ella Freulich for excellent technical assistance, and Lynn Biderman, Yan Zhu, and Masha Poyurovsky as well as other members of the Prives laboratory for helpful discussions. This work was supported by National Institutes of Health grant CA87497 and the National Institutes of Health Medical Scientist Training Program through Columbia University Medical School. The NeoAva study was cosponsored by Roche Norway. N.T.P. designed and performed most of the experiments. K.R., J.Y.Z, W.Z., O.L., and W.A.F.-P. assisted in experiments. L.S.-P., A.-L.B.-D., and O.E. conducted, analyzed, and described the NeoAva study. K.R. performed, analyzed, and described TCGA analysis. J.B. designed doxycycline-inducible cell lines. P.M.N. initiated the mass spectrometry analysis and performed experiments. S.P.N. performed mass spectrometry analysis, which J.G. supervised and described. M.H. and B.T. prepared the RNA-seq library. V.F. performed and analyzed RNA-seq analyses. C.P. supervised the project. N.T.P. and C.P. conceived of the project, designed most of the studies, analyzed the data, and wrote the manuscript. NR 70 TC 18 Z9 18 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2015 VL 29 IS 12 BP 1298 EP 1315 DI 10.1101/gad.263202.115 PG 18 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CL2RN UT WOS:000356792400008 PM 26080815 ER PT J AU Maki, T Maeda, M Uemura, M Lo, EK Terasaki, Y Liang, AC Shindo, A Choi, YK Taguchi, A Matsuyama, T Takahashi, R Ihara, M Arai, K AF Maki, Takakuni Maeda, Mitsuyo Uemura, Maiko Lo, Evan K. Terasaki, Yasukazu Liang, Anna C. Shindo, Akihiro Choi, Yoon Kyung Taguchi, Akihiko Matsuyama, Tomohiro Takahashi, Ryosuke Ihara, Masafumi Arai, Ken TI Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter SO NEUROSCIENCE LETTERS LA English DT Article DE Pericyte; Oligodendrocyte precursor cell; Perivascular niche; White matter ID ADULT BRAIN; STEM-CELLS; RAT CNS; ASTROCYTES; GROWTH; PROLIFERATION; MIGRATION; DISEASE; LINEAGE; ORIGIN AB Pericytes are embedded within basal lamina and play multiple roles in the perivascular niche in brain. Recently, oligodendrocyte precursor cells (OPCs) have also been reported to associate with cerebral endothelium. Is it possible that within this gliovascular locus, there may also exist potential spatial and functional interactions between pericytes and OPCs? Here, we demonstrated that in the perivascular region of cerebral white matter, pericytes and OPCs may attach and support each other. Immunostaining showed that pericytes and OPCs are localized in close contact with each other in mouse white matter at postnatal days 0, 60 and 240. Electron microscopic analysis confirmed that pericytes attached to OPCs via basal lamina in the perivascular region. The close proximity between these two cell types was also observed in postmortem human brains. Functional interaction between pericytes and OPCs was assessed by in vitro media transfer experiments. When OPC cultures were treated with pericyte-conditioned media, OPC number increased. Similarly, pericyte number increased when pericytes were maintained in OPC-conditioned media. Taken together, our data suggest a potential anatomical and functional interaction between pericytes and OPCs in cerebral white matter. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Maki, Takakuni; Lo, Evan K.; Terasaki, Yasukazu; Liang, Anna C.; Shindo, Akihiro; Choi, Yoon Kyung; Arai, Ken] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Boston, MA 02114 USA. [Maki, Takakuni; Lo, Evan K.; Terasaki, Yasukazu; Liang, Anna C.; Shindo, Akihiro; Choi, Yoon Kyung; Arai, Ken] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Maki, Takakuni; Lo, Evan K.; Terasaki, Yasukazu; Liang, Anna C.; Shindo, Akihiro; Choi, Yoon Kyung; Arai, Ken] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Maeda, Mitsuyo; Taguchi, Akihiko] Inst Biomed Res & Innovat, Dept Regenerat Med, Kobe, Hyogo, Japan. [Uemura, Maiko; Takahashi, Ryosuke] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto 6068501, Japan. [Matsuyama, Tomohiro] Hyogo Coll Med, Inst Adv Med Sci, Lab Neurogenesis & CNS Repair, Kobe, Hyogo, Japan. [Ihara, Masafumi] Natl Cerebral & Cardiovasc Ctr, Dept Stroke & Cerebrovasc Dis, Osaka, 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; Uemura, Maiko/0000-0001-8356-1409 FU National Institutes of Health; Uehara Memorial Foundation; Japan Society for the Promotion of Science FX Supported in part by the National Institutes of Health, the Uehara Memorial Foundation, and the Japan Society for the Promotion of Science. NR 34 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 15 PY 2015 VL 597 BP 164 EP 169 DI 10.1016/j.neulet.2015.04.047 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CK4HY UT WOS:000356186100030 PM 25936593 ER PT J AU Mercer, JL Argus, JP Crabtree, DM Keenan, MM Wilks, MQ Chi, JTA Bensinger, SJ Lavau, CP Wechsler, DS AF Mercer, Jacob L. Argus, Joseph P. Crabtree, Donna M. Keenan, Melissa M. Wilks, Moses Q. Chi, Jen-Tsan Ashley Bensinger, Steven J. Lavau, Catherine P. Wechsler, Daniel S. TI Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis SO PLOS ONE LA English DT Article ID AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA; CLATHRIN-MEDIATED ENDOCYTOSIS; MYELOID-LEUKEMIA CALM; ALZHEIMERS-DISEASE; COATED PITS; RNA INTERFERENCE; UBIQUITIN LIGASE; LIPID RAFTS; PROTEIN; RECEPTOR AB PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer's disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease. C1 [Mercer, Jacob L.; Wechsler, Daniel S.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27705 USA. [Argus, Joseph P.; Bensinger, Steven J.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Mol & Med Pharmacol, Los Angeles, CA USA. [Crabtree, Donna M.; Lavau, Catherine P.; Wechsler, Daniel S.] Duke Univ, Dept Pediat, Div Pediat Hematol Oncol, Durham, NC 27706 USA. [Keenan, Melissa M.; Chi, Jen-Tsan Ashley] Duke Univ, Dept Mol Genet & Microbiol, Durham, NC USA. [Keenan, Melissa M.; Chi, Jen-Tsan Ashley] Duke Univ, Ctr Genom & Computat Biol, Durham, NC USA. [Wilks, Moses Q.] Massachusetts Gen Hosp, Dept Radiol, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. RP Wechsler, DS (reprint author), Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27705 USA. EM dan.wechsler@duke.edu FU National Institutes of Health CBI Grant [T32 GM008469]; University of California Los Angeles Graduate Division (JPA); Sontag Foundation; National Institutes of Health [AI093768]; V Foundation/Applebee's Research Grant; St. Baldrick's Research Grant; Hyundai Hope On Wheels Grant; Schiffman Family Award FX This work was supported by National Institutes of Health CBI Grant (T32 GM008469) and the University of California Los Angeles Graduate Division (JPA); the Sontag Foundation and the National Institutes of Health (AI093768 - SJB); and a V Foundation/Applebee's Research Grant, a St. Baldrick's Research Grant, a Hyundai Hope On Wheels Grant and a Schiffman Family Award (to DSW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 1 Z9 2 U1 1 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 JUN 15 PY 2015 VL 10 IS 6 AR e0129776 DI 10.1371/journal.pone.0129776 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK6HU UT WOS:000356329900102 PM 26075887 ER PT J AU Sheth, SA Iavarone, AT Liebeskind, DS Won, SJ Swanson, RA AF Sheth, Sunil A. Iavarone, Anthony T. Liebeskind, David S. Won, Seok Joon Swanson, Raymond A. TI Targeted Lipid Profiling Discovers Plasma Biomarkers of Acute Brain Injury SO PLOS ONE LA English DT Article ID FIBRILLARY ACIDIC PROTEIN; ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; INFARCT VOLUME; WHITE-MATTER; SPHINGOLIPIDS; INTERVENTION; ASSOCIATION; GUIDELINES; PROGNOSIS AB Prior efforts to identify a blood biomarker of brain injury have relied almost exclusively on proteins; however their low levels at early time points and poor correlation with injury severity have been limiting. Lipids, on the other hand, are the most abundant molecules in the brain and readily cross the blood-brain barrier. We previously showed that certain sphingolipid (SL) species are highly specific to the brain. Here we examined the feasibility of using SLs as biomarkers for acute brain injury. A rat model of traumatic brain injury (TBI) and a mouse model of stroke were used to identify candidate SL species though our mass-spectrometry based lipid profiling approach. Plasma samples collected after TBI in the rat showed large increases in many circulating SLs following injury, and larger lesions produced proportionately larger increases. Plasma samples collected 24 hours after stroke in mice similarly revealed a large increase in many SLs. We constructed an SL score (sum of the two SL species showing the largest relative increases in the mouse stroke model) and then evaluated the diagnostic value of this score on a small sample of patients (n = 14) who presented with acute stroke symptoms. Patients with true stroke had significantly higher SL scores than patients found to have non-stroke causes of their symptoms. The SL score correlated with the volume of ischemic brain tissue. These results demonstrate the feasibility of using lipid biomarkers to diagnose brain injury. Future studies will be needed to further characterize the diagnostic utility of this approach and to transition to an assay method applicable to clinical settings. C1 [Sheth, Sunil A.; Liebeskind, David S.] Univ Calif Los Angeles, Comprehens Stroke Ctr, Los Angeles, CA 90095 USA. [Sheth, Sunil A.; Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Iavarone, Anthony T.] Univ Calif Berkeley, Chem Mass Spectrometry Facil QB3, Berkeley, CA 94720 USA. [Won, Seok Joon; Swanson, Raymond A.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Neurol & Rehabil Serv, San Francisco, CA 94143 USA. [Won, Seok Joon; Swanson, Raymond A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. RP Sheth, SA (reprint author), Univ Calif Los Angeles, Comprehens Stroke Ctr, Los Angeles, CA 90095 USA. EM ssheth@post.harvard.edu FU NIH [NS041421]; Department of Defense (RAS) [W81XWH-13-2-0091]; Department of Veterans Affairs FX This study was supported by the NIH (NS041421), Department of Defense (RAS, grant W81XWH-13-2-0091) and the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 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 JUN 15 PY 2015 VL 10 IS 6 AR e0129735 DI 10.1371/journal.pone.0129735 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK6HU UT WOS:000356329900098 PM 26076478 ER PT J AU Ferguson, BD Tan, YHC Kanteti, RS Liu, R Gayed, MJ Vokes, EE Ferguson, MK Iafrate, AJ Gill, PS Salgia, R AF Ferguson, Benjamin D. Tan, Yi-Hung Carol Kanteti, Rajani S. Liu, Ren Gayed, Matthew J. Vokes, Everett E. Ferguson, Mark K. Iafrate, A. John Gill, Parkash S. Salgia, Ravi TI Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer SO SCIENTIFIC REPORTS LA English DT Article ID AMINO-ACID SUBSTITUTIONS; DRIVER MUTATIONS; CELL-SURVIVAL; PASSENGER MUTATIONS; MISSENSE MUTATIONS; SOMATIC MUTATIONS; PHOSPHORYLATION; ADENOCARCINOMA; EXPRESSION; PREDICTION AB Lung cancer outcomes remain poor despite the identification of several potential therapeutic targets. The EPHB4 receptor tyrosine kinase (RTK) has recently emerged as an oncogenic factor in many cancers, including lung cancer. Mutations of EPHB4 in lung cancers have previously been identified, though their significance remains unknown. Here, we report the identification of novel EPHB4 mutations that lead to putative structural alterations as well as increased cellular proliferation and motility. We also conducted a bioinformatic analysis of these mutations to demonstrate that they are mutually exclusive from other common RTK variants in lung cancer, that they correspond to analogous sites of other RTKs' variations in cancers, and that they are predicted to be oncogenic based on biochemical, evolutionary, and domain-function constraints. Finally, we show that EPHB4 mutations can induce broad changes in the kinome signature of lung cancer cells. Taken together, these data illuminate the role of EPHB4 in lung cancer and further identify EPHB4 as a potentially important therapeutic target. C1 [Ferguson, Benjamin D.; Ferguson, Mark K.] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Tan, Yi-Hung Carol; Kanteti, Rajani S.; Gayed, Matthew J.; Vokes, Everett E.; Salgia, Ravi] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Ferguson, Mark K.; Salgia, Ravi] Univ Chicago, Comprehens Canc Ctr, Chicago, IL 60637 USA. [Liu, Ren; Gill, Parkash S.] Univ So Calif, Dept Med, Div Med Oncol, Los Angeles, CA USA. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Salgia, R (reprint author), Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. EM rsalgia@medicine.bsd.uchicago.edu OI Ferguson, Benjamin/0000-0001-8358-3368 NR 61 TC 3 Z9 3 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 15 PY 2015 VL 5 AR 10641 DI 10.1038/srep10641 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK8QS UT WOS:000356503700001 PM 26073592 ER PT J AU Toba, H Bras, LED Baicu, CF Zile, MR Lindsey, ML Bradshaw, AD AF Toba, Hiroe Bras, Lisandra E. de Castro Baicu, Catalin F. Zile, Michael R. Lindsey, Merry L. Bradshaw, Amy D. TI Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE secreted protein acidic and rich in cysteine; aging; heart; inflammation; macrophage ID CARDIOVASCULAR-DISEASE ENTERPRISES; EXTRACELLULAR-MATRIX; NEUTROPHIL RECRUITMENT; DIASTOLIC DYSFUNCTION; MATRICELLULAR PROTEIN; MAJOR SHAREHOLDERS; HEART-FAILURE; SPARC; FIBROSIS; EXPRESSION AB To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in age-related cardiac inflammation, we studied six groups of mice: young (3-5 mo old), middle-aged (10-12 mo old), and old (18-29 mo old) C57BL/6 wild-type (WT) and SPARC-null (Null) mice (n = 7-10/group). Cardiac function and structure were determined by echocardiography. The left ventricle was used for cytokine gene array and macrophage quantification by immunohistochemistry. Macrophage infiltration increased with age in WT (n = 5-6/group, P < 0.05 for young vs. old), but not in Null. Proinflammatory markers (Ccl5, Cx3cl1, Ccr2, and Cxcr3) increased in middle-aged and old WT, whereas they were increased only in old Null compared with respective young (n = 5-6/group, P < 0.05 for all). These results suggest that SPARC deletion delayed age-related cardiac inflammation. To further assess how SPARC affects inflammation, we stimulated peritoneal macrophages with SPARC (n = 4). SPARC treatment increased expression of proinflammatory macrophage M1 markers and decreased anti-inflammatory M2 markers. Echocardiography (n = 7-10/group) revealed an age-related increase in wall thickness of the left ventricle in WT (0.76 +/- 0.02 mm in young vs. 0.91 +/- 0.03 mm in old; P < 0.05) but not in Null (0.78 +/- 0.01 mm in young vs. 0.84 +/- 0.02 mm in old). In conclusion, SPARC deletion delayed age-related increases in macrophage infiltration and proinflammatory cytokine expression in vivo and in vitro. SPARC acts as an important mediator of age-related cardiac inflammation by increasing the expression of macrophage M1 markers and decreasing M2 markers. C1 [Toba, Hiroe; Bras, Lisandra E. de Castro; Lindsey, Merry L.] Univ Mississippi, Med Ctr, Mississippi Ctr Heart Res, Jackson, MS 39216 USA. [Toba, Hiroe; Bras, Lisandra E. de Castro; Lindsey, Merry L.] Univ Mississippi, Med Ctr, San Antonio Cardiovasc Prote Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Toba, Hiroe] Kyoto Pharmaceut Univ, Div Pathol Sci, Dept Clin Pharmacol, Kyoto 607, Japan. [Bras, Lisandra E. de Castro] E Carolina Univ, Dept Physiol, Greenville, NC USA. [Baicu, Catalin F.; Zile, Michael R.; Bradshaw, Amy D.] Med Univ S Carolina, Dept Med, Div Cardiol, Gazes Cardiac Res Inst, Charleston, SC 29425 USA. [Zile, Michael R.; Bradshaw, Amy D.] Med Ctr, Ralph H Johnson Dept Vet Affairs, Charleston, SC USA. [Lindsey, Merry L.] GV Sonny Montgomery Vet Affairs Med Ctr, Jackson, MS USA. RP Bradshaw, AD (reprint author), Med Univ S Carolina, Dept Med, Div Cardiol, Gazes Cardiac Res Inst, 171 Ashley Ave, Charleston, SC 29425 USA. EM bradshad@musc.edu FU American Heart Association [14SDG1886005]; Biomedical Laboratory Research, Development Service of the Veterans Affairs Office of Research and Development [1I01BX001385, 5I01BX000505]; National Institutes of Health [268201000036C (N01-HV-00244), HL-075360, HL-051971, GM-104357] FX We acknowledge support from the American Heart Association for 14SDG1886005, from the Biomedical Laboratory Research, Development Service of the Veterans Affairs Office of Research and Development Awards 1I01BX001385 and 5I01BX000505, and from the National Institutes of Health for HHSN 268201000036C (N01-HV-00244) for the San Antonio Cardiovascular Proteomics Center, HL-075360, HL-051971, and GM-104357. NR 58 TC 4 Z9 4 U1 2 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JUN 15 PY 2015 VL 308 IS 12 BP C972 EP C982 DI 10.1152/ajpcell.00402.2014 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA CK5DI UT WOS:000356242000003 PM 25877699 ER PT J AU Zhang, YQ Fischer, KE Soto, V Liu, YH Sosnowska, D Richardson, A Salmon, AB AF Zhang, Yiqiang Fischer, Kathleen E. Soto, Vanessa Liu, Yuhong Sosnowska, Danuta Richardson, Arlan Salmon, Adam B. TI Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Obesity; Rotarod; Longevity; Oxidation; Grip strength; Respirometry; Gait ID MN-SUPEROXIDE-DISMUTASE; INSULIN-RESISTANCE; LIFE-SPAN; COGNITIVE IMPAIRMENT; ADIPOSE-TISSUE; HEALTH; MUSCLE; OVEREXPRESSION; RESTRICTION; LONGEVITY AB Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. Published by Elsevier Inc. C1 [Zhang, Yiqiang; Soto, Vanessa; Liu, Yuhong; Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Zhang, Yiqiang] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Salmon, Adam B.] South Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. [Fischer, Kathleen E.] Univ Alabama Birmingham, Dept Biol, Birmingham, AL 35294 USA. [Sosnowska, Danuta; Richardson, Arlan] Univ Oklahoma, Hlth Sci Ctr, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK USA. [Sosnowska, Danuta; Richardson, Arlan] Oklahoma City VA Med Ctr, Oklahoma City, OK USA. RP Salmon, AB (reprint author), 15355 Lambda Dr, San Antonio, TX 78245 USA. EM salmona@uthscsa.edu FU American Federation for Aging Research; Biomedical Laboratory Research & Development Service of the Veteran's Affairs Office of Research and Development [1I01BX000547]; Geriatric Research Education and Clinical Center of the South Texas Veterans Healthcare System FX Animal studies were performed in the Healthspan and Functional Assessment Core of the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging. This research was supported in part by funding from the American Federation for Aging Research (Y.Z. and A.B.S.), the Biomedical Laboratory Research & Development Service of the Veteran's Affairs Office of Research and Development (1I01BX000547 to A.R.) and Geriatric Research Education and Clinical Center of the South Texas Veterans Healthcare System (A.B.S.). NR 45 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2015 VL 576 BP 39 EP 48 DI 10.1016/j.abb.2014.12.018 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CK3LQ UT WOS:000356118000006 PM 25558793 ER PT J AU Kwon, I Choi, S Mittman, B Bharmal, N Liu, HH Vickrey, B Song, S Araiza, D McCreath, H Seeman, T Oh, SM Trejo, L Sarkisian, C AF Kwon, Ivy Choi, Sarah Mittman, Brian Bharmal, Nazleen Liu, Honghu Vickrey, Barbara Song, Sarah Araiza, Daniel McCreath, Heather Seeman, Teresa Oh, Sang-Mi Trejo, Laura Sarkisian, Catherine TI Study protocol of "Worth the Walk": a randomized controlled trial of a stroke risk reduction walking intervention among racial/ethnic minority older adults with hypertension in community senior centers SO BMC NEUROLOGY LA English DT Article DE Seniors; Ethnic minority; Stroke; Primary prevention; Behavioral intervention; Clinical trial ID AMERICAN-HEART-ASSOCIATION; PHYSICAL-ACTIVITY; ETHNIC DISPARITIES; NORTHERN MANHATTAN; ISCHEMIC-STROKE; WARNING SIGNS; SHORT-FORM; HEALTH; KNOWLEDGE; DISEASE AB Background: Stroke disproportionately kills and disables ethnic minority seniors. Up to 30 % of ischemic strokes in the U.S. can be attributed to physical inactivity, yet most Americans, especially older racial/ethnic minorities, fail to participate in regular physical activity. We are conducting a randomized controlled trial (RCT) to test a culturally-tailored community-based walking intervention designed to reduce stroke risk by increasing physical activity among African American, Latino, Chinese, and Korean seniors with hypertension. We hypothesize that the intervention will yield meaningful changes in seniors' walking levels and stroke risk with feasibility to sustain and scale up across the aging services network. Methods/Design: In this randomized single-blind wait-list control study, high-risk ethnic minority seniors are enrolled at senior centers, complete baseline data collection, and are randomly assigned to receive the intervention "Worth the Walk" immediately (N = 120, intervention group) or in 90 days upon completion of follow-up data collection (N = 120, control group). Trained case managers employed by the senior centers implement hour-long intervention sessions twice weekly for four consecutive weeks to the intervention group. Research staff blinded to participants' group assignment collect outcome data from both intervention and wait-list control participants 1 and 3-months after baseline data collection. Primary outcome measures are mean steps/day over 7 days, stroke knowledge, and self-efficacy for reducing stroke risk. Secondary and exploratory outcome measures include selected biological markers of health, healthcare seeking, and health-related quality of life. Outcomes will be compared between the two groups using standard analytic methods for randomized trials. We will conduct a formal process evaluation to assess barriers and facilitators to successful integration of Worth the Walk into the aging services network and to calculate estimated costs to sustain and scale up the intervention. Data collection is scheduled to be completed in December 2016. Discussion: If this RCT demonstrates superior improvements in physical activity and stroke knowledge in the intervention group compared to the control group and is found to be sustainable and scalable, Worth the Walk could serve as a primary stroke prevention model for racial/ethnic communities across the nation. C1 [Kwon, Ivy; Araiza, Daniel; Seeman, Teresa; Sarkisian, Catherine] Univ Calif Los Angeles, Dept Med, Div Geriatr, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Choi, Sarah] Univ Calif Irvine, Nursing Sci, Coll Hlth Sci, Irvine, CA 92697 USA. [Mittman, Brian] VA Greater Angeles Healthcare Syst, Ctr Implementat Practice & Res Support, Sepulveda, CA 91343 USA. [Bharmal, Nazleen] Univ Calif Los Angeles, Div Gen Internal Med, Los Angeles, CA 90095 USA. [Bharmal, Nazleen] Univ Calif Los Angeles, Hlth Serv Res, Los Angeles, CA 90095 USA. [Liu, Honghu] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. [Vickrey, Barbara] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Song, Sarah] Rush Univ, Vasc Neurol, Chicago, IL 60612 USA. [McCreath, Heather] Univ Calif Los Angeles, Geriatr Res Ctr, Div Geriatr, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Oh, Sang-Mi] Amer Stroke Assoc, American Heart Assoc, San Jose, CA 95113 USA. [Trejo, Laura] City Los Angeles Dept Aging, Los Angeles, CA 90012 USA. [Sarkisian, Catherine] GRECC, VA Greater Angeles Healthcare Syst Geriatr, Los Angeles, CA 90073 USA. RP Kwon, I (reprint author), Univ Calif Los Angeles, Dept Med, Div Geriatr, David Geffen Sch Med, 10945 Conte Ave, Los Angeles, CA 90095 USA. EM IKwon@mednet.ucla.edu OI Kwon, Ivy/0000-0003-4160-6546 FU National Institute of Neurological Disorders and Stroke [1U54NS081764]; National Institute on Aging [1K24AG047899-01]; National Institute on Aging UCLA Older Americans Independence Center [P30AG028748]; National Institute on Aging Resource Centers for Minority Aging Research IV/Center for Health Improvement of Minority Elderly III [P30AG021684] FX This work was supported by the National Institute of Neurological Disorders and Stroke [1U54NS081764] and the National Institute on Aging [1K24AG047899-01]. Additional sources of support for this project include the National Institute on Aging UCLA Older Americans Independence Center [P30AG028748] and National Institute on Aging Resource Centers for Minority Aging Research IV/Center for Health Improvement of Minority Elderly III ([2] P30AG021684). NR 58 TC 3 Z9 3 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD JUN 15 PY 2015 VL 15 AR 91 DI 10.1186/s12883-015-0346-9 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA CK2KE UT WOS:000356038400001 PM 26072359 ER PT J AU Vaz-Luis, I Hughes, ME Cronin, AM Rugo, HS Edge, SB Moy, B Theriault, RL Hassett, MJ Winer, EP Lin, NU AF Vaz-Luis, Ines Hughes, Melissa E. Cronin, Angel M. Rugo, Hope S. Edge, Stephen B. Moy, Beverly Theriault, Richard L. Hassett, Michael J. Winer, Eric P. Lin, Nancy U. TI Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional study SO CANCER LA English DT Article DE chemotherapy; stage I; breast cancer; institutional variation; cost ID WOMEN; TRASTUZUMAB; PACLITAXEL; CARCINOMA; OUTCOMES; THERAPY AB BACKGROUNDAmong patients with stage I breast cancer, there is significant uncertainty concerning the optimal threshold at which to consider chemotherapy, and when considered, there is controversy regarding whether to consider non-intensive versus intensive regimens. The authors examined the types and costs of adjuvant chemotherapy received among patients with stage I breast cancer. METHODSThe current study was a prospective cohort study including patients with stage I breast cancer who were treated at a National Comprehensive Cancer Network center from 2000 through 2009. Stage was defined according to the version of the American Joint Committee on Cancer Staging Manual applicable at the time of diagnosis. Stratifying by human epidermal growth factor receptor 2 (HER2), the authors examined the percentage of patients receiving intensive versus non-intensive chemotherapy regimens and the factors associated with type of chemotherapy administered using multivariable logistic regression. Costs of the most common regimens were estimated. RESULTSOf 8907 patients, 33% received adjuvant chemotherapy. Among those individuals, there was an increase in the use of intensive chemotherapy within the last decade, from 31% in 2000 through 2005 to 63% in 2008 through 2009 (including an increase in the use of the combination of docetaxel, carboplatin, and trastuzumab) among patients with HER2-positive disease and from 15% in 2000 through 2005 to 41% in 2008 through 2009 among patients with HER2-negative disease (32% of patients with hormone receptor-positive and 59% of patients with triple-negative disease). Among patients treated with non-intensive regimens, there was an increase in the use of the combination of docetaxel and cyclophosphamide noted, with a decrease in the use of the doxorubicin and cyclophosphamide combination. The choice of regimen varied significantly by institution. The major drivers of cost variation were the incorporation of biologics (eg, trastuzumab) and growth factors, with significant variation even within non-intensive and intensive regimens. CONCLUSIONSOver time, there was an increase in use of intensive regimens among Stage I breast cancer, with striking institutional and cost variations. Cancer 2015;121:1937-1948. (c) 2015 American Cancer Society. Adjuvant chemotherapy use among patients with stage I breast cancer has changed significantly over time. There has been an intensification of treatment and an increase in the use of taxane-based regimens, with a reduction in concomitant anthracycline-based regimens. Striking institutional variations reflect a lack of certainty regarding the optimal regimens for these patients. C1 [Vaz-Luis, Ines; Hughes, Melissa E.; Cronin, Angel M.; Hassett, Michael J.; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Rugo, Hope S.] Univ Calif San Francisco, Dept Med, Div Med Oncol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Edge, Stephen B.] Baptist Canc Ctr, Dept Med Oncol, Memphis, TN USA. [Moy, Beverly] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Theriault, Richard L.] Univ Texas MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX 77030 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Nancy_Lin@dfci.harvard.edu FU Fundacao Para a Ciencia e Tecnologia (The Foundation for Science and Technology) [HMSP-ICS/0004/201]; National Cancer Institute Specialized Program of Research Excellence in Breast Cancer [NIH P50 CA089393]; National Comprehensive Cancer Network; Conquer Cancer Foundation FX Supported by a grant from the Fundacao Para a Ciencia e Tecnologia (The Foundation for Science and Technology) (HMSP-ICS/0004/201), the National Cancer Institute Specialized Program of Research Excellence in Breast Cancer (grant NIH P50 CA089393), the National Comprehensive Cancer Network, and the Conquer Cancer Foundation. NR 17 TC 4 Z9 4 U1 1 U2 3 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 JUN 15 PY 2015 VL 121 IS 12 BP 1937 EP 1948 DI 10.1002/cncr.29310 PG 12 WC Oncology SC Oncology GA CJ8QJ UT WOS:000355768300008 PM 25757412 ER PT J AU Qian, F Fonarow, GC Krim, SR Vivo, RP Cox, M Hannan, EL Shaw, BA Hernandez, AF Eapen, ZJ Yancy, CW Bhatt, DL AF Qian, Feng Fonarow, Gregg C. Krim, Selim R. Vivo, Rey P. Cox, Margueritte Hannan, Edward L. Shaw, Benjamin A. Hernandez, Adrian F. Eapen, Zubin J. Yancy, Clyde W. Bhatt, Deepak L. TI Characteristics, quality of care, and in-hospital outcomes of Asian-American heart failure patients: Findings from the American Heart Association Get With The Guidelines-Heart Failure Program SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Heart failure; Asian-American; Clinical characteristics; Quality of care; Outcome ID CARDIOVASCULAR-DISEASE; PACIFIC ISLANDERS; UNITED-STATES; ETHNIC-GROUPS; STROKE; HEALTH; DISPARITIES; MATTERS; RISK AB Background: Because little was previously known about Asian-American patients with heart failure (HF), we compared clinical profiles, quality of care, and outcomes between Asian-American and non-Hispanic white HF patients using data from the American Heart Association Get With The Guidelines-Heart Failure (GWTG-HF) program. Methods: We analyzed 153,023 HF patients (149,249 whites, 97.5%; 3774 Asian-Americans, 2.5%) from 356 U.S. centers participating in the GWTG-HF program(2005-2012). Baseline characteristics, quality of caremetrics, in-hospital mortality, discharge to home, and length of stay were examined. Results: Relative to white patients, Asian-American HF patients were younger, more likely to be male, uninsured or covered by Medicaid, and recruited in the western region. They had higher prevalence of diabetes, hypertension, and renal insufficiency, but similar ejection fraction. Overall, Asian-American HF patients had comparable quality of care except that they were less likely to receive aldosterone antagonists at discharge (relative risk < RR >, 0.88; 95% confidence interval < CI >, 0.78-0.99), and anticoagulation for atrial fibrillation (RR, 0.91; 95% CI, 0.85-0.97) even after risk adjustment. Compared with white patients, Asian-American patients had comparable risk adjusted in-hospital mortality (RR, 1.11; 95% CI, 0.91-1.35), length of stay > 4 days (RR, 1.01; 95% CI, 0.95-1.08), and were more likely to be discharged to home (RR, 1.08; 95% CI, 1.06-1.11). Conclusions: Despite some differences in clinical profiles, Asian-American patients hospitalized with HF receive very similar quality of care and have comparable health outcomes to their white counterparts. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Qian, Feng; Hannan, Edward L.; Shaw, Benjamin A.] SUNY Albany, Albany, NY 12222 USA. [Fonarow, Gregg C.; Vivo, Rey P.] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. [Krim, Selim R.] Ochsner Clin Fdn, John Ochsner Heart & Vasc Inst, New Orleans, LA USA. [Cox, Margueritte; Hernandez, Adrian F.; Eapen, Zubin J.] Duke Univ, Durham, NC USA. [Yancy, Clyde W.] Northwestern Univ, Chicago, IL USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Brigham & Womens Hosp, Boston, MA USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. RP Qian, F (reprint author), SUNY Albany, Sch Publ Hlth, Dept Hlth Policy Management & Behav, GEC Room 169,One Univ Pl, Rensselaer, NY 12144 USA. EM fqian@albany.edu RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU Abbott; Amarin; AstraZeneca; Bristol-Myers Squibb; Eisai; Ethicon; Forest Laboratories; Ischemix; Medtronic; Pfizer; Roche; Sanofi Aventis; St. Jude Medical; Medicines Company; American Heart Association; American Heart Association Pharmaceutical Roundtable; Merck FX Amgen (modest), Bayer (modest), Janssen (modest), Novartis (significant), and Medtronic (modest). Dr. Edward L. Hannan discloses a grant from Abbott (subcontract with NYU). Dr. Deepak L. Bhatt discloses the following relationships; Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, St. Jude Medical, The Medicines Company;; The Get With The Guidelines-HF program was provided by the American Heart Association. The GWTG-HF program was supported in part through the American Heart Association Pharmaceutical Roundtable and an unrestricted educational grant from Merck. NR 29 TC 2 Z9 2 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUN 15 PY 2015 VL 189 BP 141 EP 147 DI 10.1016/j.ijcard.2015.03.400 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CI9RV UT WOS:000355108300030 PM 25889445 ER PT J AU Graff, RE Pettersson, A Lis, RT DuPre, N Jordahl, KM Nuttall, E Rider, JR Fiorentino, M Sesso, HD Kenfield, SA Loda, M Giovannucci, EL Rosner, B Nguyen, PL Sweeney, CJ Mucci, LA AF Graff, Rebecca E. Pettersson, Andreas Lis, Rosina T. DuPre, Natalie Jordahl, Kristina M. Nuttall, Elizabeth Rider, Jennifer R. Fiorentino, Michelangelo Sesso, Howard D. Kenfield, Stacey A. Loda, Massimo Giovannucci, Edward L. Rosner, Bernard Nguyen, Paul L. Sweeney, Christopher J. Mucci, Lorelei A. CA Transdisciplinary Prostate Canc TI The TMPRSS2:ERG Fusion and Response to Androgen Deprivation Therapy for Prostate Cancer SO PROSTATE LA English DT Article DE TMPRSS2:ERG; androgen deprivation therapy; prostate cancer; prognosis; gene fusion ID CIRCULATING TUMOR-CELLS; ERG EXPRESSION; GENE; REARRANGEMENT; PHYSICIANS; DISCOVERY; RECURRENT; TRIAL; MEN AB BackgroundIn the United States, half of men with prostate cancer harbor the androgen-regulated gene fusion TMPRSS2:ERG. We hypothesized that men with TMPRSS2:ERG positive tumors are more responsive to androgen deprivation therapy (ADT). MethodsWe studied a cohort of 239 men with prostate cancer from the Physicians' Health Study and Health Professionals Follow-up Study who received ADT during their disease course. Fusion status was assessed on available tumor tissue by immunohistochemistry for ERG protein expression. We used Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for assessment of prostate cancer-specific mortality after ADT initiation. ResultsRoughly half of the men had stage T3 or higher tumors at diagnosis and 39% had Gleason 8-10 tumors. During an average follow up of 10.2 years, 42 men died from prostate cancer. There was a non-significant inverse association between positive fusion status and time to death from prostate cancer after ADT (multivariable HR: 0.76; 95% CI: 0.40-1.45). Harboring the TMPRSS2:ERG fusion was associated with a statistically significant lower risk of prostate cancer mortality among men who were treated with orchiectomy (multivariable HR: 0.13; 95% CI: 0.03-0.62), based on 15 events. ConclusionsOur results, combined with those from earlier studies, provide suggestive evidence that men with TMPRSS2:ERG positive tumors may have longer prostate cancer survival after ADT. Larger cohorts are needed for more robust results and to assess whether men with tumors harboring the fusion benefit from treatment with ADT in the (neo) adjuvant or metastatic setting specifically. Prostate 75:897-906, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Graff, Rebecca E.; Pettersson, Andreas; DuPre, Natalie; Jordahl, Kristina M.; Nuttall, Elizabeth; Rider, Jennifer R.; Fiorentino, Michelangelo; Sesso, Howard D.; Kenfield, Stacey A.; Giovannucci, Edward L.; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Graff, Rebecca E.] UCSF, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA. [Lis, Rosina T.; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lis, Rosina T.; Fiorentino, Michelangelo; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Rider, Jennifer R.; Kenfield, Stacey A.; Giovannucci, Edward L.; Rosner, Bernard; Mucci, Lorelei A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Fiorentino, Michelangelo] St Orsola Marcello Malpighi Hosp, Addarii Inst, Pathol Unit, Bologna, Italy. [Sesso, Howard D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Prevent Med, Boston, MA 02115 USA. [Kenfield, Stacey A.] UCSF, Dept Urol, San Francisco, CA 94158 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Sweeney, Christopher J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Graff, RE (reprint author), UCSF, Dept Epidemiol & Biostat, 1450 3rd St,Room 389, San Francisco, CA 94158 USA. EM Rebecca.Graff@ucsf.edu OI Rider, Jennifer/0000-0002-2637-6036 FU Prostate cancer [5P50CA090381]; National Institutes of Health; National Cancer Institute [CA34944, CA136578, CA141298, CA40360, CA097193, PO1 CA055075, UM1CA167552, U01CA098233, HL26490, HL34595, R25 CA098566, R25 CA112355] FX Grant sponsor: Prostate cancer; Grant number: 5P50CA090381; Grant sponsor: The National Institutes of Health and the National Cancer Institute; Grant number: CA34944, CA136578, CA141298, CA40360, CA097193, PO1 CA055075, UM1CA167552, U01CA098233, HL26490, HL34595; Grant sponsor: National Cancer Institute; Grant number: R25 CA098566, R25 CA112355. NR 24 TC 6 Z9 6 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD JUN 15 PY 2015 VL 75 IS 9 BP 897 EP 906 DI 10.1002/pros.22973 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CH7GD UT WOS:000354203000001 PM 25728532 ER PT J AU Haug, U Knudsen, AB Lansdorp-Vogelaar, I Kuntz, KM AF Haug, Ulrike Knudsen, Amy B. Lansdorp-Vogelaar, Iris Kuntz, Karen M. TI Development of new non-invasive tests for colorectal cancer screening: The relevance of information on adenoma detection SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal cancer; screening; blood test; stool test ID SOCIETY-TASK-FORCE; OCCULT BLOOD-TEST; COLLEGE-OF-RADIOLOGY; COST-EFFECTIVENESS; LARGE-INTESTINE; LARGE-BOWEL; COLONOSCOPY SURVEILLANCE; MEDICARE POPULATION; CONSENSUS UPDATE; JOINT GUIDELINE AB Researchers are actively pursuing the development of a new non-invasive test (NIT) for colorectal cancer (CRC) screening as an alternative to fecal occult blood tests (FOBTs). The majority of pilot studies focus on the detection of invasive CRC rather than precursor lesions (i.e., adenomas). We aimed to explore the relevance of adenoma detection for the viability of an NIT for CRC screening by considering a hypothetical test that does not detect adenomas beyond chance. We used the Simulation Model of Colorectal Cancer (SimCRC) to estimate the effectiveness of CRC screening and the lifetime costs (payers' perspective) for a cohort of US 50-years-old persons to whom CRC screening is offered from age 50-75. We compared annual screening with guaiac and immunochemical FOBTs (with sensitivities up to 70 and 24% for CRC and adenomas, respectively) to annual screening with a hypothetical NIT (sensitivity of 90% for CRC, no detection of adenomas beyond chance, specificity and cost similar to FOBTs). Screening with the NIT was not more effective, but was 29-44% more costly than screening with FOBTs. The findings were robust to varying the screening interval, the NIT's sensitivity for CRC, adherence rates favoring the NIT, and the NIT's unit cost. A comparative modelling approach using a model that assumes a shorter adenoma dwell time (MISCAN-COLON) confirmed the superiority of the immunochemical FOBT over an NIT with no ability to detect adenomas. Information on adenoma detection is crucial to determine whether a new NIT is a viable alternative to FOBTs for CRC screening. Current evidence thus lacks an important piece of information to identify marker candidates that hold real promise and deserve further (large-scale) evaluation. What's new? The development of new non-invasive tests (NITs) for colorectal cancer (CRC) screening has centered primarily on improving the detection of invasive disease. But according to this study, whether new NITs are viable alternatives to immunochemical fecal occult blood testsalready established screening tests for CRC-depends also on their ability to detect adenomas, the precursor lesions of CRC. Without that ability, immunochemical fecal occult blood tests retain their superiority over newer NITs, many of which attempt to detect biomarkers in stool or blood. The identification of adenoma-specific markers could be critical to the advance of NITs for CRC screening. C1 [Haug, Ulrike] German Canc Res Ctr, Epidemiol Canc Registry Baden Wuerttemberg, D-69120 Heidelberg, Germany. [Knudsen, Amy B.] Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Boston, MA 02114 USA. [Lansdorp-Vogelaar, Iris] Erasmus Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. RP Haug, U (reprint author), German Canc Res Ctr, Epidemiol Canc Registry Baden Wuerttemberg M110, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM u.haug@dkfz.de OI Haug, Ulrike/0000-0002-1886-2923 FU National Cancer Institute (NCI) [U01 CA 088204, U01 CA 152959]; German Cancer Aid [109421] FX Grant sponsor: National Cancer Institute (NCI); Grant numbers: U01 CA 088204, U01 CA 152959; Grant sponsor: German Cancer Aid; Grant number: 109421 NR 42 TC 4 Z9 4 U1 0 U2 10 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 JUN 15 PY 2015 VL 136 IS 12 BP 2864 EP 2874 DI 10.1002/ijc.29343 PG 11 WC Oncology SC Oncology GA CF8FA UT WOS:000352790300012 PM 25403937 ER PT J AU Quraishi, SA Litonjua, AA Elias, KM Gibbons, FK Giovannucci, E Camargo, CA Christopher, KB AF Quraishi, Sadeq A. Litonjua, Augusto A. Elias, Kevin M. Gibbons, Fiona K. Giovannucci, Edward Camargo, Carlos A., Jr. Christopher, Kenneth B. TI Association between pre-hospital vitamin D status and hospital-acquired new-onset delirium SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Vitamin D; 25-Hydroxyvitamin D; Delirium; Nosocomial infections; Hospital-acquired new-onset delirium ID LOCALLY WEIGHTED REGRESSION; D DEFICIENCY; MEDICAL INPATIENTS; PREDICTION RULE; HEALTH-CARE; METAANALYSIS; POPULATION; VALIDATION; PREVENTION; MORTALITY AB The goal of the present study was to determine whether pre-hospital 25-hydroxyvitamin D (25(OH)D) levels are associated with the risk of hospital-acquired new-onset delirium (HANOD). We performed a retrospective cohort study of 4508 adult inpatients at two teaching hospitals in Boston from 1993 to 2006. All patients had 25(OH)D levels measured before hospital admission. The main outcome measure was HANOD, defined as the onset of delirium during an acute care hospitalisation. Patients with a history of delirium or dementia, or those with a diagnosis of delirium or dementia upon acute care hospitalisation were excluded from the analysis. To test the association of pre-hospital 25(OH)D levels with HANOD, we constructed a multivariable logistic regression model to adjust for clinically relevant covariates. Among our patient cohort, the mean 25(OH)D level was 22 (sd 13)ng/ml and approximately 4% of patients met the criteria for HANOD. Following adjustment for age, sex, race (non-white v. white), patient type (medical v. surgical) and Deyo-Charlson Index, patients with 25(OH)D levels <10, 10-19.9 and 20-29.9ng/ml had higher odds of HANOD than patients with 25(OH)D levels 30ng/ml: OR 2.15 (95% CI 1.32, 3.50), OR 1.54 (95% CI 0.98, 2.43) and OR 1.23 (95% CI, 0.76, 1.99), respectively. These data support the rationale for randomised, controlled trials to test the role of vitamin D supplementation in the prevention of HANOD. C1 [Quraishi, Sadeq A.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Quraishi, Sadeq A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Litonjua, Augusto A.; Gibbons, Fiona K.; Camargo, Carlos A., Jr.; Christopher, Kenneth B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Litonjua, Augusto A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med & Pulm, Boston, MA 02115 USA. [Litonjua, Augusto A.] Brigham & Womens Hosp, Dept Med, Crit Care Div, Boston, MA 02115 USA. [Elias, Kevin M.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Gibbons, Fiona K.] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Camargo, Carlos A., Jr.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Christopher, Kenneth B.] Brigham & Womens Hosp, Dept Med, Div Renal, Nathan E Hellman Mem Lab, Boston, MA 02115 USA. RP Christopher, KB (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. EM kbchristopher@partners.org OI Elias, Kevin/0000-0003-1502-5553 FU US National Institutes of Health [5T32GM007592, UL1 RR025758, R01 AI093723, U01 AI087881, K08AI060881] FX S. A. Q. was financially supported by the US National Institutes of Health 5T32GM007592 and UL1 RR025758. C. A. C. was supported by the US National Institutes of Health R01 AI093723 and U01 AI087881. K. B. C. was supported by the US National Institutes of Health K08AI060881. NR 52 TC 2 Z9 2 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD JUN 14 PY 2015 VL 113 IS 11 BP 1753 EP 1760 DI 10.1017/S0007114515001245 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CL4LQ UT WOS:000356924700010 PM 26067807 ER PT J AU O'Donoghue, ML Ruff, CT Giugliano, RP Murphy, SA Grip, LT Mercuri, MF Rutman, H Shi, MG Kania, G Cermak, O Braunwald, E Antman, EM AF O'Donoghue, Michelle L. Ruff, Christian T. Giugliano, Robert P. Murphy, Sabina A. Grip, Laura T. Mercuri, Michele F. Rutman, Howard Shi, Minggao Kania, Grzegorz Cermak, Ondrej Braunwald, Eugene Antman, Elliott M. TI Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation SO EUROPEAN HEART JOURNAL LA English DT Article DE Edoxaban; Warfarin; Atrial fibrillation; Novel oral anticoagulant ID RANDOMIZED CONTROLLED-TRIAL; SPORTIF-III; THERAPY; STROKE; ANTICOAGULATION; PREVENTION; OUTCOMES; ASPIRIN; QUALITY; COHORTS AB Aims Edoxaban is an oral, once-daily factor Xa inhibitor that is non-inferior to well-managed warfarin in patients with atrial fibrillation (AF) for the prevention of stroke and systemic embolic events (SEEs). We examined the efficacy and safety of edoxaban vs. warfarin in patients who were vitamin K antagonist (VKA) naive or experienced. Methods and results ENGAGE AF-TIMI 48 randomized 21 105 patients with AF at moderate-to-high risk of stroke to once-daily edoxaban vs. warfarin. Subjects were followed for a median of 2.8 years. The primary efficacy endpoint was stroke or SEE. As a pre-specified subgroup, we analysed outcomes for those with or without prior VKA experience (> 60 consecutive days). Higher-dose edoxaban significantly reduced the risk of stroke or SEE in patients who were VKA naive [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.56-0.90] and was similar to warfarin in the VKA experienced (HR 1.01, 95% CI 0.82-1.24; P interaction = 0.028). Lower-dose edoxaban was similar to warfarin for stroke or SEE prevention in patients who were VKA naive (HR 0.92, 95% CI 0.73-1.15), but was inferior to warfarin in those who were VKA experienced (HR 1.31, 95% 1.08-1.60; P interaction = 0.019). Both higher-dose and lower-dose edoxaban regimens significantly reduced the risk of major bleeding regardless of prior VKA experience (P interaction = 0.90 and 0.71, respectively). Conclusion In patients with AF, edoxaban appeared to demonstrate greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced. Edoxaban significantly reduced major bleeding compared with warfarin regardless of prior VKA exposure. C1 [O'Donoghue, Michelle L.; Ruff, Christian T.; Giugliano, Robert P.; Murphy, Sabina A.; Grip, Laura T.; Braunwald, Eugene; Antman, Elliott M.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Mercuri, Michele F.; Shi, Minggao] Daiichi Sankyo Pharma Dev, Edison, NJ USA. [Rutman, Howard] Daiichi Sankyo Inc, Parsippany, NJ USA. [Kania, Grzegorz] Ctr Medyczne Ogrodowa, Skierniewice, Poland. [Cermak, Ondrej] Slany Municipal Hosp, Slany, Czech Republic. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM modonoghue@partners.org FU Deutsche Herzstiftung; DFG; National Heart, Lung, and Blood Institute [R01-HL114477, R01-HL095629, R01-HL117829, HHSN268201000044C] FX This work was funded in part by grants from the Deutsche Herzstiftung, DFG, and from the National Heart, Lung, and Blood Institute (R01-HL114477, R01-HL095629, R01-HL117829, and HHSN268201000044C). NR 13 TC 16 Z9 17 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JUN 14 PY 2015 VL 36 IS 23 BP 1470 EP + DI 10.1093/eurheartj/ehv014 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL0IT UT WOS:000356626300014 PM 25687352 ER PT J AU Leuschner, F Courties, G Dutta, P Mortensen, LJ Gorbatov, R Sena, B Novobrantseva, TI Borodovsky, A Fitzgerald, K Koteliansky, V Iwamoto, Y Bohlender, M Meyer, S Lasitschka, F Meder, B Katus, HA Lin, C Libby, P Swirski, FK Anderson, DG Weissleder, R Nahrendorf, M AF Leuschner, Florian Courties, Gabriel Dutta, Partha Mortensen, Luke J. Gorbatov, Rostic Sena, Brena Novobrantseva, Tatiana I. Borodovsky, Anna Fitzgerald, Kevin Koteliansky, Victor Iwamoto, Yoshiko Bohlender, Marina Meyer, Soeren Lasitschka, Felix Meder, Benjamin Katus, Hugo A. Lin, Charles Libby, Peter Swirski, Filip K. Anderson, Daniel G. Weissleder, Ralph Nahrendorf, Matthias TI Silencing of CCR2 in myocarditis SO EUROPEAN HEART JOURNAL LA English DT Article DE Inflammation; Myocarditis; Molecular imaging; siRNA; Nanoparticle ID EXPERIMENTAL AUTOIMMUNE MYOCARDITIS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; CARDIOVASCULAR MAGNETIC-RESONANCE; LIPID-LIKE MATERIALS; CARDIAC TROPONIN-I; DILATED CARDIOMYOPATHY; ENDOMYOCARDIAL BIOPSY; SPLENIC RESERVOIR; EUROPEAN-SOCIETY; PROGENITOR CELLS AB Background Myocarditis is characterized by inflammatory cell infiltration of the heart and subsequent deterioration of cardiac function. Monocytes are the most prominent population of accumulating leucocytes. We investigated whether in vivo administration of nanoparticle-encapsulated siRNA targeting chemokine (C-C motif) receptor 2 (CCR2)-a chemokine receptor crucial for leucocyte migration in humans and mice-reduces inflammation in autoimmune myocarditis. Methods and results In myocardium of patients with myocarditis, CCL2 mRNA levels and CCR2(+) cells increased (P < 0.05), motivating us to pursue CCR2 silencing. Flow cytometric analysis showed that siRNA silencing of CCR2 (siCCR2) reduced the number of Ly6C(high) monocytes in hearts of mice with acute autoimmune myocarditis by 69% (P < 0.05), corroborated by histological assessment. The nanoparticle-delivered siRNA was not only active in monocytes but also in bone marrow haematopoietic progenitor cells. Treatment with siCCR2 reduced the migration of bone marrow granulocyte macrophage progenitors into the blood. Cellular magnetic resonance imaging (MRI) after injection of macrophage-avid magnetic nanoparticles detected myocarditis and therapeutic effects of RNAi non-invasively. Mice with acute myocarditis showed enhanced macrophage MRI contrast, which was prevented by siCCR2 (P < 0.05). Follow-up MRI volumetry revealed that siCCR2 treatment improved ejection fraction (P < 0.05 vs. control siRNA-treated mice). Conclusion This study highlights the importance of CCR2 in the pathogenesis of myocarditis. In addition, we show that siCCR2 affects leucocyte progenitor trafficking. The data also point to a novel therapeutic strategy for the treatment of myocarditis. C1 [Leuschner, Florian; Courties, Gabriel; Dutta, Partha; Mortensen, Luke J.; Gorbatov, Rostic; Sena, Brena; Iwamoto, Yoshiko; Lin, Charles; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Leuschner, Florian; Courties, Gabriel; Dutta, Partha; Mortensen, Luke J.; Gorbatov, Rostic; Sena, Brena; Iwamoto, Yoshiko; Lin, Charles; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Leuschner, Florian; Bohlender, Marina; Meyer, Soeren; Meder, Benjamin; Katus, Hugo A.] Med Univ Hosp Heidelberg, Dept Cardiol, D-69120 Heidelberg, Germany. [Leuschner, Florian; Bohlender, Marina; Meyer, Soeren; Meder, Benjamin; Katus, Hugo A.] DZHK German Ctr Cardiovasc Res, Heidelberg, Germany. [Novobrantseva, Tatiana I.; Borodovsky, Anna; Fitzgerald, Kevin] Alnylam Pharmaceut, Cambridge, MA 02142 USA. [Koteliansky, Victor; Anderson, Daniel G.] Univ Heidelberg Hosp, Massachusetts Inst Technol, Dept Chem Engn, D-69120 Heidelberg, Germany. [Lasitschka, Felix] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany. [Libby, Peter] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Anderson, Daniel G.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Anderson, Daniel G.] MIT, Div Hlth Sci Technol, Cambridge, MA 02139 USA. [Anderson, Daniel G.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Leuschner, F (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM florian.leuschner@med.uni-heidelberg.de; mnahrendorf@mgh.harvard.edu RI Katus, Hugo/P-1712-2016 FU Deutsche Herzstiftung; DFG; National Heart, Lung, and Blood Institute [R01-HL114477, R01-HL095629, R01-HL117829, HHSN268201000044C] FX This work was funded in part by grants from the Deutsche Herzstiftung, DFG, and from the National Heart, Lung, and Blood Institute (R01-HL114477, R01-HL095629, R01-HL117829, and HHSN268201000044C). NR 41 TC 8 Z9 9 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JUN 14 PY 2015 VL 36 IS 23 BP 1478 EP U41 DI 10.1093/eurheartj/ehu225 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL0IT UT WOS:000356626300015 PM 24950695 ER PT J AU Washam, JB Stevens, SR Lokhnygina, Y Halperin, JL Breithardt, G Singer, DE Mahaffey, KW Hankey, GJ Berkowitz, SD Nessel, CC Fox, KAA Califf, RM Piccini, JP Patel, MR AF Washam, Jeffrey B. Stevens, Susanna R. Lokhnygina, Yuliya Halperin, Jonathan L. Breithardt, Guenter Singer, Daniel E. Mahaffey, Kenneth W. Hankey, Graeme J. Berkowitz, Scott D. Nessel, Christopher C. Fox, Keith A. A. Califf, Robert M. Piccini, Jonathan P. Patel, Manesh R. CA ROCKET AF Steering Comm Investigat TI Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) SO LANCET LA English DT Article ID HEART-FAILURE; INCREASED MORTALITY; EPIDEMIOLOGY; WARFARIN; AFFIRM; COHORT; RISK AB Background Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Methods For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767. Findings In 14 171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0.0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5.41 vs 4.30 events per 100 patients-years; hazard ratio 1.17; 95% CI 1.04-1.32; p=0.0093), vascular death (3.55 vs 2.69 per 100 patient-years; 1.19; 1.03-1.39, p=0.0201), and sudden death (1.68 vs 1.12 events per 100 patient-years; 1.36; 1.08-1.70, p=0.0076). Interpretation Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed. C1 [Washam, Jeffrey B.] Duke Univ, Med Ctr, Duke Heart Ctr, Durham, NC 27705 USA. [Stevens, Susanna R.; Lokhnygina, Yuliya; Piccini, Jonathan P.; Patel, Manesh R.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC 27705 USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Breithardt, Guenter] Hops Univ Munster, Munster, Germany. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Mahaffey, Kenneth W.] Stanford Sch Med, Stanford, CA USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Whippany, NJ USA. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Patel, MR (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. EM manesh.patel@duke.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Janssen Research Development; Bayer HealthCare AG FX Janssen Research & Development and Bayer HealthCare AG. NR 24 TC 22 Z9 23 U1 2 U2 6 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 JUN 13 PY 2015 VL 385 IS 9985 BP 2363 EP 2370 DI 10.1016/S0140-6736(14)61836-5 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK1XV UT WOS:000356003700029 PM 25749644 ER PT J AU Hui, ST Parks, BW Org, E Norheim, F Che, N Pan, C Castellani, LW Charugundla, S Dirks, DL Psychogios, N Neuhaus, I Gerszten, RE Kirchgessner, T Gargalovic, PS Lusis, AJ AF Hui, Simon T. Parks, Brian W. Org, Elin Norheim, Frode Che, Nam Pan, Calvin Castellani, Lawrence W. Charugundla, Sarada Dirks, Darwin L. Psychogios, Nikolaos Neuhaus, Isaac Gerszten, Robert E. Kirchgessner, Todd Gargalovic, Peter S. Lusis, Aldons J. TI The genetic architecture of NAFLD among inbred strains of mice SO ELIFE LA English DT Article ID NONALCOHOLIC FATTY LIVER; GENOME-WIDE ASSOCIATION; INDUCED HEPATIC STEATOSIS; DIET-INDUCED OBESITY; TRAIT LOCI ANALYSIS; INSULIN-RESISTANCE; METABOLIC SYNDROME; GUT MICROBIOTA; GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE; CONFERS SUSCEPTIBILITY AB To identify genetic and environmental factors contributing to the pathogenesis of nonalcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A > 30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis. C1 [Hui, Simon T.; Parks, Brian W.; Org, Elin; Che, Nam; Pan, Calvin; Castellani, Lawrence W.; Charugundla, Sarada; Dirks, Darwin L.; Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA. [Norheim, Frode] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Fac Med, Oslo, Norway. [Psychogios, Nikolaos; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Neuhaus, Isaac; Gargalovic, Peter S.] Bristol Myers Squibb Co, Dept Computat Genom, Princeton, NJ USA. [Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Kirchgessner, Todd] Bristol Myers Squibb Co, Dept Cardiovasc Drug Discovery, Princeton, NJ USA. RP Hui, ST (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA. EM sthui@mednet.ucla.edu; JLusis@mednet.ucla.edu OI Psychogios, Nikolaos/0000-0002-2747-6012; Org, Elin/0000-0003-1451-9375 FU National Heart, Lung, and Blood Institute (NHBLI) [HL028481]; European Commission (EC) [FP7 - 330381]; Norges Forskningsrad [240405/F20]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK094311]; National Institutes of Health (NIH) [T32-HD07228] FX National Heart, Lung, and Blood Institute (NHBLI) HL028481 Aldons J Lusis; European Commission (EC) FP7 - 330381 Elin Org; Norges Forskningsrad 240405/F20 Frode Norheim; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) DK094311 Aldons J Lusis; National Institutes of Health (NIH) T32-HD07228 Brian W Parks NR 100 TC 13 Z9 13 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 12 PY 2015 VL 4 AR e05607 DI 10.7554/eLife.05607 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ5LU UT WOS:000374250800001 PM 26067236 ER PT J AU Germine, L Dunn, EC McLaughlin, KA Smoller, JW AF Germine, Laura Dunn, Erin C. McLaughlin, Katie A. Smoller, Jordan W. TI Childhood Adversity Is Associated with Adult Theory of Mind and Social Affiliation, but Not Face Processing SO PLOS ONE LA English DT Article ID EARLY EXPERIENCE; FACIAL EXPRESSIONS; EMOTION; RECOGNITION; DISORDERS; HEALTH; CHILDREN; WORLD; PSYCHOPATHOLOGY; PROSOPAGNOSICS AB People vary substantially in their ability to acquire and maintain social ties. Here, we use a combined epidemiological and individual differences approach to understand the childhood roots of adult social cognitive functioning. We assessed exposure to 25 forms of traumatic childhood experiences in over 5000 adults, along with measures of face discrimination, face memory, theory of mind, social motivation, and social support. Retrospectively-reported experiences of parental maltreatment in childhood (particularly physical abuse) were the most broadly and robustly associated with adult variations in theory of mind, social motivation, and social support. Adult variations in face discrimination and face memory, on the other hand, were not significantly associated with exposure to childhood adversity. Our findings indicate domains of social cognition that may be particularly vulnerable to the effects of adverse childhood environments, and suggest mechanisms whereby environmental factors might influence the development of social abilities. C1 [Germine, Laura; Dunn, Erin C.; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Germine, Laura; Dunn, Erin C.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Germine, Laura; Dunn, Erin C.; Smoller, Jordan W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Germine, Laura] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [McLaughlin, Katie A.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Germine, L (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. EM lgermine@gmail.com OI Germine, Laura/0000-0001-8690-8412 FU US National Institute of Mental Health [K24 MH094614, T32MH016259, F32MH102971] FX This work was supported by US National Institute of Mental Health grants to JWS (K24 MH094614) and to LG (T32MH016259 and F32MH102971). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 3 Z9 3 U1 7 U2 23 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 JUN 12 PY 2015 VL 10 IS 6 AR e0129612 DI 10.1371/journal.pone.0129612 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK6GR UT WOS:000356327000095 PM 26068107 ER PT J AU Kim, LA Wong, LL Amarnani, DS Bigger-Allen, AA Hu, Y Marko, CK Eliott, D Shah, VA McGuone, D Stemmer-Rachamimov, AO Gai, XW D'Amore, PA Arboleda-Velasquez, JF AF Kim, Leo A. Wong, Lindsay L. Amarnani, Dhanesh S. Bigger-Allen, Alexander A. Hu, Yang Marko, Christina K. Eliott, Dean Shah, Vinay A. McGuone, Declan Stemmer-Rachamimov, Anat O. Gai, Xiaowu D'Amore, Patricia A. Arboleda-Velasquez, Joseph F. TI Characterization of cells from patient-derived fibrovascular membranes in proliferative diabetic retinopathy SO MOLECULAR VISION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INTRAVITREAL BEVACIZUMAB AVASTIN; EPITHELIAL-MESENCHYMAL TRANSITION; ANIMAL-MODELS; RETINAL NEOVASCULARIZATION; BLOOD-VESSELS; MOUSE MODEL; ANGIOPOIETIN-1; PERICYTES; ABNORMALITIES AB Purpose: Epiretinal fibrovascular membranes (FVMs) are a hallmark of proliferative diabetic retinopathy (PDR). Surgical removal of FVMs is often indicated to treat tractional retinal detachment. This potentially informative pathological tissue is usually disposed of after surgery without further examination. We developed a method for isolating and characterizing cells derived from FVMs and correlated their expression of specific markers in culture with that in tissue. Methods: FVMs were obtained from 11 patients with PDR during diabetic vitrectomy surgery and were analyzed with electron microscopy (EM), comparative genomic hybridization (CGH), immunohistochemistry, and/or digested with collagenase II for cell isolation and culture. Antibody arrays and enzyme-linked immunosorbent assay (ELISA) were used to profile secreted angiogenesis-related proteins in cell culture supernatants. Results: EM analysis of the FVMs showed abnormal vessels composed of endothelial cells with large nuclei and plasma membrane infoldings, loosely attached perivascular cells, and stromal cells. The cellular constituents of the FVMs lacked major chromosomal aberrations as shown with CGH. Cells derived from FVMs (C-FVMs) could be isolated and maintained in culture. The C-FVMs retained the expression of markers of cell identity in primary culture, which define specific cell populations including CD31-positive, alpha-smooth muscle actin-positive (SMA), and glial fibrillary acidic protein-positive (GFAP) cells. In primary culture, secretion of angiopoietin-1 and thrombospondin-1 was significantly decreased in culture conditions that resemble a diabetic environment in SMA-positive C-FVMs compared to human retinal pericytes derived from a non-diabetic donor. Conclusions: C-FVMs obtained from individuals with PDR can be isolated, cultured, and profiled in vitro and may constitute a unique resource for the discovery of cell signaling mechanisms underlying PDR that extends beyond current animal and cell culture models. C1 [Kim, Leo A.; Wong, Lindsay L.; Amarnani, Dhanesh S.; Bigger-Allen, Alexander A.; Hu, Yang; Marko, Christina K.; D'Amore, Patricia A.; Arboleda-Velasquez, Joseph F.] Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst Massachusetts Eye & Ear, Boston, MA USA. [Kim, Leo A.; Eliott, Dean] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv, Boston, MA USA. [Shah, Vinay A.] Univ Oklahoma, Hlth Sci Ctr, Dean McGee Eye Inst, Oklahoma City, OK USA. [McGuone, Declan; Stemmer-Rachamimov, Anat O.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Gai, Xiaowu] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst, Boston, MA USA. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Arboleda-Velasquez, JF (reprint author), 20 Staniford St, Boston, MA 02114 USA. EM joseph_arboleda@meei.harvard.edu FU NIH grants [R01EY005318, R00EY021624, K12EY16335]; American Diabetes Association Innovation Award [7-12-IN-11]; Massachusetts Lions Eye Research Fund; Department of Ophthalmology, Harvard Medical School FX The authors thank Magali Saint-Geniez, Ph.D., Lucia Sobrin, M.D. and Eric Ng, Ph.D. for valuable discussions and advice, Vincent Primo for expert technical assistance, Mark Consugar and DanYi Wang for help with conducting the SNP array analysis, Maria Ericsson and the Electron Microscopy Facility at Harvard Medical School for assistance with electron microscopy, and Patricia Houlihan, Anne Marie Lane, and Meredith Ryan for assistance with the IRB protocols and clinical coordination. The work performed in this manuscript was supported by NIH grants R01EY005318 (P.A.D.), R00EY021624 (J.F.A.-V.), and K12EY16335 (L.A.K.); American Diabetes Association Innovation Award 7-12-IN-11 (P.A.D.); Massachusetts Lions Eye Research Fund (L.A.K. and J.F.A.-V.); and the Department of Ophthalmology, Harvard Medical School (J.F.A.-V. and X.G.). The sponsors and funding organizations had no role in the design or conduct of this research and none of the authors have any commercial interests in the topics discussed in this manuscript. Patricia A. D'Amore, Ph.D. (patricia_damore@meei.harvard.edu) and Joseph F. Arboleda-Velasquez, M.D., Ph.D. (joseph_arboleda@meei.harvard.edu) are co-corresponding authors on this manuscript. NR 58 TC 0 Z9 0 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 12 PY 2015 VL 21 BP 673 EP 687 PG 15 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA CL1JE UT WOS:000356697900003 PM 26120272 ER PT J AU Eneanya, ND Goff, SL Martinez, T Gutierrez, N Klingensmith, J Griffith, JL Garvey, C Kitsen, J Germain, MJ Marr, L Berzoff, J Unruh, M Cohen, LM AF Eneanya, Nwamaka D. Goff, Sarah L. Martinez, Talaya Gutierrez, Natalie Klingensmith, Jamie Griffith, John L. Garvey, Casey Kitsen, Jenny Germain, Michael J. Marr, Lisa Berzoff, Joan Unruh, Mark Cohen, Lewis M. TI Shared decision-making in end-stage renal disease: a protocol for a multi-center study of a communication intervention to improve end-of-life care for dialysis patients SO BMC PALLIATIVE CARE LA English DT Article DE Dialysis; End-of-life; Advance care planning; Preferences; Palliative nephrology ID MAINTENANCE HEMODIALYSIS; DISCUSSING PROGNOSIS; PERITONEAL-DIALYSIS; ONCOLOGY FELLOWS; QUALITY; HEALTH; CANCER; SKILLS; QUESTIONNAIRE; RELIABILITY AB Background: End-stage renal disease carries a prognosis similar to cancer yet only 20 % of end-stage renal disease patients are referred to hospice. Furthermore, conversations between dialysis team members and patients about end-of-life planning are uncommon. Lack of provider training about how to communicate prognostic data may contribute to the limited number of end-of-life care discussions that take place with this chronically ill population. In this study, we will test the Shared Decision-Making Renal Supportive Care communication intervention to systematically elicit patient and caretaker preferences for end-of-life care so that care concordant with patients' goals can be provided. Methods/design: This multi-center study will deploy an intervention to improve end-of-life communication for hemodialysis patients who are at high risk of death in the ensuing six months. The intervention will be carried out as a prospective cohort with a retrospective cohort serving as the comparison group. Patients will be recruited from 16 dialysis units associated with two large academic centers in Springfield, Massachusetts and Albuquerque, New Mexico. Critical input from patient advisory boards, a stakeholder panel, and initial qualitative analysis of patient and caretaker experiences with advance care planning have informed the communication intervention. Rigorous communication training for hemodialysis social workers and providers will ensure that standardized study procedures are performed at each dialysis unit. Nephrologists and social workers will communicate prognosis and provide advance care planning in face-to-face encounters with patients and families using a social work-centered algorithm. Study outcomes including frequency and timing of hospice referrals, patient and caretaker satisfaction, quality of end-of-life discussions, and quality of death will be assessed over an 18 month period. Discussion: The Shared Decision-Making Renal Supportive Care Communication intervention intends to improve discussions about prognosis and end-of-life care with end-stage renal disease patients. We anticipate that the intervention will help guide hemodialysis staff and providers to effectively participate in advance care planning for patients and caretakers to establish preferences and goals at the end of life. C1 [Eneanya, Nwamaka D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol,Dept Internal Med, Boston, MA 02115 USA. [Goff, Sarah L.] Baystate Med Ctr, Dept Internal Med, Div Gen Med, Springfield, MA USA. [Goff, Sarah L.] Baystate Med Ctr, Ctr Qual Care Res, Springfield, MA USA. [Martinez, Talaya; Gutierrez, Natalie; Unruh, Mark] Univ New Mexico, Dept Internal Med, Div Nephrol, Albuquerque, NM 87131 USA. [Klingensmith, Jamie; Cohen, Lewis M.] Baystate Med Ctr, Dept Psychiat, Springfield, MA USA. [Griffith, John L.] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Garvey, Casey] Northeastern Univ, Bouve Coll Hlth Sci, Sch Nursing, Boston, MA 02115 USA. [Kitsen, Jenny] Kitsen & Associates, Chester, CT USA. [Germain, Michael J.] Baystate Med Ctr, Dept Internal Med, Div Nephrol, Springfield, MA USA. [Marr, Lisa] Univ New Mexico, Dept Internal Med, Div Geriatr & Palliat Med, Albuquerque, NM 87131 USA. [Berzoff, Joan] Smith Coll, Sch Social Work, Northampton, MA 01063 USA. RP Eneanya, ND (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol,Dept Internal Med, Boston, MA 02115 USA. EM Aeneanya@partners.org FU Patient-Centered Outcomes Research Institute (PCORI) Program Award [1304-7360] FX This work is supported by the Patient-Centered Outcomes Research Institute (PCORI) Program Award 1304-7360. NR 44 TC 0 Z9 0 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-684X J9 BMC PALLIAT CARE JI BMC Palliat. Care PD JUN 12 PY 2015 VL 14 AR UNSP 30 DI 10.1186/s12904-015-0027-x PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CK1KB UT WOS:000355965100001 PM 26066323 ER PT J AU Gong, C Liu, BD Yao, YD Qu, SH Luo, W Tan, WG Liu, Q Yao, HR Zou, L Su, FX Song, EW AF Gong, Chang Liu, Bodu Yao, Yandan Qu, Shaohua Luo, Wei Tan, Weige Liu, Qiang Yao, Herui Zou, Lee Su, Fengxi Song, Erwei TI Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANCER STEM-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; TRIPLE-NEGATIVE BREAST; PROSTATE-CANCER; KAPPA-B; SURVIVAL; METASTASIS; REPAIR; SUSCEPTIBILITY; COMBINATION AB Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by sup-pressing the chemoresistance of CTCs and reducing the risk of cancer metastasis. C1 [Gong, Chang; Liu, Bodu; Yao, Yandan; Qu, Shaohua; Luo, Wei; Tan, Weige; Liu, Qiang; Song, Erwei] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou 510120, Guangdong, Peoples R China. [Gong, Chang; Liu, Bodu; Yao, Yandan; Qu, Shaohua; Luo, Wei; Tan, Weige; Liu, Qiang; Su, Fengxi; Song, Erwei] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Breast Tumor Ctr, Guangzhou 510120, Guangdong, Peoples R China. [Yao, Herui] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Oncol, Guangzhou 510120, Guangdong, Peoples R China. [Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Su, FX (reprint author), Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Breast Tumor Ctr, 107 Yanjiang West Rd, Guangzhou 510120, Guangdong, Peoples R China. EM fengxisu@vip.163.com; songerwei02@aliyun.com RI Liu, Bodu/G-5222-2016 OI Liu, Bodu/0000-0003-2097-725X FU Ministry of Science and Technology of China [2011CB504203]; Natural Science Foundation of China [81172524, 81230060, 81261140373, 81272893, 81102023, 81372819, 81372817, 81272894, 81272897, 81472466, 81490751, 81442009]; Specialized Research Fund for the Doctoral Program of Higher Education Grant [20120171110075]; Program for New Century Excellent Talents in University [NCET-12-0565]; National Science Foundation of Guangdong Province [2011A080300002, 2014A03036003, S2012030006287, 2014A030310378]; Guangdong Department of Science and Technology Translational Medicine Center [2011A080300002]; Guangzhou Science and Technology Bureau [2012J2200092, 2014J4100170]; Sun Yat-sen University Training Project [12ykpy32, 13ykzd14]; Special Project on New Drug Innovation of Sun Yat-sen University; Elite Young Scholars Program of Sun Yat-sen Memorial Hospital [Y201401]; Yat-Sen Scholarship for Young Scientist and Translational Medicine Public Platform of Guangdong Province [4202037]; Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes [KLB09001]; Sun Yat-Sen University; Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology [(2013)163] FX This work was supported by 973 Grant 2011CB504203 from Projects from Ministry of Science and Technology of China; Natural Science Foundation of China Grants 81172524, 81230060, 81261140373, 81272893, 81102023, 81372819, 81372817, 81272894, 81272897, 81472466, 81490751, and 81442009; Specialized Research Fund for the Doctoral Program of Higher Education Grant 20120171110075; Program for New Century Excellent Talents in University Grant NCET-12-0565; National Science Foundation of Guangdong Province Grants 2011A080300002, 2014A03036003, S2012030006287, and 2014A030310378; Guangdong Department of Science and Technology Translational Medicine Center Grant 2011A080300002; Guangzhou Science and Technology Bureau Grants 2012J2200092 and 2014J4100170; Sun Yat-sen University Training Project Grants 12ykpy32 and 13ykzd14; Special Project on New Drug Innovation of Sun Yat-sen University; Elite Young Scholars Program of Sun Yat-sen Memorial Hospital Grant Y201401; Yat-Sen Scholarship for Young Scientist and Translational Medicine Public Platform of Guangdong Province Grant 4202037; Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes Grant KLB09001; Sun Yat-Sen University; and Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology Grant (2013)163. NR 48 TC 3 Z9 3 U1 0 U2 7 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 JUN 12 PY 2015 VL 290 IS 24 BP 14811 EP 14825 DI 10.1074/jbc.M115.652628 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK4FK UT WOS:000356177300002 PM 25897074 ER PT J AU Hori, Y Hashimoto, T Nomoto, H Hyman, BT Iwatsubo, T AF Hori, Yukiko Hashimoto, Tadafumi Nomoto, Hidetoshi Hyman, Bradley T. Iwatsubo, Takeshi TI Role of Apolipoprotein E in beta-Amyloidogenesis ISOFORM-SPECIFIC EFFECTS ON PROTOFIBRIL TO FIBRIL CONVERSION OF A beta IN VITRO AND BRAIN A beta DEPOSITION IN VIVO SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAMILIAL ALZHEIMER-DISEASE; CENTRAL-NERVOUS-SYSTEM; AMYLOID-BETA; MOUSE MODEL; PROTEIN FIBRILLOGENESIS; STABLE COMPLEXES; TRANSGENIC MICE; TYPE-4 ALLELE; PEPTIDE; PATHOGENESIS AB Human APOE beta 4 allele is a strong genetic risk factor of Alzheimer disease. Neuropathological and genetic studies suggested that apolipoprotein E4 (apoE4) protein facilitates deposition of amyloid beta peptide (A beta) in the brain, although the mechanism whereby apoE4 increases amyloid aggregates remains elusive. Here we show that injection of A beta protofibrils induced A beta deposition in the brain of APP transgenic mice, suggesting that A beta protofibrils acted as a seed for aggregation and deposition of A beta in vivo. Injection of A beta protofibrils together with apoE3 significantly attenuated A beta deposition, whereas apoE4 did not have this effect. In vitro assays revealed that the conversion of A beta protofibrils to fibrils progressed more slowly upon coincubation with apoE2 or apoE3 compared with that with apoE4. A beta protofibrils complexed with apoE4 were less stable than those with apoE2 or apoE3. These data suggest that the suppression effect of apoE2 or apoE3 on the structural conversion of A beta protofibrils to fibrils is stronger than those of apoE4, thereby impeding beta-amyloid deposition. C1 [Hori, Yukiko; Hashimoto, Tadafumi; Nomoto, Hidetoshi; Iwatsubo, Takeshi] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Tokyo 1130033, Japan. [Hashimoto, Tadafumi; Iwatsubo, Takeshi] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Tokyo 1130033, Japan. [Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. RP Iwatsubo, T (reprint author), Univ Tokyo, Grad Sch Med, Dept Neuropathol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM iwatsubo@m.u-tokyo.ac.jp FU Core Research for Evolutional Science and Technology of Japan Science and Technology Agency; Strategic Research Program for Brain Science from MEXT; Health Labor Sciences Research Grant on Amyloidosis FX This work was supported by Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, the Strategic Research Program for Brain Science from MEXT, and the Health Labor Sciences Research Grant on Amyloidosis. NR 47 TC 4 Z9 4 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 JUN 12 PY 2015 VL 290 IS 24 BP 15163 EP 15174 DI 10.1074/jbc.M114.622209 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK4FK UT WOS:000356177300030 PM 25918154 ER PT J AU Freitag, SK Cunnane, ME Yoon, MK Barnes, JA Winkfield, KM Sohani, AR AF Freitag, Suzanne K. Cunnane, Mary E. Yoon, Michael K. Barnes, Jeffrey A. Winkfield, Karen M. Sohani, Aliyah R. TI Case 18-2015: A 41-Year-Old Woman with Decreased Vision in the Left Eye and Diplopia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID B-CELL LYMPHOMA; RITUXIMAB PLUS CYCLOPHOSPHAMIDE; RADIATION-THERAPY; OCULAR ADNEXA; ORBIT; CLASSIFICATION; VINCRISTINE; DOXORUBICIN; PREDNISONE; EXPRESSION C1 [Freitag, Suzanne K.; Yoon, Michael K.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Cunnane, Mary E.] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Barnes, Jeffrey A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Winkfield, Karen M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Freitag, Suzanne K.; Yoon, Michael K.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Barnes, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Winkfield, Karen M.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Cunnane, Mary E.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Freitag, SK (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. FU Seattle Genetics FX Dr. Sohani reports receiving lecture fees from Seattle Genetics. No other potential conflict of interest relevant to this article was reported. NR 25 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 11 PY 2015 VL 372 IS 24 BP 2337 EP 2345 DI 10.1056/NEJMcpc1415170 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CK2DB UT WOS:000356019200011 PM 26061839 ER PT J AU Brown, RE McKenna, JT AF Brown, Ritchie E. McKenna, James T. TI Turning a negative into a positive: ascending GABAergic control of cortical activation and arousal SO FRONTIERS IN NEUROLOGY LA English DT Review DE wakefulness; gamma rhythm; theta rhythm; EEG; arousal; hypnotics ID VENTRAL TEGMENTAL AREA; BASAL FOREBRAIN NEURONS; SLEEP-WAKE CYCLE; THALAMIC RETICULAR NUCLEUS; HIPPOCAMPAL-THETA-RHYTHM; GABA-CONTAINING NEURONS; NIGRA PARS RETICULATA; DIAGONAL BAND COMPLEX; C-FOS EXPRESSION; URETHANE-ANESTHETIZED RATS AB Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Recent technological advances have illuminated the role of GABAergic neurons in control of cortical arousal and sleep. Sleep-promoting GABAergic neurons in the preoptic hypothalamus are well-known. Less well-appreciated are GABAergic projection neurons in the brainstem, midbrain, hypothalamus, and basal forebrain, which paradoxically promote arousal and fast electroencephalographic (EEG) rhythms. Thus, GABA is not purely a sleep-promoting neurotransmitter. GABAergic projection neurons in the brainstem nucleus incertus and ventral tegmental nucleus of Gudden promote theta (4-8 Hz) rhythms. Ventral tegmental area GABAergic neurons, neighboring midbrain dopamine neurons, project to the frontal cortex and nucleus accumbens. They discharge faster during cortical arousal and regulate reward. Thalamic reticular nucleus GABAergic neurons initiate sleep spindles in non-REM sleep. In addition, however, during wakefulness, they tonically regulate the activity of thalamocortical neurons. Other GABAergic inputs to the thalamus arising in the globus pallidus pars intema, substantia nigra pars reticulata, zona incerta, and basal forebrain regulate motor activity, arousal, attention, and sensory transmission. Several subpopulations of cortically projecting GABAergic neurons in the basal forebrain project to the thalamus and neocortex and preferentially promote cortical gamma-band (30-80 Hz) activity and wakefulness. Unlike sleep-active GABAergic neurons, these ascending GABAergic neurons are fast-firing neurons which disinhibit and synchronize the activity of their forebrain targets, promoting the fast EEG rhythms typical of conscious states. They are prominent targets of GABAergic hypnotic agents. Understanding the properties of ascending GABAergic neurons may lead to novel treatments for diseases involving disorders of cortical activation and wakefulness. C1 [Brown, Ritchie E.; McKenna, James T.] Harvard Univ, VA Boston Healthcare Syst, Neurosci Lab, Dept Psychiat,Med Sch, Brockton, MA 02301 USA. RP Brown, RE (reprint author), Harvard Univ, VA Boston Healthcare Syst, VA Med Ctr Brockton, Dept Psychiat,Lab Neurosci,Med Sch, Res 151C,940,Belmont St, Brockton, MA 02301 USA. EM ritchie_brown@hms.harvard.edu OI Brown, Ritchie/0000-0002-7164-4132 FU VA; NIMH [R01 MH039683, R21 MH094803]; NHLBI [HL095491] FX This work was supported by VA, by NIMH R01 MH039683, NHLBI HL095491, and NIMH R21 MH094803. NR 210 TC 8 Z9 9 U1 3 U2 16 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD JUN 11 PY 2015 VL 6 AR UNSP 135 DI 10.3389/fneur.2015.00135 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CU9EZ UT WOS:000363848100001 PM 26124745 ER PT J AU Vardi, R Goldental, A Marmari, H Brama, H Stern, EA Sardi, S Sabo, P Kanter, I AF Vardi, Roni Goldental, Amir Marmari, Hagar Brama, Haya Stern, Edward A. Sardi, Shira Sabo, Pinhas Kanter, Ido TI Neuronal response impedance mechanism implementing cooperative networks with low firing rates and mu s precision SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE neural networks; neuronal response latency; low firing rates; neuronal temporal precision; temporal code; rate code ID EXCITATORY-INHIBITORY BALANCE; IN-VIVO; CORTEX; SPIKING; TRANSMISSION; INFORMATION; RELIABILITY; PLASTICITY; DYNAMICS; MEMORY AB Realizations of low firing rates in neural networks usually require globally balanced distributions among excitatory and inhibitory links, while feasibility of temporal coding is limited by neuronal millisecond precision. We show that cooperation, governing global network features, emerges through nodal properties, as opposed to link distributions. Using in vitro and in vivo experiments we demonstrate microsecond precision of neuronal response timings under low stimulation frequencies, whereas moderate frequencies result in a chaotic neuronal phase characterized by degraded precision. Above a critical stimulation frequency, which varies among neurons, response failures were found to emerge stochastically such that the neuron functions as a low pass filter, saturating the average inter-spike-interval. This intrinsic neuronal response impedance mechanism leads to cooperation on a network level, such that firing rates are suppressed toward the lowest neuronal critical frequency simultaneously with neuronal microsecond precision. Our findings open up opportunities of controlling global features of network dynamics through few nodes with extreme properties. C1 [Vardi, Roni; Marmari, Hagar; Brama, Haya; Stern, Edward A.; Sardi, Shira; Sabo, Pinhas; Kanter, Ido] Bar Ilan Univ, Gonda Interdisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel. [Vardi, Roni; Marmari, Hagar; Brama, Haya; Stern, Edward A.; Sardi, Shira; Sabo, Pinhas; Kanter, Ido] Bar Ilan Univ, Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Goldental, Amir; Sardi, Shira; Sabo, Pinhas; Kanter, Ido] Bar Ilan Univ, Dept Phys, IL-52900 Ramat Gan, Israel. [Stern, Edward A.] Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis, Dept Neurol, Boston, MA 02114 USA. RP Kanter, I (reprint author), Bar Ilan Univ, Gonda Interdisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel. EM ido.kanter@biu.ac.il FU Ministry of Science and Technology, Israel FX We thank Moshe Abeles for stimulating discussions. Invaluable computational assistance by Igor Reidler and technical assistance by Hana Arnon are acknowledged. This research was supported by the Ministry of Science and Technology, Israel. NR 57 TC 4 Z9 4 U1 1 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD JUN 11 PY 2015 VL 9 AR 29 DI 10.3389/fncir.2015.00029 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CL0JW UT WOS:000356630000001 PM 26124707 ER PT J AU Zhang, CZ Spektor, A Cornils, H Francis, JM Jackson, EK Liu, SW Meyerson, M Pellman, D AF Zhang, Cheng-Zhong Spektor, Alexander Cornils, Hauke Francis, Joshua M. Jackson, Emily K. Liu, Shiwei Meyerson, Matthew Pellman, David TI Chromothripsis from DNA damage in micronuclei SO NATURE LA English DT Article ID GENOMIC REARRANGEMENTS; CANCER GENOMES; DOUBLE MINUTES; MECHANISMS; EVOLUTION; REPAIR; BREAKS; AMPLIFICATION; ARCHITECTURE; CHROMOSOMES AB Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome. C1 [Zhang, Cheng-Zhong; Francis, Joshua M.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Zhang, Cheng-Zhong; Spektor, Alexander; Cornils, Hauke; Jackson, Emily K.; Liu, Shiwei; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Zhang, Cheng-Zhong; Francis, Joshua M.; Meyerson, Matthew; Pellman, David] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Zhang, Cheng-Zhong; Spektor, Alexander; Cornils, Hauke; Jackson, Emily K.; Liu, Shiwei; Pellman, David] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Spektor, Alexander] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Jackson, Emily K.; Pellman, David] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. RP Pellman, D (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM david_pellman@dfci.harvard.edu FU Bridge Project of the Dana-Farber Cancer Institute; Koch Institute of MIT; Claudia Adams Barr Program in Innovative Cancer Research; NIH [GM083299-18] FX We thank R. Beroukhim, J. Walter and N. Ganem for comments on the manuscript, V. A. Adalsteinsson and J.C. Love for help with preliminary experiments, and A. Salic and S. Rosenberg for reagents. A.S. was a resident in the American Board of Radiology Holman Research Pathway; H.C. was a fellow of the Leukemia and Lymphoma Society; C.-Z.Z., J.M.F. and M.M. were supported by the Bridge Project of the Dana-Farber Cancer Institute and the Koch Institute of MIT; M.M. and D.P. were supported by the Claudia Adams Barr Program in Innovative Cancer Research; D.P. is a HHMI investigator and is supported by NIH grant GM083299-18. NR 34 TC 106 Z9 107 U1 5 U2 44 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 JUN 11 PY 2015 VL 522 IS 7555 BP 179 EP + DI 10.1038/nature14493 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK2CI UT WOS:000356016700031 PM 26017310 ER PT J AU Khullar, D Chokshi, DA Kocher, R Reddy, A Basu, K Conway, PH Rajkumar, R AF Khullar, Dhruv Chokshi, Dave A. Kocher, Robert Reddy, Ashok Basu, Karna Conway, Patrick H. Rajkumar, Rahul TI Behavioral Economics and Physician Compensation - Promise and Challenges SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HEALTH-CARE C1 [Khullar, Dhruv] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chokshi, Dave A.] New York City Hlth & Hosp Corp, New York, NY USA. [Chokshi, Dave A.] NYU, Langone Med Ctr, Dept Populat Hlth, New York, NY USA. [Basu, Karna] CUNY, Hunter Coll, Dept Econ, New York, NY 10021 USA. [Basu, Karna] CUNY, Grad Ctr, New York, NY USA. [Kocher, Robert] Venrock Partners, Palo Alto, CA USA. [Reddy, Ashok] Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, Philadelphia, PA 19104 USA. [Conway, Patrick H.; Rajkumar, Rahul] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. RP Khullar, D (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. OI Chokshi, Dave/0000-0001-7467-4591 NR 5 TC 16 Z9 16 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 11 PY 2015 VL 372 IS 24 BP 2281 EP 2283 DI 10.1056/NEJMp1502312 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CK2DB UT WOS:000356019200003 PM 26061834 ER PT J AU Kaliannan, K Wang, B Li, XY Kim, KJ Kang, JX AF Kaliannan, Kanakaraju Wang, Bin Li, Xiang-Yong Kim, Kui-Jin Kang, Jing X. TI A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia SO SCIENTIFIC REPORTS LA English DT Article ID INTESTINAL ALKALINE-PHOSPHATASE; HIGH-FAT DIET; LOW-GRADE INFLAMMATION; GUT MICROBIOTA; TRANSGENIC MICE; INSULIN-RESISTANCE; CHRONIC DISEASES; INDUCED OBESITY; ACID RATIO; IN-VITRO AB Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co-housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today's health epidemics. C1 [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Kang, JX (reprint author), Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02129 USA. EM kang.jing@mgh.harvard.edu FU Sansun Life Sciences; Fortune Education Foundation FX This study was supported by the generous funding from Sansun Life Sciences and the Fortune Education Foundation. The authors are also grateful to Hang Lee of the MGH Biostatistics Unit for his assistance with statistical analysis, Lorenzo Ramos-Mucci and Amy Goodale for their experimental assistance, and Marina Kang for her editorial assistance. NR 61 TC 16 Z9 16 U1 4 U2 11 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 JUN 11 PY 2015 VL 5 AR 11276 DI 10.1038/srep11276 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK3EI UT WOS:000356099000001 PM 26062993 ER PT J AU Chang, DK Moniz, RJ Xu, ZY Sun, JS Signoretti, S Zhu, Q Marasco, WA AF Chang, De-Kuan Moniz, Raymond J. Xu, Zhongyao Sun, Jiusong Signoretti, Sabina Zhu, Quan Marasco, Wayne A. TI Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo SO MOLECULAR CANCER LA English DT Article DE Orthotopic tumor; NSG mouse; Antibody engineering; Carbonic anhydrase IX; Immunotherapy; Xenograft ID CARBONIC-ANHYDRASE-IX; MONOCLONAL-ANTIBODY; TARGETED THERAPIES; INTRACELLULAR PH; FC-RECEPTORS; EXPRESSION; PROGNOSIS; CANCER; MICE; BREAST AB Background: Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). Therapeutic approaches targeting CAIX have focused on the development of CAIX inhibitors and specific immunotherapies including monoclonal antibodies (mAbs). However, current in vivo mouse models used to characterize the anti-tumor properties of fully human anti-CAIX mAbs have significant limitations since the role of human effector cells in tumor cell killing in vivo is not directly evaluated. Methods: The role of human anti-CAIX mAbs on CAIX(+) RCC tumor cell killing by immunocytes or complement was tested in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) as well as on CAIX(+) RCC cellular motility, wound healing, migration and proliferation. The in vivo therapeutic activity mediated by anti-CAIX mAbs was determined by using a novel orthotopic RCC xenograft humanized animal model and analyzed by histology and FACS staining. Results: Our studies demonstrate the capacity of human anti-CAIX mAbs that inhibit CA enzymatic activity to result in immune-mediated killing of RCC, including nature killer (NK) cell-mediated ADCC, CDC, and macrophage-mediated ADCP. The killing activity correlated positively with the level of CAIX expression on RCC tumor cell lines. In addition, Fc engineering of anti-CAIX mAbs was shown to enhance the ADCC activity against RCC. We also demonstrate that these anti-CAIX mAbs inhibit migration of RCC cells in vitro. Finally, through the implementation of a novel orthotopic RCC model utilizing allogeneic human peripheral blood mononuclear cells in NOD/SCID/IL2R gamma(-/-) mice, we show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX(+) tumor growth. Conclusions: Our findings demonstrate that these novel human anti-CAIX mAbs have therapeutic potential in the unmet medical need of targeted killing of HIF-driven CAIX+ RCC. The orthotopic tumor xenografted humanized mouse provides an improved model to evaluate the in vivo anti-tumor capabilities of fully human mAbs for RCC therapy. C1 [Chang, De-Kuan; Moniz, Raymond J.; Xu, Zhongyao; Sun, Jiusong; Zhu, Quan; Marasco, Wayne A.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Chang, De-Kuan; Moniz, Raymond J.; Sun, Jiusong; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Signoretti, Sabina] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Signoretti, Sabina] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Marasco, WA (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 450 Brookline Ave, Boston, MA 02115 USA. EM wayne_marasco@dfci.harvard.edu NR 61 TC 4 Z9 4 U1 6 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUN 11 PY 2015 VL 14 AR 119 DI 10.1186/s12943-015-0384-3 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA CK0PL UT WOS:000355907000002 PM 26062742 ER PT J AU Grover, S Balogun, OD Yamoah, K Groen, R Shah, M Rodin, D Martei, Y Olson, AC Slone, JS Shulman, LN Coleman, CN Hahn, SM AF Grover, Surbhi Balogun, Onyinye D. Yamoah, Kosj Groen, Reinou Shah, Mira Rodin, Danielle Martei, Yehoda Olson, Adam C. Slone, Jeremy S. Shulman, Lawrence N. Coleman, C. Norman Hahn, Stephen M. TI Training global oncologists: addressing the global cancer control problem (vol 5, pg 80, 2015) SO FRONTIERS IN ONCOLOGY LA English DT Correction DE global health; oncology training; radiation oncology; surgical oncology; medical oncology; corrigendum C1 [Grover, Surbhi; Hahn, Stephen M.] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Balogun, Onyinye D.] NYU, Perlmutter Canc Ctr, Dept Radiat Oncol, New York, NY USA. [Yamoah, Kosj] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Groen, Reinou] Johns Hopkins Univ Hosp, Dept Gynecol & Obstet, Baltimore, MD 21287 USA. [Shah, Mira] Henry Ford Hlth Syst, Dept Radiat Oncol, Detroit, MI USA. [Rodin, Danielle] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Martei, Yehoda] Hosp Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Olson, Adam C.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27708 USA. [Slone, Jeremy S.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Shulman, Lawrence N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Coleman, C. Norman] NCI, Radiat Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Coleman, C. Norman] Int Canc Expert Corps, Chevy Chase, MD USA. RP Olson, AC (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27708 USA. EM adam.olson@duke.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD JUN 10 PY 2015 VL 5 AR 133 DI 10.3389/fonc.2015.00133 PG 1 WC Oncology SC Oncology GA CO4QD UT WOS:000359144700002 PM 26114095 ER PT J AU Ok, CY Ye, Q Li, L Manyam, GC Deng, LJ Goswami, RR Wang, XX Montes-Moreno, S Visco, C Tzankov, A Dybkaer, K Zhang, L Abramson, J Sohani, AR Chiu, A Orazi, A Zu, YL Bhagat, G Richards, KL Hsi, ED Choi, WWL van Krieken, JH Huh, J Ponzoni, M Ferreri, AJM Zhang, SX Parsons, BM Xu, MN Moller, MB Winter, JN Piris, MA Xu-Monette, ZY Medeiros, LJ Young, KH AF Ok, Chi Young Ye, Qing Li, Ling Manyam, Ganiraju C. Deng, Lijuan Goswami, Rashmi R. Wang, Xiaoxiao Montes-Moreno, Santiago Visco, Carlo Tzankov, Alexandar Dybkaer, Karen Zhang, Li Abramson, Jeremy Sohani, Aliyah R. Chiu, April Orazi, Attilio Zu, Youli Bhagat, Govind Richards, Kristy L. Hsi, Eric D. Choi, William W. L. van Krieken, J. Han Huh, Jooryung Ponzoni, Maurilio Ferreri, Andres J. M. Zhang, Shanxiang Parsons, Ben M. Xu, Mina Moller, Michael B. Winter, Jane N. Piris, Miguel A. Xu-Monette, Zijun Y. Medeiros, L. Jeffrey Young, Ken H. TI Age cutoff for Epstein-Barr virus-positive diffuse large B-cell lymphoma - is it necessary? SO ONCOTARGET LA English DT Article DE EBV; DLBCL; elderly; gene expression profiling ID CLINICAL-IMPLICATIONS; RITUXIMAB-CHOP; PREVALENCE; POPULATION; EXPRESSION AB Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a molecularly distinct variant of DLBCL, characterized by a monoclonal B-cell proliferation that occurs in patients >50 years of age without a history or clinicopathologic evidence of immunodeficiency. However, patients with EBV+ DLBCL younger than 50-years-old also exist in Western countries. We evaluated the clinicopathologic, immunophenotypic and genetic features in Cacausian patients with EBV+ DLBCL who are <= 50 years of age and compared this patient group to patients who are >50 years. In patients who are <= 50 years, less frequent expression of BCL6 and a trend of more frequent expression of CD30 and pSTAT3 were found in patients with EBV+ DLBCL. In patients who are >50 years, common expression of CD30, p50, pSTAT3 and less frequent expression of BCL6 were observed. Older patients also more commonly had a poor performance status (ECOG >= 2). Comparing EBV+ DLBCL patients in <= 50 years versus >50 years, both groups had similar clinicopathologic, immunophenotypic and genetic features. Gene expression profiling, microRNA profiling and treatment outcome of the younger patients with EBV+ DLBCL was not distinctive from tumors in older patients. Based on our data, we suggest that the arbitrary age cutoff for EBV+ DLBCL is unnecessary and should be eliminated in the WHO lymphoma classification scheme. C1 [Ok, Chi Young; Ye, Qing; Li, Ling; Deng, Lijuan; Goswami, Rashmi R.; Wang, Xiaoxiao; Xu-Monette, Zijun Y.; Medeiros, L. Jeffrey; Young, Ken H.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Manyam, Ganiraju C.; Zhang, Li] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Montes-Moreno, Santiago; Piris, Miguel A.] Hosp Univ Marques de Valdecilla, Santander, Spain. [Visco, Carlo] San Bortolo Hosp, Vicenza, Italy. [Tzankov, Alexandar] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Dybkaer, Karen] Aalborg Univ Hosp, Aalborg, Denmark. [Abramson, Jeremy; Sohani, Aliyah R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Abramson, Jeremy; Sohani, Aliyah R.] Harvard Univ, Sch Med, Boston, MA USA. [Chiu, April] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Orazi, Attilio] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Zu, Youli] Houston Methodist Hosp, Houston, TX USA. [Bhagat, Govind] Columbia Univ, Med Ctr, New York, NY USA. [Bhagat, Govind] New York Presbyterian Hosp, New York, NY USA. [Richards, Kristy L.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Hsi, Eric D.] Cleveland Clin, Cleveland, OH 44106 USA. Univ Hong Kong, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [van Krieken, J. Han] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Huh, Jooryung] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Ponzoni, Maurilio; Ferreri, Andres J. M.] Ist Sci San Raffaele, Milan, Italy. [Zhang, Shanxiang] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Parsons, Ben M.] Gundersen Lutheran Hlth Syst, La Crosse, WI USA. [Xu, Mina] Yale Univ, Sch Med, New Haven, CT USA. [Moller, Michael B.] Odense Univ Hosp, DK-5000 Odense, Denmark. [Winter, Jane N.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Young, Ken H.] Univ Texas Houston, Sch Med, Grad Sch Biomed Sci, Houston, TX USA. RP Young, KH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. EM khyoung@mdanderson.org RI van Krieken, Joannes/D-4138-2009; Manyam, Ganiraju/E-9150-2012; Moller, Michael/G-8340-2016; Piris, Miguel/B-7067-2008 OI van Krieken, Joannes/0000-0001-6544-1040; Manyam, Ganiraju/0000-0001-6006-8961; Moller, Michael/0000-0003-2041-3630; Piris, Miguel/0000-0001-5839-3634 FU National Cancer Institute; National Institutes of Health [R01CA138688, R01CA187415, P50CA136411, P50CA142509]; advanced molecular pathology fellowship award; advanced molecular hematopathology research fellowship award; Harold C. and Mary L. Daily Endowment Fellowships; Shannon Timmins Fellowship for Leukemia Research Award; Michael and Susan Dell Foundation; University of Texas MD Anderson Cancer Center Institutional Research Grant Award; MD Anderson Lymphoma Specialized Programs of Research Excellence (SPORE) Research Development Program Award; MD Anderson Myeloma SPORE Research Development Program Award; MD Anderson Collaborative Research Funds with High-Throughput Molecular Diagnostics; Gilead Pharmaceutical; Adaptive Biotechnology; Roche Molecular Systems; MD Anderson Cancer Center Support Grant [CA016672] FX This study is supported by the National Cancer Institute and National Institutes of Health grants (R01CA138688 and R01CA187415, K.H.Y). CYO is the recipient of the advanced molecular pathology fellowship and hematopathology research awards; ZYXM is the recipient of the Harold C. and Mary L. Daily Endowment Fellowships and Shannon Timmins Fellowship for Leukemia Research Award. GM is supported by a grant from the Michael and Susan Dell Foundation. KHY is supported by The University of Texas MD Anderson Cancer Center Institutional Research Grant Award, an MD Anderson Lymphoma Specialized Programs of Research Excellence (SPORE) Research Development Program Award, an MD Anderson Myeloma SPORE Research Development Program Award, MD Anderson Collaborative Research Funds with High-Throughput Molecular Diagnostics, Gilead Pharmaceutical, Adaptive Biotechnology, and Roche Molecular Systems. This work was also partially supported by National Cancer Institute and National Institutes of Health grants (P50CA136411 and P50CA142509), and by the MD Anderson Cancer Center Support Grant CA016672. NR 22 TC 9 Z9 10 U1 2 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 JUN 10 PY 2015 VL 6 IS 16 BP 13935 EP 13946 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2TR UT WOS:000359010000012 PM 26101854 ER PT J AU Gosain, A Barlow-Anacker, AJ Erickson, CS Pierre, JF Heneghan, AF Epstein, ML Kudsk, KA AF Gosain, Ankush Barlow-Anacker, Amanda J. Erickson, Chris S. Pierre, Joseph F. Heneghan, Aaron F. Epstein, Miles L. Kudsk, Kenneth A. TI Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung's Disease SO PLOS ONE LA English DT Article ID ENTERIC NERVOUS-SYSTEM; PEYERS-PATCHES; INTESTINAL AGANGLIONOSIS; ANATOMICAL EVIDENCE; SURGICAL-CORRECTION; ULCERATIVE-COLITIS; CROHNS-DISEASE; L-SELECTIN; RAT MODEL; ENTEROCOLITIS AB Hirschsprung's disease (HSCR) is characterized by aganglionosis from failure of neural crest cell (NCC) migration to the distal hindgut. Up to 40% of HSCR patients suffer Hirschsprung's-associated enterocolitis (HAEC), with an incidence that is unchanged from the pre-operative to the post-operative state. Recent reports indicate that signaling pathways involved in NCC migration may also be involved in the development of secondary lymphoid organs. We hypothesize that gastrointestinal (GI) mucosal immune defects occur in HSCR that may contribute to enterocolitis. EdnrB was deleted from the neural crest (EdnrB(NCC-/-)) resulting in mutants with defective NCC migration, distal colonic aganglionosis and the development of enterocolitis. The mucosal immune apparatus of these mice was interrogated at post-natal day (P) 2124, prior to histological signs of enterocolitis. We found that EdnrB(NCC-/-) display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity. EdnrB(NCC-/-) Peyer's Patches demonstrate decreased B-lymphocytes, specifically IgM(+)IgD(hi) (Mature) B-lymphocytes, which are normally activated and produce IgA following antigen presentation. EdnrB(NCC-/-) animals demonstrate decreased small intestinal secretory IgA, but unchanged nasal and bronchial airway secretory IgA, indicating a gut-specific defect in IgA production or secretion. In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes, EdnrB(NCC-/-) animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes. EdnrB(NCC-/-) spleens are also small and show altered architecture, with decreased red pulp and a paucity of B-lymphocytes in the germinal centers and marginal zone. Taken together, these findings suggest impaired GI mucosal immunity in EdnrB(NCC-/-) animals, with the spleen as a potential site of the defect. These findings build upon the growing body of literature that suggests that intestinal defects in HSCR are not restricted to the aganglionic colon but extend proximally, even into the ganglionated small intestine and immune cells. C1 [Gosain, Ankush; Barlow-Anacker, Amanda J.; Erickson, Chris S.; Pierre, Joseph F.; Heneghan, Aaron F.; Kudsk, Kenneth A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI 53706 USA. [Gosain, Ankush; Epstein, Miles L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurosci, Madison, WI USA. [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Gosain, A (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI 53706 USA. EM gosain@surgery.wisc.edu OI Gosain, Ankush/0000-0002-0428-1503 FU National Institutes of Health [NIDDK RO1DK081634, NIDDK K08DK098271]; Veteran's Affairs Office of Research and Development (Biomedical Laboratory Research & Development Award) [I01BX001672]; Central Surgical Association Foundation (Turcotte Award); American Pediatric Surgical Association Foundation Award FX This work was supported by the National Institutes of Health (NIDDK RO1DK081634) to MLE, the Veteran's Affairs Office of Research and Development (Biomedical Laboratory Research & Development Award I01BX001672) to KAK, the Central Surgical Association Foundation (2012 Turcotte Award) to AG, the American Pediatric Surgical Association Foundation Award to AG, and the National Institutes of Health (NIDDK K08DK098271) to AG. The contents of this article do not represent the views of the Veterans Affairs or the United States Government (KAK). NR 76 TC 10 Z9 10 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 JUN 10 PY 2015 VL 10 IS 6 AR e0128822 DI 10.1371/journal.pone.0128822 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1PO UT WOS:000355979500100 PM 26061883 ER PT J AU Rajamuthiah, R Jayamani, E Conery, AL Fuchs, BB Kim, W Johnston, T Vilcinskas, A Ausubel, FM Mylonakis, E AF Rajamuthiah, Rajmohan Jayamani, Elamparithi Conery, Annie L. Fuchs, Beth Burgwyn Kim, Wooseong Johnston, Tatiana Vilcinskas, Andreas Ausubel, Frederick M. Mylonakis, Eleftherios TI A Defensin from the Model Beetle Tribolium castaneum Acts Synergistically with Telavancin and Daptomycin against Multidrug Resistant Staphylococcus aureus SO PLOS ONE LA English DT Article ID GRAM-POSITIVE BACTERIA; ANTIMICROBIAL PEPTIDES; CAENORHABDITIS-ELEGANS; TEICHOIC-ACIDS; HOST; IDENTIFICATION; MEMBRANE AB The red flour beetle Tribolium castaneum is a common insect pest and has been established as a model beetle to study insect development and immunity. This study demonstrates that defensin 1 from T. castaneum displays in vitro and in vivo antimicrobial activity against drug resistant Staphylococcus aureus strains. The minimum inhibitory concentration (MIC) of defensin 1 against 11 reference and clinical staphylococcal isolates was between 16-64 mu g/ml. The putative mode of action of the defensin peptide is disruption of the bacterial cell membrane. The antibacterial activity of defensin 1 was attenuated by salt concentrations of 1.56 mM and 25 mM for NaCl and CaCl2 respectively. Treatment of defensin 1 with the reducing agent dithiothreitol (DTT) at concentrations 1.56 to 3.13 mM abolished the antimicrobial activity of the peptide. In the presence of subinhibitory concentrations of antibiotics that also target the bacterial cell envelope such as telavancin and daptomycin, the MIC of the peptide was as low as 1 mu g/ml. Moreover, when tested against an S. aureus strain that was defective in D-alanylation of the cell wall, the MIC of the peptide was 0.5 mu g/ml. Defensin 1 exhibited no toxicity against human erythrocytes even at 400 mu g/ml. The in vivo activity of the peptide was validated in a Caenorhabditis elegans-MRSA liquid infection assay. These results suggest that defensin 1 behaves similarly to other cationic AMPs in its mode of action against S. aureus and that the activity of the peptide can be enhanced in combination with other antibiotics with similar modes of action or with compounds that have the ability to decrease D-alanylation of the bacterial cell wall. C1 [Rajamuthiah, Rajmohan; Jayamani, Elamparithi; Fuchs, Beth Burgwyn; Kim, Wooseong; Johnston, Tatiana; Mylonakis, Eleftherios] Brown Univ, Alpert Med Sch, Rhode Isl Hosp, Div Infect Dis, Providence, RI 02903 USA. [Rajamuthiah, Rajmohan; Jayamani, Elamparithi; Conery, Annie L.; Ausubel, Frederick M.; Mylonakis, Eleftherios] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vilcinskas, Andreas] Univ Giessen, Inst Phytopathol & Appl Zool, D-35392 Giessen, Germany. RP Mylonakis, E (reprint author), Brown Univ, Alpert Med Sch, Rhode Isl Hosp, Div Infect Dis, Providence, RI 02903 USA. EM emylonakis@lifespan.org RI Kim, Wooseong/A-9256-2017 OI Kim, Wooseong/0000-0002-4597-8374 FU National Institutes of Health [P01 AI083214, R01 AI085581] FX This study was supported by the National Institutes of Health grant P01 AI083214 to EM and FMA and National Institutes of Health grant R01 AI085581 to FMA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 6 Z9 6 U1 0 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 JUN 10 PY 2015 VL 10 IS 6 AR e0128576 DI 10.1371/journal.pone.0128576 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1PO UT WOS:000355979500089 PM 26062137 ER PT J AU Chang, L Dhruva, SS Chu, J Bero, LA Redberg, RF AF Chang, Lee Dhruva, Sanket S. Chu, Janet Bero, Lisa A. Redberg, Rita F. TI Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID MEDICAL DEVICES; PUBLICATION; CLINICALTRIALS.GOV; ACCESS; STENT; TIME AB OBJECTIVE To investigate characteristics of clinical trials and results on safety and effectiveness reported in US Food and Drug Administration (FDA) documents for recently approved high risk cardiovascular devices compared with the characteristics and results reported in peer reviewed publications. DESIGN A search of the publicly available FDA database was performed for all cardiovascular devices that received premarket approval from 1 January 2000 to 31 December 2010. For each study listed in the premarket approval documents, a Medline search was conducted to obtain the corresponding publication. MAIN OUTCOME MEASURES Clinical trial characteristics, primary endpoints, and safety and efficacy results in the FDA documents and corresponding publications. RESULTS 106 cardiovascular devices received premarket approval from 1 January 2000 to 31 December 2010. FDA premarket approval documents for these devices contained 177 studies, of which 86 (49%) had been published by 1 January 2013. These 86 publications corresponded to 60 distinct devices. The mean time from FDA approval to publication in a peer reviewed journal was 6.5 months (range -4.8-7.5 years). In 22 (26%) of the 86 compared studies the number of participants enrolled in the study differed in the FDA summary and the corresponding publications. Of 152 primary endpoints identified in the FDA documents, in the corresponding publications three (2%) were labeled as secondary, 43 (28%) were unlabeled, and 15 (10%) were not found. Among the primary results, 69 (45%) were identical, 35 (23%) were similar, 17 (11%) were substantially different, and 31 (20%) could not be compared. CONCLUSIONS Many clinical trials for high risk cardiovascular devices approved by the FDA remain unpublished. Even when trials are published, the study population, primary endpoints, and results can differ substantially from data submitted to the FDA. C1 [Chang, Lee] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dhruva, Sanket S.] Univ Calif Davis, Div Cardiovasc Med, Sacramento, CA 95817 USA. [Chu, Janet] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Bero, Lisa A.] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Redberg, Rita F.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA. RP Redberg, RF (reprint author), Univ Calif San Francisco, Div Cardiol, Suite M-1180,505 Parnassus Ave, San Francisco, CA 94143 USA. EM redberg@medicine.ucsf.edu NR 28 TC 7 Z9 7 U1 0 U2 2 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 JUN 10 PY 2015 VL 350 AR h2613 DI 10.1136/bmj.h2613 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CK7CZ UT WOS:000356389600002 PM 26063311 ER PT J AU Ribas, A Flaherty, KT AF Ribas, Antoni Flaherty, Keith T. TI Gauging the Long-Term Benefits of Ipilimumab in Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BRAF-MUTATED MELANOMA; METASTATIC MELANOMA; MEK INHIBITION; IMPROVED SURVIVAL; VEMURAFENIB; THERAPY C1 [Ribas, Antoni] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Ribas, Antoni] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Ribas, A (reprint author), Univ Calif Los Angeles, Los Angeles, CA 90095 USA. NR 18 TC 7 Z9 9 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1865 EP U11 DI 10.1200/JCO.2014.59.5041 PG 4 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800002 PM 25667273 ER PT J AU Hong, TS Ryan, DP AF Hong, Theodore S. Ryan, David P. TI Adjuvant Chemotherapy for Locally Advanced Rectal Cancer: Is It a Given? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PHASE-III TRIAL; PREOPERATIVE CHEMORADIOTHERAPY; RADIATION-THERAPY; COLON-CANCER; FLUOROURACIL; OXALIPLATIN; RADIOTHERAPY; LEUCOVORIN; SURVIVAL C1 [Hong, Theodore S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 14 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1878 EP U31 DI 10.1200/JCO.2015.60.8554 PG 4 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800006 PM 25940719 ER PT J AU Costa, DB Shaw, AT Ou, SHI Solomon, BJ Riely, GJ Ahn, MJ Zhou, CC Shreeve, M Selaru, P Polli, A Schnell, P Wilner, KD Wiltshire, R Camidge, DR Crino, L AF Costa, Daniel B. Shaw, Alice T. Ou, Sai-Hong I. Solomon, Benjamin J. Riely, Gregory J. Ahn, Myung-Ju Zhou, Caicun Shreeve, Martin Selaru, Paulina Polli, Anna Schnell, Patrick Wilner, Keith D. Wiltshire, Robin Camidge, D. Ross Crino, Lucio TI Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; LEPTOMENINGEAL METASTASES; INHIBITOR CRIZOTINIB; EGFR MUTATIONS; OPEN-LABEL; CHEMOTHERAPY; GEFITINIB; ERLOTINIB; DISEASE AB Purpose Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients and Methods Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). Results At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Conclusion Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib. (C) 2015 by American Society of Clinical Oncology C1 [Costa, Daniel B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Cambridge, MA 02138 USA. [Shaw, Alice T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Ou, Sai-Hong I.] Univ Calif Irvine, Sch Med, Chao Family Comprehens Canc Ctr, Irvine, CA 92717 USA. [Shreeve, Martin; Selaru, Paulina; Wilner, Keith D.] Pfizer Oncol, La Jolla, CA USA. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Schnell, Patrick] Pfizer Oncol, New York, NY USA. [Ahn, Myung-Ju] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Zhou, Caicun] Shanghai Pulm Hosp, Shanghai, Peoples R China. [Polli, Anna] Pfizer Oncol, Milan, Italy. [Crino, Lucio] Univ Perugia, Sch Med, I-06100 Perugia, Italy. [Wiltshire, Robin] Pfizer Oncol, Tadworth, Surrey, England. [Camidge, D. Ross] Univ Colorado Denver, Aurora, CO USA. RP Costa, DB (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, 330 Brookline Ave, Boston, MA 02215 USA. EM dbcosta@bidmc.harvard.edu OI Costa, Daniel/0000-0002-0689-395X FU Pfizer; National Cancer Institute [CA090578, CA058187, CA164273]; American Society of Clinical Oncology Conquer Cancer Foundation; American Cancer Society [RSG 11-186] FX Supported by Pfizer and in part by Grants No. CA090578, CA058187, and CA164273 from the National Cancer Institute, by the American Society of Clinical Oncology Conquer Cancer Foundation, and by Grant No. RSG 11-186 from the American Cancer Society. NR 39 TC 121 Z9 126 U1 2 U2 20 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 JUN 10 PY 2015 VL 33 IS 17 BP 1881 EP U41 DI 10.1200/JCO.2014.59.0539 PG 10 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800007 PM 25624436 ER PT J AU Schadendorf, D Hodi, FS Robert, C Weber, JS Margolin, K Hamid, O Patt, D Chen, TT Berman, DM Wolchok, JD AF Schadendorf, Dirk Hodi, F. Stephen Robert, Caroline Weber, Jeffrey S. Margolin, Kim Hamid, Omid Patt, Debra Chen, Tai-Tsang Berman, David M. Wolchok, Jedd D. TI Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol ID THERAPY; EFFICACY AB Purpose To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies. Methods The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method. Results Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3. Conclusion To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma. (C) 2015 by American Society of Clinical Oncology C1 [Schadendorf, Dirk] Univ Hosp Essen, D-45122 Essen, Germany. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Robert, Caroline] Inst Gustave Roussy, Villejuif, France. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Margolin, Kim] Univ Washington, Seattle, WA 98195 USA. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Patt, Debra] McKesson Specialty Hlth, US Oncol Network, Houston, TX USA. [Chen, Tai-Tsang] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Berman, David M.] Bristol Myers Squibb Co, Lawrenceville, NJ USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Schadendorf, D (reprint author), Univ Hosp Essen, Dept Dermatol, HufelandStr 55, D-45122 Essen, Germany. EM Dirk.Schadendorf@uk-essen.de OI CHEN, TAI-TSANG/0000-0003-2524-0409 FU NCI NIH HHS [P30 CA008748] NR 24 TC 290 Z9 297 U1 8 U2 27 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 JUN 10 PY 2015 VL 33 IS 17 BP 1889 EP U48 DI 10.1200/JCO.2014.56.2736 PG 7 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800008 PM 25667295 ER PT J AU Telli, ML Jensen, KC Vinayak, S Kurian, AW Lipson, JA Flaherty, PJ Timms, K Abkevich, V Schackmann, EA Wapnir, IL Carlson, RW Chang, PJ Sparano, JA Head, B Goldstein, LJ Haley, B Dakhil, SR Reid, JE Hartman, AR Manola, J Ford, JM AF Telli, Melinda L. Jensen, Kristin C. Vinayak, Shaveta Kurian, Allison W. Lipson, Jafi A. Flaherty, Patrick J. Timms, Kirsten Abkevich, Victor Schackmann, Elizabeth A. Wapnir, Irene L. Carlson, Robert W. Chang, Pei-Jen Sparano, Joseph A. Head, Bobbie Goldstein, Lori J. Haley, Barbara Dakhil, Shaker R. Reid, Julia E. Hartman, Anne-Renee Manola, Judith Ford, James M. TI Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol ID POLY(ADP-RIBOSE) POLYMERASE; DNA-REPAIR; CELL-LINES; CHEMOTHERAPY; CISPLATIN; SENSITIVITY; SUBTYPES; INHIBITION; SURVIVAL AB Purpose This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. Patients and Methods This single-arm phase II study enrolled patients with stage I to IIIA (T >= 1 cm) estrogen receptor-negative (<= 5%), progesterone receptor-negative (<= 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies. Results Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted. (C) 2015 by American Society of Clinical Oncology C1 [Telli, Melinda L.; Jensen, Kristin C.; Vinayak, Shaveta; Kurian, Allison W.; Lipson, Jafi A.; Flaherty, Patrick J.; Schackmann, Elizabeth A.; Wapnir, Irene L.; Carlson, Robert W.; Chang, Pei-Jen; Ford, James M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Head, Bobbie] Marin Specialty Care, Greenbrae, CA USA. [Timms, Kirsten; Abkevich, Victor; Reid, Julia E.; Hartman, Anne-Renee] Myriad Genet, Salt Lake City, UT USA. [Sparano, Joseph A.] Albert Einstein Coll Med, New York, NY USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Haley, Barbara] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Dakhil, Shaker R.] Canc Ctr Kansas, Wichita, KS USA. [Manola, Judith] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Telli, ML (reprint author), Stanford Univ, Sch Med, Dept Med, Div Oncol, 875 Blake Wilbur Dr,MC 5826, Stanford, CA 94305 USA. EM mtelli@stanford.edu FU NCATS NIH HHS [UL1 TR001073]; NCI NIH HHS [K12 CA076917, P30 CA013330, T32 CA121940] NR 26 TC 37 Z9 37 U1 1 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1895 EP U57 DI 10.1200/JCO.2014.57.0085 PG 9 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800009 PM 25847929 ER PT J AU Isakoff, SJ Mayer, EL He, L Traina, TA Carey, LA Krag, KJ Rugo, HS Liu, MC Stearns, V Come, SE Timms, KM Hartman, AR Borger, DR Finkelstein, DM Garber, JE Ryan, PD Winer, EP Goss, PE Ellisen, LW AF Isakoff, Steven J. Mayer, Erica L. He, Lei Traina, Tiffany A. Carey, Lisa A. Krag, Karen J. Rugo, Hope S. Liu, Minetta C. Stearns, Vered Come, Steven E. Timms, Kirsten M. Hartman, Anne-Renee Borger, Darrel R. Finkelstein, Dianne M. Garber, Judy E. Ryan, Paula D. Winer, Eric P. Goss, Paul E. Ellisen, Leif W. TI TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHEMOTHERAPY; CISPLATIN; SUBTYPES; CARBOPLATIN; CETUXIMAB; PATTERNS; BASAL; NEED AB Purpose The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates. Patients and Methods Patients with mTNBC received first-or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. Results Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. Conclusion Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted. (C) 2015 by American Society of Clinical Oncology C1 [Isakoff, Steven J.; He, Lei; Borger, Darrel R.; Finkelstein, Dianne M.; Ryan, Paula D.; Goss, Paul E.; Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Isakoff, Steven J.; Mayer, Erica L.; He, Lei; Krag, Karen J.; Come, Steven E.; Borger, Darrel R.; Finkelstein, Dianne M.; Garber, Judy E.; Ryan, Paula D.; Winer, Eric P.; Goss, Paul E.; Ellisen, Leif W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Mayer, Erica L.; Garber, Judy E.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA USA. [Come, Steven E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Krag, Karen J.] Massachusetts Gen Hosp, North Shore Canc Ctr, Danvers, MA USA. [Traina, Tiffany A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Carey, Lisa A.] Univ N Carolina, Chapel Hill, NC USA. [Rugo, Hope S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Liu, Minetta C.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Stearns, Vered] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Stearns, Vered] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Timms, Kirsten M.] Myriad Genet, Salt Lake City, UT USA. [Hartman, Anne-Renee] Myriad Genet Labs, Salt Lake City, UT USA. RP Isakoff, SJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,LH308, Boston, MA 02114 USA. EM sisakoff@mgh.harvard.edu FU Translational Breast Cancer Research Consortium; Avon Foundation; Breast Cancer Research Foundation; Susan G. Komen for the Cure; Boston Chapter of Golfers Against Cancer FX We thank Charles Perou and Chris Fan for conducting PAM50 gene expression subtype analysis, Carrie Quadrino for regulatory assistance and trial management, Ranjit Shetty, Susan Boivert, and Hector Lopez for help with correlative studies, Nora Horick for help with statistical analyses, and the patients who participated in this trial. We also thank the Translational Breast Cancer Research Consortium and its three founding partners (the Avon Foundation, the Breast Cancer Research Foundation, and Susan G. Komen for the Cure), Robert Howe, Lee Kennedy, and the Boston Chapter of Golfers Against Cancer for research support. NR 23 TC 55 Z9 58 U1 3 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 JUN 10 PY 2015 VL 33 IS 17 BP 1902 EP U67 DI 10.1200/JCO.2014.57.6660 PG 10 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800010 PM 25847936 ER PT J AU Wolfe, J Orellana, L Ullrich, C Cook, EF Kang, TI Rosenberg, A Geyer, R Feudtner, C Dussel, V AF Wolfe, Joanne Orellana, Liliana Ullrich, Christine Cook, E. Francis Kang, Tammy I. Rosenberg, Abby Geyer, Russ Feudtner, Chris Dussel, Veronica TI Symptoms and Distress in Children With Advanced Cancer: Prospective Patient-Reported Outcomes From the PediQUEST Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; PEDIATRIC PALLIATIVE CARE; CONTROLLED-TRIAL; THE-LITERATURE; PARENTS; END; ADOLESCENTS; NATIONWIDE; THERAPY AB Purpose Thousands of children are living with advanced cancer; yet patient-reported outcomes (PROs) have rarely been used to describe their experiences. We aimed to describe symptom distress in 104 children age 2 years or older with advanced cancer enrolled onto the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) Study (multisite clinical trial evaluating an electronic PRO system). Methods Symptom data were collected using age-and respondent-adapted versions of the PediQUEST Memorial Symptom Assessment Scale (PQ-MSAS) at most once per week. Clinical and treatment data were obtained from medical records. Individual symptom scores were dichotomized into high/low distress. Determinants of PQ-MSAS scores were explored using linear mixed-effects models. Results During 9 months of follow-up, PQ-MSAS was administered 920 times: 459 times in teens (99% self-report), 249 times in children ages 7 to 12 years (96% child/ parent report), and 212 times in those ages 2 to 6 years (parent reports). Common symptoms included pain (48%), fatigue (46%), drowsiness (39%), and irritability (37%); most scores indicated high distress. Among the 73 PQ-MSAS surveys administered in the last 12 weeks of life, pain was highly prevalent (62%; 58% with high distress). Being female, having a brain tumor, experiencing recent disease progression, and receiving moderate-or high-intensity cancer-directed therapy in the prior 10 days were associated with worse PQ-MSAS scores. In the final 12 weeks of life, receiving mild cancer-directed therapy was associated with improved psychological PQ-MSAS scores. Conclusion Children with advanced cancer experience high symptom distress. Strategies to promote intensive symptom management are indicated, especially with disease progression or administration of intensive treatments. (C) 2015 by American Society of Clinical Oncology C1 [Wolfe, Joanne; Ullrich, Christine] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. [Dussel, Veronica] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wolfe, Joanne; Ullrich, Christine] Boston Childrens Hosp, Boston, MA USA. [Wolfe, Joanne; Ullrich, Christine] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Cook, E. Francis] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Orellana, Liliana] Deakin Univ, Geelong, Vic 3217, Australia. [Kang, Tammy I.; Feudtner, Chris] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Kang, Tammy I.; Feudtner, Chris] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Rosenberg, Abby; Geyer, Russ] Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Rosenberg, Abby; Geyer, Russ] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Dussel, Veronica] Ctr Res & Implementat Palliat Care, Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Pediat Palliat Care Serv, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02215 USA. EM joanne_wolfe@dfci.harvard.edu RI Orellana, Liliana/I-5249-2013; Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337; Orellana, Liliana/0000-0003-3736-4337 FU National Institutes of Health National Cancer Institute Grant [1K07 CA096746-01]; Charles H. Hood Foundation Child Health Research Award; American Cancer Society Pilot and Exploratory Project Award in Palliative Care of Cancer Patients and Their Families FX The PediQUEST (Evaluation of Pediatric Quality of Life and Evaluation of Symptoms Technology in Children with Cancer) study was supported by National Institutes of Health National Cancer Institute Grant No. 1K07 CA096746-01, by a Charles H. Hood Foundation Child Health Research Award, and by a American Cancer Society Pilot and Exploratory Project Award in Palliative Care of Cancer Patients and Their Families. NR 34 TC 16 Z9 16 U1 2 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1928 EP U101 DI 10.1200/JCO.2014.59.1222 PG 11 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800013 PM 25918277 ER PT J AU Advani, RH Hong, FX Fisher, RI Bartlett, NL Robinson, KS Gascoyne, RD Wagner, H Stiff, PJ Cheson, BD Stewart, DA Gordon, LI Kahl, BS Friedberg, JW Blum, KA Habermann, TM Tuscano, JM Hoppe, RT Horning, SJ AF Advani, Ranjana H. Hong, Fangxin Fisher, Richard I. Bartlett, Nancy L. Robinson, K. Sue Gascoyne, Randy D. Wagner, Henry, Jr. Stiff, Patrick J. Cheson, Bruce D. Stewart, Douglas A. Gordon, Leo I. Kahl, Brad S. Friedberg, Jonathan W. Blum, Kristie A. Habermann, Thomas M. Tuscano, Joseph M. Hoppe, Richard T. Horning, Sandra J. TI Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; FINAL ANALYSIS; DISEASE; CHEMOTHERAPY; THERAPY; INVOLVEMENT; EXPERIENCE; RADIATION; STANDARD; BEACOPP AB Purpose The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL). Patients and Methods Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites >= 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS). Results Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm. Conclusion For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies. (C) 2015 by American Society of Clinical Oncology C1 [Advani, Ranjana H.; Fisher, Richard I.; Horning, Sandra J.] Stanford Univ, Stanford, CA 94305 USA. [Tuscano, Joseph M.] Univ Calif Davis, Davis Canc Ctr, Sacramento, CA 95817 USA. [Hong, Fangxin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fisher, Richard I.; Friedberg, Jonathan W.] Univ Rochester, Rochester, NY USA. [Bartlett, Nancy L.] Washington Univ, Sch Med, St Louis, MO USA. [Robinson, K. Sue] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Stewart, Douglas A.] Tim Baker Canc Inst, Calgary, AB, Canada. [Wagner, Henry, Jr.] Penn State Canc Inst, Hershey, PA USA. [Stiff, Patrick J.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Gordon, Leo I.] Northwestern Univ, Chicago, IL 60611 USA. [Cheson, Bruce D.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Kahl, Brad S.] Univ Wisconsin, Madison, WI USA. [Blum, Kristie A.] Ohio State Univ, Columbus, OH 43210 USA. [Habermann, Thomas M.] Mayo Clin, Rochester, MN USA. RP Advani, RH (reprint author), Stanford Univ, Stanford Canc Ctr, 875 Blake Wilbur Dr,Suite CC 2338, Stanford, CA 94305 USA. EM radvani@stanford.edu FU Millennium: Takeda Oncology (Inst); Seattle Genetics (Inst); Genentech/ Roche (Inst); Allos Therapeutics (Inst); Pharmacyclics (Inst); Janssen Pharmaceuticals (Inst); Celgene (Inst); Idera Pharmaceuticals (Inst); Millennium Pharmaceuticals (Inst); Pfizer (Inst); Novartis (Inst); MedImmune (Inst); ImaginAb (Inst); Genentech (Inst); Janssen Research Foundation (Inst); AstraZeneca (Inst); Teva (Inst); Gilead Sciences (Inst); Acerta Pharma (Inst); Roche/Genentech (Inst); Gilead Sciences; Constellation Pharmaceuticals (Inst); Celgene; Millennium Pharmaceuticals FX Millennium: Takeda Oncology (Inst), Seattle Genetics (Inst), Genentech/ Roche (Inst), Allos Therapeutics (Inst), Pharmacyclics (Inst), Janssen Pharmaceuticals (Inst), Celgene (Inst), Idera Pharmaceuticals (Inst); Seattle Genetics (Inst), Millennium Pharmaceuticals (Inst), Pfizer (Inst), Pharmacyclics (Inst), Novartis (Inst), MedImmune (Inst), Celgene (Inst), ImaginAb (Inst), Genentech (Inst), Janssen Research Foundation (Inst), AstraZeneca (Inst); Celgene (Inst), Teva (Inst), MedImmune (Inst), Pharmacyclics (Inst), Gilead Sciences (Inst), Seattle Genetics (Inst), Acerta Pharma (Inst), Roche/Genentech (Inst); Seattle Genetics (Inst), Genentech (Inst), Millennium Pharmaceuticals (Inst), Janssen Pharmaceuticals (Inst); Pharmacyclics (Inst), Janssen Pharmaceuticals (Inst), Celgene (Inst), Millennium Pharmaceuticals (Inst), Seattle Genetics (Inst), Gilead Sciences, Novartis (Inst), Constellation Pharmaceuticals (Inst); Celgene, Millennium Pharmaceuticals NR 34 TC 6 Z9 6 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1936 EP U111 DI 10.1200/JCO.2014.57.8138 PG 10 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800014 PM 25897153 ER PT J AU Martel, JM Smith, KC Dlamini, M Pletcher, K Yang, J Karabacak, M Haber, DA Kapur, R Toner, M AF Martel, Joseph M. Smith, Kyle C. Dlamini, Mcolisi Pletcher, Kendall Yang, Jennifer Karabacak, Murat Haber, Daniel A. Kapur, Ravi Toner, Mehmet TI Continuous Flow Microfluidic Bioparticle Concentrator SO SCIENTIFIC REPORTS LA English DT Article ID CIRCULATING TUMOR-CELLS; DETERMINISTIC LATERAL DISPLACEMENT; GENE-EXPRESSION; SINGLE-CELLS; SEPARATION; FILTRATION; PARTICLES; DEVICE; CENTRIFUGATION; ENRICHMENT AB Innovative microfluidic technology has enabled massively parallelized and extremely efficient biological and clinical assays. Many biological applications developed and executed with traditional bulk processing techniques have been translated and streamlined through microfluidic processing with the notable exception of sample volume reduction or centrifugation, one of the most widely utilized processes in the biological sciences. We utilize the high-speed phenomenon known as inertial focusing combined with hydraulic resistance controlled multiplexed micro-siphoning allowing for the continuous concentration of suspended cells into pre-determined volumes up to more than 400 times smaller than the input with a yield routinely above 95% at a throughput of 240 ml/hour. Highlighted applications are presented for how the technology can be successfully used for live animal imaging studies, in a system to increase the efficient use of small clinical samples, and finally, as a means of macro-to-micro interfacing allowing large samples to be directly coupled to a variety of powerful microfluidic technologies. C1 [Martel, Joseph M.; Smith, Kyle C.; Dlamini, Mcolisi; Pletcher, Kendall; Yang, Jennifer; Karabacak, Murat; Kapur, Ravi; Toner, Mehmet] Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, BioMEMS Resource Ctr, Boston, MA 02114 USA. [Martel, Joseph M.; Smith, Kyle C.; Dlamini, Mcolisi; Pletcher, Kendall; Yang, Jennifer; Karabacak, Murat; Kapur, Ravi; Toner, Mehmet] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. RP Toner, M (reprint author), Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, BioMEMS Resource Ctr, Boston, MA 02114 USA. EM mehmet_toner@hms.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering (BioMEMS Resource Center) [P41 EB002503]; Quantum Grant [5R01EB007047] FX Thanks to Eduardo Reategui for scanning electron micrographs. Thanks to Keith Wong, Shannon Tessier and Katy Miller with assistance with leukocyte activation measurements. This work was supported in part by the National Institute of Biomedical Imaging and Bioengineering (BioMEMS Resource Center, P41 EB002503) and Quantum Grant (5R01EB007047). NR 51 TC 10 Z9 11 U1 9 U2 50 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 JUN 10 PY 2015 VL 5 AR 11300 DI 10.1038/srep11300 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK3CD UT WOS:000356092400001 PM 26061253 ER PT J AU Desikan, RS Schork, AJ Wang, Y Thompson, WK Dehghan, A Ridker, PM Chasman, DI McEvoy, LK Holland, D Chen, CH Karow, DS Brewer, JB Hess, CP Williams, J Sims, R O'Donovan, MC Choi, SH Bis, JC Ikram, MA Gudnason, V DeStefano, AL van der Lee, SJ Psaty, BM van Duijn, CM Launer, L Seshadri, S Pericak-Vance, MA Mayeux, R Haines, JL Farrer, LA Hardy, J Ulstein, ID Aarsland, D Fladby, T White, LR Sando, SB Rongve, A Witoelar, A Djurovic, S Hyman, BT Snaedal, J Steinberg, S Stefansson, H Stefansson, K Schellenberg, GD Andreassen, OA Dale, AM AF Desikan, Rahul S. Schork, Andrew J. Wang, Yunpeng Thompson, Wesley K. Dehghan, Abbas Ridker, Paul M. Chasman, Daniel I. McEvoy, Linda K. Holland, Dominic Chen, Chi-Hua Karow, David S. Brewer, James B. Hess, Christopher P. Williams, Julie Sims, Rebecca O'Donovan, Michael C. Choi, Seung Hoan Bis, Joshua C. Ikram, M. Arfan Gudnason, Vilmundur DeStefano, Anita L. van der Lee, Sven J. Psaty, Bruce M. van Duijn, Cornelia M. Launer, Lenore Seshadri, Sudha Pericak-Vance, Margaret A. Mayeux, Richard Haines, Jonathan L. Farrer, Lindsay A. Hardy, John Ulstein, Ingun Dina Aarsland, Dag Fladby, Tormod White, Linda R. Sando, Sigrid B. Rongve, Arvid Witoelar, Aree Djurovic, Srdjan Hyman, Bradley T. Snaedal, Jon Steinberg, Stacy Stefansson, Hreinn Stefansson, Kari Schellenberg, Gerard D. Andreassen, Ole A. Dale, Anders M. CA Inflammation Working Grp Int Genomics Alzheimer's Dis Proje DemGene Investigators TI Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease SO CIRCULATION LA English DT Article DE Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids ID COMMON VARIANTS; BLOOD-LIPIDS; RISK; ASSOCIATION; ONSET; LOCI; METAANALYSIS; CHOLESTEROL; PLEIOTROPY; DIAGNOSIS AB Background-Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results-Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high-and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86x10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38x10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions-We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD. C1 [Desikan, Rahul S.; McEvoy, Linda K.; Chen, Chi-Hua; Karow, David S.; Brewer, James B.; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, 8950 Villa Jolla Dr,Ste C10, La Jolla, CA 92037 USA. [Schork, Andrew J.; Dale, Anders M.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Wang, Yunpeng; Holland, Dominic; Brewer, James B.; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Thompson, Wesley K.; Andreassen, Ole A.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Wang, Yunpeng; Chen, Chi-Hua; Fladby, Tormod; Witoelar, Aree; Andreassen, Ole A.; Dale, Anders M.] Univ Oslo, Inst Clin Med, NORMENT, N-0316 Oslo, Norway. [Wang, Yunpeng; Chen, Chi-Hua; Witoelar, Aree; Andreassen, Ole A.; Dale, Anders M.] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0450 Oslo, Norway. [Ulstein, Ingun Dina] Oslo Univ Hosp, Norwegian Ctr Dementia Res, Dept Old Age Psychiat, N-0450 Oslo, Norway. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, N-0450 Oslo, Norway. [Dehghan, Abbas; Ikram, M. Arfan; van der Lee, Sven J.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Cardiovasc Dis Prevent,Div Preventat Med, Boston, MA 02115 USA. [Hess, Christopher P.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Williams, Julie; Sims, Rebecca; O'Donovan, Michael C.] Cardiff Univ, Sch Med, Med Res Council Ctr Neuropsychiatr Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Choi, Seung Hoan; DeStefano, Anita L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bis, Joshua C.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Bis, Joshua C.] Univ Washington, Seattle, WA 98195 USA. [Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [DeStefano, Anita L.; Seshadri, Sudha] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Washington, DC USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol Ophthalmol, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat & Epidemiol, Boston, MA 02215 USA. [Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Coral Gables, FL 33124 USA. [Mayeux, Richard] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Mayeux, Richard] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Inst Computat Biol, Cleveland, OH 44106 USA. [Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Aarsland, Dag] Karolinska Inst, Alzheimers Dis Res Ctr, Dept Neurobiol, Care Sci & Soc, Stockholm, Sweden. [Aarsland, Dag] Stavanger Univ Hosp, Ctr Age Related Med, Stavanger, Norway. [Aarsland, Dag] Akershus Univ Hosp, Dept Geriatr Psychiat, Oslo, Norway. [Fladby, Tormod] Akershus Univ Hosp, Dept Neurol, Akershus, Norway. [White, Linda R.; Sando, Sigrid B.] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [White, Linda R.; Sando, Sigrid B.] Univ Trondheim Hosp, St Olavs Hosp, Dept Neurol, Trondheim, Norway. [Rongve, Arvid] Haugesund Hosp, Dept Psychiat, Haugesund, Norway. [Djurovic, Srdjan] Univ Bergen, NORMENT, KG Jebsen Ctr Psychosis Res, Dept Clin Sci, N-5020 Bergen, Norway. [Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Snaedal, Jon] Univ Hosp Reykjavik, Dept Geriatr Med, Reykjavik, Iceland. [Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. RP Desikan, RS (reprint author), Univ Calif San Diego, Dept Radiol, 8950 Villa Jolla Dr,Ste C10, La Jolla, CA 92037 USA. EM rdesikan@ucsd.edu; o.a.andreassen@medisin.uio.no RI Hardy, John/C-2451-2009; Gudnason, Vilmundur/K-6885-2015; OI Farrer, Lindsay/0000-0001-5533-4225; Seshadri, Sudha/0000-0001-6135-2622; Dehghan, Abbas/0000-0001-6403-016X; Aarsland, Dag/0000-0001-6314-216X; Gudnason, Vilmundur/0000-0001-5696-0084; Stefansson, Hreinn/0000-0002-9331-6666 FU National Institutes of Health [K02 NS067427, T32 EB005970, R01GM104400-01A, R01MH100351, AG033193, U0149505, RC2DA029475, R01HD061414]; Research Council of Norway [213837, 225989, 223273, 237250/EU JPND]; South East Norway Health Authority [2013-123]; Norwegian Health Association; KG Jebsen Foundation; Robert J. Glushko and Pamela Samuelson Graduate Fellowship; NWO [916.12.154]; Erasmus University Rotterdam Fellowship FX This research was supported by grants from the National Institutes of Health (K02 NS067427, T32 EB005970, R01GM104400-01A, R01MH100351, AG033193, and U0149505), the Research Council of Norway (grants 213837, 225989, 223273, 237250/EU JPND), the South East Norway Health Authority (2013-123), the Norwegian Health Association, and the KG Jebsen Foundation. A.J. Schork was supported by National Institutes of Health grants RC2DA029475 and R01HD061414 and the Robert J. Glushko and Pamela Samuelson Graduate Fellowship. Dr Dehghan was supported by an NWO grant (veni, 916.12.154) and the Erasmus University Rotterdam Fellowship. Please see the Acknowledgments in the online-only Data Supplement for IGAP funding sources. NR 32 TC 15 Z9 16 U1 1 U2 5 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 JUN 9 PY 2015 VL 131 IS 23 BP 2061 EP 2069 DI 10.1161/CIRCULATIONAHA.115.015489 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IJ UT WOS:000369254400010 PM 25862742 ER PT J AU O'Donovan, SM Hasselfeld, K Bauer, D Simmons, M Roussos, P Haroutunian, V Meador-Woodruff, JH McCullumsmith, RE AF O'Donovan, S. M. Hasselfeld, K. Bauer, D. Simmons, M. Roussos, P. Haroutunian, V. Meador-Woodruff, J. H. McCullumsmith, R. E. TI Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; ELDERLY-PATIENTS; RAT-BRAIN; DIFFERENTIAL EXPRESSION; TRANSCRIPT EXPRESSION; ASPARTATE TRANSPORTER; NEURONAL EXPRESSION; ABNORMAL EXPRESSION; ALZHEIMERS-DISEASE; EAAT2 POLYMORPHISM AB Dysregulation of the glutamate transporters EAAT1 and EAAT2 and their isoforms have been implicated in schizophrenia. EAAT1 and EAAT2 expression has been studied in different brain regions but the prevalence of astrocytic glutamate transporter expression masks the more subtle changes in excitatory amino acid transporters (EAATs) isoforms in neurons in the cortex. Using laser capture microdissection, pyramidal neurons were cut from the anterior cingulate cortex of postmortem schizophrenia (n = 20) and control (n = 20) subjects. The messenger RNA (mRNA) levels of EAAT1, EAAT2 and the splice variants EAAT1 exon9skipping, EAAT2 exon9skipping and EAAT2b were analyzed by real time PCR (RT-PCR) in an enriched population of neurons. Region-level expression of these transcripts was measured in postmortem schizophrenia (n = 25) and controls (n = 25). The relationship between selected EAAT polymorphisms and EAAT splice variant expression was also explored. Anterior cingulate cortex pyramidal cell expression of EAAT2b mRNA was increased (P<0.001; 67%) in schizophrenia subjects compared with controls. There was no significant change in other EAAT variants. EAAT2 exon9skipping mRNA was increased (P<0.05; 38%) at region level in the anterior cingulate cortex with no significant change in other EAAT variants at region level. EAAT2 single-nucleotide polymorphisms were significantly associated with changes in EAAT2 isoform expression. Haloperidol decanoate-treated animals, acting as controls for possible antipsychotic effects, did not have significantly altered neuronal EAAT2b mRNA levels. The novel finding that EAAT2b levels are increased in populations of anterior cingulate cortex pyramidal cells further demonstrates a role for neuronal glutamate transporter splice variant expression in schizophrenia. C1 [O'Donovan, S. M.; Hasselfeld, K.; McCullumsmith, R. E.] Univ Cincinnati, Dept Psychiat & Behav Neurosci, Cincinnati, OH 45267 USA. [Bauer, D.; McCullumsmith, R. E.] Wellesley Coll, Dept Neurosci, Wellesley, MA 02181 USA. [Simmons, M.; Meador-Woodruff, J. H.; McCullumsmith, R. E.] Univ Alabama Birmingham, Dept Psychiat, Birmingham, AL USA. [Roussos, P.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Dept Psychiat, New York, NY 10029 USA. [Roussos, P.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Roussos, P.] Mental Illness Res Educ & Clin Ctr, James J Peters VA Med Ctr, Bronx, NY USA. [Haroutunian, V.] Icahn Sch Med Mt Sinai, Dept Psychiat & Neurosci, New York, NY 10029 USA. RP McCullumsmith, RE (reprint author), Univ Cincinnati, Dept Psychiat & Behav Neurosci, CARE 5830,231 Albert Sabin Way Cincinnati, Cincinnati, OH 45267 USA. EM robert.mccullumsmith@uc.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU NIH [MH074016, MH087752, MH094445]; Doris Duke Clinical Scientist Award; Lindsay Brinkmeyer Schizophrenia Research Fund FX This research was funded by NIH grant numbers: MH074016, MH087752, MH094445 and the Doris Duke Clinical Scientist Award (REM). This work was also supported by the Lindsay Brinkmeyer Schizophrenia Research Fund. We gratefully acknowledge Bronx VA and Mount Sinai Centre Brain Bank for providing tissue samples. NR 66 TC 3 Z9 3 U1 3 U2 4 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 JUN 9 PY 2015 VL 5 AR e579 DI 10.1038/tp.2015.74 PG 9 WC Psychiatry SC Psychiatry GA DA2WT UT WOS:000367658600003 PM 26057049 ER PT J AU Goldhirsch, A Colleoni, M Regan, M AF Goldhirsch, Aron Colleoni, Marco Regan, Meredith TI Improved adjuvant endocrine therapy for premenopausal women with endocrine responsive disease SO ECANCERMEDICALSCIENCE LA English DT Article DE adjuvant endocrine therapy; breast cancer; SOFT & TEXT; ovarian function suppression; exemestane ID BREAST-CANCER; OVARIAN SUPPRESSION; TAMOXIFEN AB Results from two randomised global trials (SOFT & TEXT) designed to newly define the most effective components of adjuvant endocrine therapy for premenopausal women with endocrine responsive disease, showed that for some, those with high risk of relapse, the use of the aromatase inhibitor exemestane together with ovarian function suppression with GnRH analogue (triptorelin) yielded the most favourable treatment outcome compared with tamoxifen. For women with low risk of relapse, treatment with tamoxifen was similar to ovarian function suppression together with either exemestane or tamoxifen. For women with intermediate risk of relapse, ovarian function suppression added to tamoxifen was not inferior to exemestane, while it resulted in superior outcomes compared to tamoxifen alone. Now, these trials provide critical information for the adjuvant treatment of premenopausal women with endocrine responsive breast cancer and are important for the development of future trials for further improvement of adjuvant endocrine therapies for the younger population. C1 [Goldhirsch, Aron] European Inst Oncol, Program Breast Hlth Senol, I-20141 Milan, Italy. [Colleoni, Marco] European Inst Oncol, Div Med Senol, I-20141 Milan, Italy. [Regan, Meredith] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Goldhirsch, Aron; Colleoni, Marco; Regan, Meredith] IBCSG, CH-3008 Bern, Switzerland. RP Goldhirsch, A (reprint author), European Inst Oncol, Program Breast Hlth Senol, Via Ripamonti 435, I-20141 Milan, Italy. EM aron.goldhirsch@ibcsg.org NR 5 TC 0 Z9 0 U1 1 U2 1 PU CANCER INTELLIGENCE LTD PI BRISTOL PA 11 ALMA VALE RD,, BRISTOL, BS8 2HL, ENGLAND SN 1754-6605 J9 ECANCERMEDICALSCIENC JI eCancerMedicalScience PD JUN 9 PY 2015 VL 9 AR 544 DI 10.3332/ecancer.2015.544 PG 3 WC Oncology SC Oncology GA CQ4ZJ UT WOS:000360612800001 PM 26082801 ER PT J AU Lee, JJ Sholl, LM Lindeman, NI Granter, SR Laga, AC Shivdasani, P Chin, G Luke, JJ Ott, PA Hodi, FS Mihm, MC Lin, JY Werchniak, AE Haynes, HA Bailey, N Liu, R Murphy, GF Lian, CG AF Lee, Jonathan J. Sholl, Lynette M. Lindeman, Neal I. Granter, Scott R. Laga, Alvaro C. Shivdasani, Priyanka Chin, Gary Luke, Jason J. Ott, Patrick A. Hodi, F. Stephen Mihm, Martin C., Jr. Lin, Jennifer Y. Werchniak, Andrew E. Haynes, Harley A. Bailey, Nancy Liu, Robert Murphy, George F. Lian, Christine G. TI Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naive patient melanomas SO CLINICAL EPIGENETICS LA English DT Article DE Melanoma; Next-generation sequencing (NGS); Epigenetics; MECOM (MDS1 and EV1 complex locus); MLL2; Ten-eleven translocation (TET); Isocitrate dehydrogenase 2 (IDH2); 5-hydroxymethylcytosine; DNA demethylation ID ACUTE MYELOID-LEUKEMIA; BRAF-MUTATED MELANOMA; MEK INHIBITION; METASTATIC MELANOMA; MALIGNANT-MELANOMA; SOMATIC MUTATIONS; GENETIC LANDSCAPE; IMPROVED SURVIVAL; DRIVER MUTATIONS; CANCER GENOMICS AB Background: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naive, patient melanoma specimens obtained from one academic institution. Results: Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naive patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. Conclusions: Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma. C1 [Lee, Jonathan J.; Sholl, Lynette M.; Lindeman, Neal I.; Granter, Scott R.; Laga, Alvaro C.; Shivdasani, Priyanka; Chin, Gary; Liu, Robert; Murphy, George F.; Lian, Christine G.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Luke, Jason J.; Ott, Patrick A.; Hodi, F. Stephen; Mihm, Martin C., Jr.; Lin, Jennifer Y.; Werchniak, Andrew E.; Haynes, Harley A.; Bailey, Nancy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Ctr, Boston, MA 02115 USA. RP Murphy, GF (reprint author), Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, 221 Longwood Ave,EBRC Suite 401, Boston, MA 02115 USA. EM gmurphy@rics.bwh.harvard.edu; cglian@partners.org OI Lian, Christine/0000-0003-4626-1612 FU NIH [5P40CA093683-09]; Bristol-Myers-Squibb; Harvard Medical School Eleanor and Miles Shore Fellowship Program; Karin Grunebaum Cancer Research Foundation; Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCRR) [UL1 TR001102]; Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCATS, NIH) [UL1 TR001102]; Harvard University FX This study was supported by NIH grant 5P40CA093683-09 to the SPORE Core at Brigham and Women's Hospital. GFM received funding from Bristol-Myers-Squibb for work on melanoma biomarkers (not a funding source for this study). This work is also supported by Harvard Medical School Eleanor and Miles Shore Fellowship Program (CGL) and Karin Grunebaum Cancer Research Foundation (CGL). This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCRR and NCATS, NIH Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. NR 66 TC 13 Z9 13 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD JUN 9 PY 2015 VL 7 AR 59 DI 10.1186/s13148-015-0091-3 PG 17 WC Oncology SC Oncology GA CN5PP UT WOS:000358481600001 PM 26221190 ER PT J AU Kollu, S Abou-Khalil, R Shen, C Brack, AS AF Kollu, Swapna Abou-Khalil, Rana Shen, Carl Brack, Andrew S. TI The Spindle Assembly Checkpoint Safeguards Genomic Integrity of Skeletal Muscle Satellite Cells SO STEM CELL REPORTS LA English DT Article ID VERTEBRATE MITOTIC CHECKPOINT; STEM-CELLS; SELF-RENEWAL; DNA-DAMAGE; CHROMOSOMAL INSTABILITY; REVERSIBLE QUIESCENCE; GENOTOXIC STRESS; GENE-EXPRESSION; P53 BINDING; IN-VIVO AB To ensure accurate genomic segregation, cells evolved the spindle assembly checkpoint (SAC), whose role in adult stem cells remains unknown. Inducible perturbation of a SAC kinase, Mps1, and its downstream effector, Mad2, in skeletal muscle stem cells shows the SAC to be critical for normal muscle growth, repair, and self-renewal of the stem cell pool. SAC-deficient muscle stem cells arrest in G1 phase of the cell cycle with elevated aneuploidy, resisting differentiation even under inductive conditions. p21(CIP1) is responsible for these SAC-deficient phenotypes. Despite aneuploidy's correlation with aging, we find that aged proliferating muscle stem cells display robust SAC activity without elevated aneuploidy. Thus, muscle stem cells have a two-step mechanism to safeguard their genomic integrity. The SAC prevents chromosome missegregation and, if it fails, p21(CIP1)-dependent G1 arrest limits cellular propagation and tissue integration. These mechanisms ensure that muscle stem cells with compromised genomes do not contribute to tissue homeostasis. C1 [Kollu, Swapna; Abou-Khalil, Rana; Shen, Carl; Brack, Andrew S.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Kollu, Swapna; Abou-Khalil, Rana; Shen, Carl; Brack, Andrew S.] Harvard Stem Cell Inst, Boston, MA 02114 USA. [Brack, Andrew S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Brack, AS (reprint author), Univ Calif San Francisco, Dept Orthopaed Surg, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. EM andrew.brack@ucsf.edu FU MGH start-up funds; NIH [R01 AR060868, R01 AR061002] FX The authors would like to thank Peter Sorger (Harvard University) for mice, Hallie Nelson for technical assistance, members of the A.S.B. laboratory for reading the manuscript, and Laura Pricket-Rice, Kat Foltz-Donahue, and Meredith Weglartz of the MGH FACS Core Facility and Shumei Wang, Anita Hawkins, and Abha Aggarwal of the CytoGenomics Core Facility at Brigham and Women's Hospital for their contribution. This work was supported by grants from MGH start-up funds and NIH grants (R01 AR060868, R01 AR061002) to A.S.B. NR 75 TC 2 Z9 2 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD JUN 9 PY 2015 VL 4 IS 6 BP 1061 EP 1074 DI 10.1016/j.stemcr.2015.04.006 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CK2UF UT WOS:000356068100012 PM 25960061 ER PT J AU Sujobert, P Poulain, L Paubelle, E Zylbersztejn, F Grenier, A Lambert, M Townsend, EC Brusq, JM Nicodeme, E Decrooqc, J Nepstad, I Green, AS Mondesir, J Hospital, MA Jacque, N Christodoulou, A Desouza, TA Hermine, O Foretz, M Viollet, B Lacombe, C Mayeux, P Weinstock, DM Moura, IC Bouscary, D Tamburini, J AF Sujobert, Pierre Poulain, Laury Paubelle, Etienne Zylbersztejn, Florence Grenier, Adrien Lambert, Mireille Townsend, Elizabeth C. Brusq, Jean-Marie Nicodeme, Edwige Decrooqc, Justine Nepstad, Ina Green, Alexa S. Mondesir, Johanna Hospital, Marie-Anne Jacque, Nathalie Christodoulou, Alexandra Desouza, Tiffany A. Hermine, Olivier Foretz, Marc Viollet, Benoit Lacombe, Catherine Mayeux, Patrick Weinstock, David M. Moura, Ivan C. Bouscary, Didier Tamburini, Jerome TI Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia SO CELL REPORTS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; HEMATOPOIETIC STEM-CELLS; PROMISING THERAPEUTIC TARGET; MOUSE MODEL; ER STRESS; IN-VIVO; AUTOPHAGY; HOMEOSTASIS; PHOSPHORYLATION; METABOLISM AB AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acutemyeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2 alpha/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. C1 [Sujobert, Pierre; Poulain, Laury; Grenier, Adrien; Lambert, Mireille; Green, Alexa S.; Mondesir, Johanna; Hospital, Marie-Anne; Jacque, Nathalie; Foretz, Marc; Viollet, Benoit; Lacombe, Catherine; Mayeux, Patrick; Bouscary, Didier; Tamburini, Jerome] Inst Cochin, INSERM U1016, F-75014 Paris, France. [Sujobert, Pierre; Poulain, Laury; Grenier, Adrien; Lambert, Mireille; Green, Alexa S.; Mondesir, Johanna; Hospital, Marie-Anne; Jacque, Nathalie; Foretz, Marc; Viollet, Benoit; Lacombe, Catherine; Mayeux, Patrick; Bouscary, Didier; Tamburini, Jerome] CNRS UMR8104, F-75014 Paris, France. [Sujobert, Pierre; Poulain, Laury; Grenier, Adrien; Lambert, Mireille; Green, Alexa S.; Mondesir, Johanna; Hospital, Marie-Anne; Jacque, Nathalie; Foretz, Marc; Viollet, Benoit; Lacombe, Catherine; Mayeux, Patrick; Bouscary, Didier; Tamburini, Jerome] Univ Paris 05, Fac Med, Sorbonne Paris Cite, F-75005 Paris, France. [Sujobert, Pierre; Poulain, Laury; Grenier, Adrien; Lambert, Mireille; Green, Alexa S.; Mondesir, Johanna; Hospital, Marie-Anne; Jacque, Nathalie; Lacombe, Catherine; Mayeux, Patrick; Bouscary, Didier; Tamburini, Jerome] Equipe Labellisee Ligue Natl Canc LNCC, F-75013 Paris, France. [Paubelle, Etienne; Zylbersztejn, Florence; Decrooqc, Justine; Hermine, Olivier; Moura, Ivan C.] INSERM UMR1163, Lab Cellular & Mol Mech Hematol Disorders & Thera, F-75015 Paris, France. [Paubelle, Etienne; Zylbersztejn, Florence; Decrooqc, Justine; Hermine, Olivier; Moura, Ivan C.] Paris Descartes Univ, Sorbonne Paris Cite, Imagine Inst, F-75015 Paris, France. [Paubelle, Etienne; Zylbersztejn, Florence; Decrooqc, Justine; Hermine, Olivier; Moura, Ivan C.] CNRS ERL 8254, F-75015 Paris, France. [Paubelle, Etienne; Zylbersztejn, Florence; Decrooqc, Justine; Foretz, Marc; Viollet, Benoit; Moura, Ivan C.] Lab Excellence GR Ex, F-75015 Paris, France. [Townsend, Elizabeth C.; Christodoulou, Alexandra; Desouza, Tiffany A.; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Townsend, Elizabeth C.; Christodoulou, Alexandra; Desouza, Tiffany A.; Weinstock, David M.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Brusq, Jean-Marie; Nicodeme, Edwige] GlaxoSmithKline Res Ctr, F-91490 Les Ulis, France. [Nepstad, Ina] Haukeland Hosp, Dept Med, Div Hematol, N-5021 Bergen, Norway. RP Tamburini, J (reprint author), Inst Cochin, INSERM U1016, F-75014 Paris, France. EM jerome.tamburini@inserm.fr OI Cruz Moura, Ivan/0000-0002-8418-2803; Moura, Ivan/0000-0002-2977-0354 FU INSERM(poste d'accueil INSERM); Association pour la Recherche sur le Cancer (ARC); Fondation pour la Recherche Medicale (FRM) FX The authors would like to thank Olivier Mirguet and Anne Bouillot for the discovery and synthesis of GSK621, Veronique Beneton for quantification of GSK621 levels in mouse sera, Pascal Grondin and Alizon Riou-Aymard for the in vitro AMPK screen assay (GSK Les Ulis). We also thank Alain Schmitt (Genomic Facility, Cochin Institute) for help with electron microscopy experiments and analysis, Franck Letourneur and Florent Dumont (transcriptomic Facility, Cochin Institute) for transcriptomic and bioinformatics analysis and Dr. Diane Damotte for helping in immunohistochemistry analysis. The authors also thank Dr. Bob Weinberg and Dr. Dmitri Wiederschain for sharing the pLKO and Tet-pLKO-puro plasmids, respectively, Dr. Eric Campeau for sharing pLenti PGK Puro DEST (w529-2) and pLenti PGK Blati DEST plasmids, Dr. Feng Zhang for sharing the lentiCRISPR plasmid, Dr. Xin Chen for the myrAKT plasmid, and Dr. Yihong Ye for the ATF4 plasmid, all through Addgene. We are also grateful to Dr. Nabih Azar (Pitie-Salpetriere Hospital, Paris, France) for contributing to the normal CD34+ cell samples and to Dr. Isabelle Dusanter for providing human cord blood cells. P.S. was supported by grants from the INSERM(poste d'accueil INSERM) and from Association pour la Recherche sur le Cancer (ARC). A.G. received grants from Fondation pour la Recherche Medicale (FRM). J.-M.B. and E.N. are employees of the GlaxoSmithKline French research center (Les Ulis). D.M.W. is a paid consultant and receives research NR 51 TC 16 Z9 16 U1 3 U2 12 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 JUN 9 PY 2015 VL 11 IS 9 BP 1446 EP 1457 DI 10.1016/j.celrep.2015.04.063 PG 12 WC Cell Biology SC Cell Biology GA CK2UR UT WOS:000356069500012 PM 26004183 ER PT J AU Kim, H Frederick, DT Levesque, MP Cooper, ZA Feng, YM Krepler, C Brill, L Samuels, Y Hayward, NK Perlina, A Piris, A Zhang, TW Halaban, R Herlyn, MM Brown, KM Wargo, JA Dummer, R Flaherty, KT Ronai, ZA AF Kim, Hyungsoo Frederick, Dennie T. Levesque, Mitchell P. Cooper, Zachary A. Feng, Yongmei Krepler, Clemens Brill, Laurence Samuels, Yardena Hayward, Nicholas K. Perlina, Ally Piris, Adriano Zhang, Tongwu Halaban, Ruth Herlyn, Meenhard M. Brown, Kevin M. Wargo, Jennifer A. Dummer, Reinhard Flaherty, Keith T. Ronai, Ze'ev A. TI Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation SO CELL REPORTS LA English DT Article ID BRAF(V600E) INHIBITION; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; DRIVEN RESISTANCE; UP-REGULATION; EGF RECEPTOR; CANCER; VEMURAFENIB; ACTIVATION; MUTATIONS AB Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression. C1 [Kim, Hyungsoo; Feng, Yongmei; Brill, Laurence; Perlina, Ally; Ronai, Ze'ev A.] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. [Frederick, Dennie T.; Piris, Adriano; Flaherty, Keith T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02114 USA. [Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich, CH-8091 Zurich, Switzerland. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Krepler, Clemens] Wistar Inst Anat & Biol, Melanoma Res Ctr, Philadelphia, PA 19104 USA. [Samuels, Yardena] Weizmann Inst Sci, IL-76100 Rehovot, Israel. [Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Zhang, Tongwu; Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Halaban, Ruth] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. RP Kim, H (reprint author), Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. EM hkim@sbmri.org; ronai@sbmri.org RI Zhang, Tongwu/M-4975-2015; hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; RONAI, ZEEV/0000-0002-3859-0400; Cooper, Zachary/0000-0003-1059-0940 FU NCI [CA128814]; Melanoma Research Foundation; Hervey Family Non-endowment Fund at The San Diego Foundation FX We thank Holly Yin for providing the UACC cell lines used in this study. We also thank members of Z.A.R.'s laboratory for extensive discussions. This work was supported by grants from the NCI (CA128814), the Melanoma Research Foundation, and the Hervey Family Non-endowment Fund at The San Diego Foundation (to Z.A.R.). NR 44 TC 6 Z9 6 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 JUN 9 PY 2015 VL 11 IS 9 BP 1458 EP 1473 DI 10.1016/j.celrep.2015.04.049 PG 16 WC Cell Biology SC Cell Biology GA CK2UR UT WOS:000356069500013 PM 26027934 ER PT J AU Wayne, PM Hausdorff, JM Lough, M Gow, BJ Lipsitz, L Novak, V Macklin, EA Peng, CK Manor, B AF Wayne, Peter M. Hausdorff, Jeffrey M. Lough, Matthew Gow, Brian J. Lipsitz, Lewis Novak, Vera Macklin, Eric A. Peng, Chung-Kang Manor, Brad TI Tai Chi training may reduce dual task gait variability, a potential mediator of fall risk, in healthy older adults: cross-sectional and randomized trial studies SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE Tai Chi; gait analysis; dual task performance; falls and fall risk prevention; cognition ID PARKINSONS-DISEASE; POSTURAL CONTROL; PHYSICAL PERFORMANCE; LENGTH VARIABILITY; EXECUTIVE CONTROL; ELDERLY FALLERS; SENILE-DEMENTIA; INITIATION; EXERCISE; BALANCE AB Background: Tai Chi (TC) exercise improves balance and reduces falls in older, health-impaired adults. TC's impact on dual task (DT) gait parameters predictive of falls, especially in healthy active older adults, however, is unknown. Purpose: To compare differences in usual and DT gait between long-term TC-expert practitioners and age-/gender-matched TC-naive adults, and to determine the effects of short-term TC training on gait in healthy, non-sedentary older adults. Methods: A cross-sectional study compared gait in healthy TC-naive and TC-expert (24.5 +/- 12 years experience) older adults. TC-naive adults then completed a 6-month, two-arm, wait-list randomized clinical trial of TC training. Gait speed and stride time variability (Coefficient of Variation %) were assessed during 90 s trials of undisturbed and cognitive DT (serial subtractions) conditions. Results: During DT, gait speed decreased (p < 0.003) and stride time variability increased (p < 0.004) in all groups. Cross-sectional comparisons indicated that stride time variability was lower in the TC-expert vs. TC-naive group, significantly so during DT (2.11 vs. 2.55%; p = 0.027); by contrast, gait speed during both undisturbed and DT conditions did not differ between groups. Longitudinal analyses of TC-naive adults randomized to 6 months of TC training or usual care identified improvement in DT gait speed in both groups. A small improvement in DT stride time variability (effect size = 0.2) was estimated with TC training, but no significant differences between groups were observed. Potentially important improvements after TC training could not be excluded in this small study. Conclusion: In healthy active older adults, positive effects of short- and long-term TC were observed only under cognitively challenging DT conditions and only for stride time variability. DT stride time variability offers a potentially sensitive metric for monitoring TC's impact on fall risk with healthy older adults. C1 [Wayne, Peter M.; Gow, Brian J.] Brigham & Womens Hosp, Osher Ctr Integrat Med, Div Prevent Med, Boston, MA 02115 USA. [Wayne, Peter M.; Gow, Brian J.; Macklin, Eric A.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Hausdorff, Jeffrey M.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Ctr Study Movement Cognit & Mobil, Dept Neurol, IL-69978 Tel Aviv, Israel. [Lough, Matthew; Lipsitz, Lewis; Manor, Brad] Hebrew Sr Life, Inst Aging Res, Boston, MA USA. [Novak, Vera] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Peng, Chung-Kang] Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Boston, MA 02215 USA. [Peng, Chung-Kang] Natl Cent Univ, Ctr Dynam Biomarkers & Translat Med, Chungli 32054, Taiwan. RP Wayne, PM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Osher Ctr Integrat Med, 900 Commonwealth Ave,3rd Floor, Boston, MA 02215 USA. EM pwayne@partners.org OI Macklin, Eric/0000-0003-1618-3502 FU National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health (NIH) [R21 AT005501-01A1]; National Institute on Aging (NIA) [R03-AG25037]; Irving and Edyth S. Usen and Family Chair in Geriatric Medicine at Hebrew Senior Life; Ministry of Science and Technology of Taiwan [NSC 102-2911-1-008-001]; Harvard Catalyst [5 KL2 RR025757-04]; National Institute on Aging [1K01 AG044543-01A1] FX We thank Danielle Berkowitz. This work was supported by grant R21 AT005501-01A1 from the National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health (NIH). Dr. LL was supported by grant R03-AG25037 from the National Institute on Aging (NIA) and the Irving and Edyth S. Usen and Family Chair in Geriatric Medicine at Hebrew Senior Life. Dr. VN was supported by R21 AT005501-01A1. Dr. CP was supported by a grant (NSC 102-2911-1-008-001) from Ministry of Science and Technology of Taiwan. Dr. BM was supported by grant 5 KL2 RR025757-04 from the Harvard Catalyst and grant 1K01 AG044543-01A1 from the National Institute on Aging. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCCAM, NIA, or NIH. NR 71 TC 3 Z9 4 U1 6 U2 28 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUN 9 PY 2015 VL 9 AR 332 DI 10.3389/fnhum.2015.00332 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA CK4EH UT WOS:000356173400001 PM 26106316 ER PT J AU Jain, NB Ayers, GD Peterson, EN Harris, MB Morse, L O'Connor, KC Garshick, E AF Jain, Nitin B. Ayers, Gregory D. Peterson, Emily N. Harris, Mitchel B. Morse, Leslie O'Connor, Kevin C. Garshick, Eric TI Traumatic Spinal Cord Injury in the United States, 1993-2012 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PREVALENCE; EPIDEMIOLOGY; MORTALITY AB IMPORTANCE Acute traumatic spinal cord injury results in disability and use of health care resources, yet data on contemporary national trends of traumatic spinal cord injury incidence and etiology are limited. OBJECTIVE To assess trends in acute traumatic spinal cord injury incidence, etiology, mortality, and associated surgical procedures in the United States from 1993 to 2012. DESIGN, SETTING, AND PARTICIPANTS Analysis of survey data from the US Nationwide Inpatient Sample databases for 1993-2012, including a total of 63 109 patients with acute traumatic spinal cord injury. MAIN OUTCOMES AND MEASURES Age-and sex-stratified incidence of acute traumatic spinal cord injury; trends in etiology and in-hospital mortality of acute traumatic spinal cord injury. RESULTS In 1993, the estimated incidence of acute spinal cord injury was 53 cases (95% CI, 52-54 cases) per 1 million persons based on 2659 actual cases. In 2012, the estimated incidence was 54 cases (95% CI, 53-55 cases) per 1 million population based on 3393 cases (average annual percentage change, 0.2%; 95% CI, -0.5% to 0.9%). Incidence rates among the younger male population declined from 1993 to 2012: for age 16 to 24 years, from 144 cases/million (2405 cases) to 87 cases/million (1770 cases) (average annual percentage change, -2.5%; 95% CI, -3.3% to -1.8%); for age 25 to 44 years, from 96 cases/million (3959 cases) to 71 cases/million persons (2930 cases), (average annual percentage change, -1.2%; 95% CI, -2.1% to -0.3%). A high rate of increase was observed in men aged 65 to 74 years (from 84 cases/million in 1993 [695 cases] to 131 cases/million [1465 cases]; average annual percentage change, 2.7%; 95% CI, 2.0%-3.5%). The percentage of spinal cord injury associated with falls increased significantly from 28%(95% CI, 26%-30%) in 1997-2000 to 66%(95% CI, 64%-68%) in 2010-2012 in those aged 65 years or older (P <.001). Although overall in-hospital mortality increased from 6.6%(95% CI, 6.1%-7.0%) in 1993-1996 to 7.5% (95% CI, 7.0%-8.0%) in 2010-2012 (P <.001), mortality decreased significantly from 24.2% (95% CI, 19.7%-28.7%) in 1993-1996 to 20.1% (95% CI, 17.0%-23.2%) in 2010-2012 (P =.003) among persons aged 85 years or older. CONCLUSIONS AND RELEVANCE Between 1993 and 2012, the incidence rate of acute traumatic spinal cord injury remained relatively stable but, reflecting an increasing population, the total number of cases increased. The largest increase in incidence was observed in older patients, largely associated with an increase in falls, and in-hospital mortality remained high, especially among elderly persons. C1 [Jain, Nitin B.] Vanderbilt Univ, Sch Med, Dept Phys Med & Rehabil, Nashville, TN 37202 USA. [Jain, Nitin B.] Vanderbilt Univ, Sch Med, Dept Orthopaed & Rehabil, Nashville, TN 37202 USA. [Ayers, Gregory D.; Peterson, Emily N.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37202 USA. [Harris, Mitchel B.] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Harris, Mitchel B.; Morse, Leslie; Garshick, Eric] Harvard Univ, Sch Med, Boston, MA USA. [Morse, Leslie; O'Connor, Kevin C.] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Garshick, Eric] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Garshick, Eric] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Med Serv, Boston, MA USA. RP Jain, NB (reprint author), Vanderbilt Univ, Sch Med, Dept Phys Med & Rehabil, 2201 Childrens Way,Ste 1318, Nashville, TN 37202 USA. EM nitin.jain@vanderbilt.edu RI Morse, Leslie/C-9442-2015 OI Morse, Leslie/0000-0002-7426-6341 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [1K23AR059199]; Foundation for Physical Medicine and Rehabilitation; VA Rehabilitation Research and Development Merit Review grants [B6618R, I01RX000792]; National Institute of Health [AR059270]; US Department of Education National Institute on Disability and Rehabilitation Research grant [H133N110010] FX Dr Jain is supported by funding from National Institute of Arthritis and Musculoskeletal and Skin Diseases project 1K23AR059199 and the Foundation for Physical Medicine and Rehabilitation. Drs Morse and Garshick are supported by VA Rehabilitation Research and Development Merit Review grants B6618R and I01RX000792, National Institute of Health grant AR059270, and US Department of Education National Institute on Disability and Rehabilitation Research grant H133N110010. NR 37 TC 37 Z9 38 U1 3 U2 12 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 JUN 9 PY 2015 VL 313 IS 22 BP 2236 EP 2243 DI 10.1001/jama.2015.6250 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK1VH UT WOS:000355995300017 PM 26057284 ER PT J AU Czanner, G Sarma, SV Ba, D Eden, UT Wu, W Eskandar, E Lim, HH Temereanca, S Suzuki, WA Brown, EN AF Czanner, Gabriela Sarma, Sridevi V. Ba, Demba Eden, Uri T. Wu, Wei Eskandar, Emad Lim, Hubert H. Temereanca, Simona Suzuki, Wendy A. Brown, Emery N. TI Measuring the signal-to-noise ratio of a neuron SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SNR; signal-to-noise ratio; neuron; simulation; point processes ID MAXIMUM-LIKELIHOOD-ESTIMATION; REGRESSION-MODELS; SPIKE TRAINS; INFORMATION; STIMULATION; ENSEMBLE; DYNAMICS; CELLS; TRIAL AB The signal-to-noise ratio (SNR), a commonly used measure of fidelity in physical systems, is defined as the ratio of the squared amplitude or variance of a signal relative to the variance of the noise. This definition is not appropriate for neural systems in which spiking activity is more accurately represented as point processes. We show that the SNR estimates a ratio of expected prediction errors and extend the standard definition to one appropriate for single neurons by representing neural spiking activity using point process generalized linear models (PP-GLM). We estimate the prediction errors using the residual deviances from the PP-GLM fits. Because the deviance is an approximate chi(2) random variable, we compute a bias-corrected SNR estimate appropriate for single-neuron analysis and use the bootstrap to assess its uncertainty. In the analyses of four systems neuroscience experiments, we show that the SNRs are -10 dB to -3 dB for guinea pig auditory cortex neurons, -18 dB to -7 dB for rat thalamic neurons, -28 dB to -14 dB for monkey hippocampal neurons, and -29 dB to -20 dB for human subthalamic neurons. The new SNR definition makes explicit in the measure commonly used for physical systems the often-quoted observation that single neurons have low SNRs. The neuron's spiking history is frequently a more informative covariate for predicting spiking propensity than the applied stimulus. Our new SNR definition extends to any GLM system in which the factors modulating the response can be expressed as separate components of a likelihood function. C1 [Czanner, Gabriela] Univ Liverpool, Fac Hlth & Life Sci, Dept Biostat, Liverpool L69 3GA, Merseyside, England. [Czanner, Gabriela] Univ Liverpool, Fac Hlth & Life Sci, Dept Eye & Vis Sci, Liverpool L69 3GA, Merseyside, England. [Sarma, Sridevi V.] Johns Hopkins Univ, Inst Computat Med, Dept Biomed Engn, Baltimore, MD 21218 USA. [Ba, Demba; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Eden, Uri T.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Wu, Wei] S China Univ Technol, Sch Automat Sci & Engn, Guangzhou 510640, Guangdong, Peoples R China. [Eskandar, Emad] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. [Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Lim, Hubert H.] Univ Minnesota, Inst Translat Neurosci, Dept Biomed Engn, Minneapolis, MN 55455 USA. [Temereanca, Simona] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging,Med Sch, Charlestown, MA 02129 USA. [Suzuki, Wendy A.] NYU, Ctr Neural Sci, New York, NY 10003 USA. RP Czanner, G (reprint author), Univ Liverpool, Fac Hlth & Life Sci, Dept Biostat, Liverpool L69 3GA, Merseyside, England. EM czanner@liverpool.ac.uk; enb@neurostat.mit.edu OI Czanner, Gabriela/0000-0002-1157-2093 FU Clinical Eye Research Centre, St. Paul's Eye Unit, Royal Liverpool and Broadgreen University Hospitals National Health Service Trust, United Kingdom; US National Institutes of Health (NIH) Biomedical Research Engineering Partnership Award [R01-DA015644, DP1 OD003646, GM 104948]; NIH [P41 EB2030, T32 DC00011] FX This research was supported in part by the Clinical Eye Research Centre, St. Paul's Eye Unit, Royal Liverpool and Broadgreen University Hospitals National Health Service Trust, United Kingdom (G.C.); the US National Institutes of Health (NIH) Biomedical Research Engineering Partnership Award R01-DA015644 (to E.N.B. and W.A.S.), Pioneer Award DP1 OD003646 (to E.N.B.), and Transformative Research Award GM 104948 (to E.N.B.); and NIH grants that supported the guinea pig experiments P41 EB2030 and T32 DC00011 (to H.H.L.). NR 39 TC 4 Z9 4 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 2015 VL 112 IS 23 BP 7141 EP 7146 DI 10.1073/pnas.1505545112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9LG UT WOS:000355823200031 PM 25995363 ER PT J AU Carpio, MA Michaud, M Zhou, WP Fisher, JK Walensky, LD Katz, SG AF Carpio, Marcos A. Michaud, Michael Zhou, Wenping Fisher, Jill K. Walensky, Loren D. Katz, Samuel G. TI BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BOK; apoptosis; BCL-2 family; endoplasmic reticulum stress; unfolded protein response ID CELL-DEATH; PROAPOPTOTIC BAX; PROTEIN FAMILY; EXPRESSION; TISSUES; ABSENCE AB B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a BCL-2 family protein with high homology to the multidomain proapoptotic proteins BAX and BAK, yet Bok(-/-) and even Bax(-/-) Bok(-/-) and Bak(-/-) Bok(-/-) mice were reported to have no overt phenotype or apoptotic defects in response to a host of classical stress stimuli. These surprising findings were interpreted to reflect functional compensation among the BAX, BAK, and BOK proteins. However, BOK cannot compensate for the severe apoptotic defects of Bax(-/-) Bak(-/-) mice despite its widespread expression. Here, we independently developed Bok(-/-) mice and found that Bok(-/-) cells are selectively defective in their response to endoplasmic reticulum (ER) stress stimuli, consistent with the predominant subcellular localization of BOK at the ER. Whereas Bok(-/-) mouse embryonic fibroblasts exposed to thapsigargin, A23187, brefeldin A, DTT, geldanamycin, or bortezomib manifested reduced activation of the mitochondrial apoptotic pathway, the death response to other stimuli such as etoposide, staurosporine, or UV remained fully intact. Multiple organs in Bok(-/-) mice exhibited resistance to thapsigargin-induced apoptosis in vivo. Although the ER stress agents activated the unfolded protein response, both ATF4 and CHOP activation were diminished in Bok(-/-) cells and mice. Importantly, BAX and BAK were unable to compensate for the defective apoptotic response to ER stress observed in SV40-transformed and primary Bok(-/-) cells, and in vivo. These findings support a selective and distinguishing role for BOK in regulating the apoptotic response to ER stress, revealing-to our knowledge-the first bona fide apoptotic defect linked to Bok deletion. C1 [Carpio, Marcos A.; Michaud, Michael; Zhou, Wenping; Katz, Samuel G.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Fisher, Jill K.; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Fisher, Jill K.; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA. RP Walensky, LD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM loren_walensky@dfci.harvard.edu; samuel.katz@yale.edu FU NIH [5R01CA050239, 5K08HL103847]; Leukemia and Lymphoma Society (LLS) Marshall A. Lichtman Specialized Center of Research project grant; LLS Scholar Award FX This work was supported by NIH Grant 5R01CA050239, a Leukemia and Lymphoma Society (LLS) Marshall A. Lichtman Specialized Center of Research project grant, and LLS Scholar Award (to L.D.W.), and NIH Grant 5K08HL103847 (to S.G.K.). NR 24 TC 20 Z9 21 U1 1 U2 8 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 JUN 9 PY 2015 VL 112 IS 23 BP 7201 EP 7206 DI 10.1073/pnas.1421063112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9LG UT WOS:000355823200041 PM 26015568 ER PT J AU Gilmore, MS Rauch, M Ramsey, MM Himes, PR Varahan, S Manson, JM Lebreton, F Hancock, LE AF Gilmore, Michael S. Rauch, Marcus Ramsey, Matthew M. Himes, Paul R. Varahan, Sriram Manson, Janet M. Lebreton, Francois Hancock, Lynn Ernest TI Pheromone killing of multidrug-resistant Enterococcus faecalis V583 by native commensal strains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Enterococcus; vancomycin; antibiotics; resistance; fitness cost ID SEX-PHEROMONE; STREPTOCOCCUS-FAECALIS; PATHOGENICITY ISLAND; PLASMID TRANSFER; EVOLUTION; VIRULENCE; IDENTIFICATION; BACTERIOCIN; SENSITIVITY; CONJUGATION AB Multidrug-resistant Enterococcus faecalis possess numerous mobile elements that encode virulence and antibiotic resistance traits as well as new metabolic pathways, often constituting over one-quarter of the genome. It was of interest to determine how this large accretion of mobile elements affects competitive growth in the gastrointestinal (GI) tract consortium. We unexpectedly observed that the prototype clinical isolate strain V583 was actively killed by GI tract flora, whereas commensal enterococci flourished. It was found that killing of V583 resulted from lethal cross-talk between accumulated mobile elements and that this cross-talk was induced by a heptapeptide pheromone produced by native E. faecalis present in the fecal consortium. These results highlight two important aspects of the evolution of multidrug-resistant enterococci: (i) the accretion of mobile elements in E. faecalis V583 renders it incompatible with commensal strains, and (ii) because of this incompatibility, multidrug-resistant strains sharing features found in V583 cannot coexist with commensal strains. The accumulation of mobile elements in hospital isolates of enterococci can include those that are inherently incompatible with native flora, highlighting the importance of maintaining commensal populations as means of preventing colonization and subsequent infection by multidrug-resistant strains. C1 [Gilmore, Michael S.; Rauch, Marcus; Ramsey, Matthew M.; Himes, Paul R.; Manson, Janet M.; Lebreton, Francois] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Gilmore, Michael S.; Rauch, Marcus; Ramsey, Matthew M.; Himes, Paul R.; Manson, Janet M.; Lebreton, Francois] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Varahan, Sriram; Hancock, Lynn Ernest] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. RP Gilmore, MS (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM michael_gilmore@meei.harvard.edu FU NIAID NIH HHS [R01 AI077782] NR 45 TC 5 Z9 5 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 JUN 9 PY 2015 VL 112 IS 23 BP 7273 EP 7278 DI 10.1073/pnas.1500553112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9LG UT WOS:000355823200053 PM 26039987 ER PT J AU Camarata, TD Weaver, GC Vasilyev, A Arnaout, MA AF Camarata, Troy D. Weaver, Grant C. Vasilyev, Alexandr Arnaout, M. Amin TI Negative Regulation of TGF beta Signaling by Stem Cell Antigen-1 Protects against Ischemic Acute Kidney Injury SO PLOS ONE LA English DT Article ID MESENCHYMAL TRANSITION; GENE-EXPRESSION; RENAL FIBROSIS; MUSCLE-CELLS; NULL MICE; SCA-1; PROLIFERATION; RECEPTOR; DIFFERENTIATION; DISEASE AB Acute kidney injury, often caused by an ischemic insult, is associated with significant short-term morbidity and mortality, and increased risk of chronic kidney disease. The factors affecting the renal response to injury following ischemia and reperfusion remain to be clarified. We found that the Stem cell antigen-1 (Sca-1), commonly used as a stem cell marker, is heavily expressed in renal tubules of the adult mouse kidney. We evaluated its potential role in the kidney using Sca-1 knockout mice submitted to acute ischemia reperfusion injury (IRI), as well as cultured renal proximal tubular cells in which Sca-1 was stably silenced with shRNA. IRI induced more severe injury in Sca-1 null kidneys, as assessed by increased expression of Kim-1 and Ngal, rise in serum creatinine, abnormal pathology, and increased apoptosis of tubular epithelium, and persistent significant renal injury at day 7 post IRI, when recovery of renal function in control animals was nearly complete. Serum creatinine, Kim-1 and Ngal were slightly but significantly elevated even in uninjured Sca-1-/- kidneys. Sca-1 constitutively bound both TGF beta receptors I and II in cultured normal proximal tubular epithelial cells. Its genetic loss or silencing lead to constitutive TGF beta receptor-mediated activation of canonical Smad signaling even in the absence of ligand and to KIM-1 expression in the silenced cells. These studies demonstrate that by normally repressing TGF beta-mediated canonical Smad signaling, Sca-1 plays an important in renal epithelial cell homeostasis and in recovery of renal function following ischemic acute kidney injury. C1 [Camarata, Troy D.; Weaver, Grant C.; Vasilyev, Alexandr; Arnaout, M. Amin] Massachusetts Gen Hosp, Leukocyte Biol & Inflammat Program, Div Renal, Charlestown, MA 02114 USA. [Camarata, Troy D.; Weaver, Grant C.; Vasilyev, Alexandr; Arnaout, M. Amin] Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA. [Arnaout, M. Amin] Massachusetts Gen Hosp, Dept Med, Ctr Regenerat Med, Charlestown, MA USA. RP Arnaout, MA (reprint author), Massachusetts Gen Hosp, Leukocyte Biol & Inflammat Program, Div Renal, Charlestown, MA 02114 USA. EM aarnaout1@mgh.harvard.edu FU NIH [DK088327, DK48549, DK007540]; National Institutes of Diabetes, Digestive and Kidney diseases (NIDDK) of the National Institutes of Health [F32DK088437] FX This research was supported by NIH grants DK088327, DK48549 and DK007540 (to MAA) and F32DK088437 (to TC) from the National Institutes of Diabetes, Digestive and Kidney diseases (NIDDK) of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 1 Z9 2 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 JUN 8 PY 2015 VL 10 IS 6 AR e0129561 DI 10.1371/journal.pone.0129561 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1GM UT WOS:000355955300143 PM 26053644 ER PT J AU Moledina, DG Parikh, CR Garg, AX Thiessen-Philbrook, H Koyner, JL Patel, UD Devarajan, P Shlipak, MG Coca, SG AF Moledina, Dennis G. Parikh, Chirag R. Garg, Amit X. Thiessen-Philbrook, Heather Koyner, Jay L. Patel, Uptal D. Devarajan, Prasad Shlipak, Michael G. Coca, Steven G. CA TRIBE-AKI Consortium TI Association of Perioperative Plasma Neutrophil Gelatinase-Associated Lipocalin Levels with 3-Year Mortality after Cardiac Surgery: A Prospective Observational Cohort Study SO PLOS ONE LA English DT Article ID ACUTE KIDNEY INJURY; GLOMERULAR-FILTRATION-RATE; ISCHEMIC RENAL INJURY; POOR OUTCOMES; BIOMARKERS; NGAL; DISEASE; AKI AB Background Higher levels of plasma neutrophil gelatinase-associated lipocalin (pNGAL) are an early marker of acute kidney injury and are associated with increased risk of short-term adverse outcomes. The independent association between pNGAL and long-term mortality is unknown. Methods In this prospective observational cohort study, we studied 1191 adults who underwent cardiac surgery between 2007 and 2009 at 6 centers in the TRIBE-AKI cohort. We measured the pNGAL on the pre-operative and first 3 post-operative days and assessed the relationship of peri-operative pNGAL concentrations with all-cause mortality. Results During a median follow-up of 3.0 years, 139 participants died (50/1000 person-years). Pre-operative levels of pNGAL were associated with 3-year mortality (unadjusted HR 1.96, 95% CI 1.34,2.85) and the association persisted after adjustment for pre-operative variables including estimated glomerular filtration rate (adjusted HR 1.48, 95% CI 1.04-2.12). After adjustment for pre- and intra-operative variables, including pre-operative NGAL levels, the highest tertiles of first post-operative and peak post-operative pNGAL were also independently associated with 3-year mortality risk (adjusted HR 1.31, 95% CI 1.0-1.7 and adjusted HR 1.78, 95% CI 1.2-2.7, respectively). However, after adjustment for peri-operative changes in serum creatinine, there was no longer an independent association between the first post-operative and peak post-operative pNGAL and long-term mortality (adjusted HR 0.98,95% CI 0.79-1.2 for first pNGAL and adjusted HR 1.19, 95% CI 0.87-1.61 for peak pNGAL). Conclusions Pre-operative pNGAL levels were independently associated with 3-year mortality after cardiac surgery. While post-operative pNGAL levels were also associated with 3-year mortality, this relationship was not independent of changes in serum creatinine. These findings suggest that while pre-operative pNGAL adds prognostic value for mortality beyond routinely available serum creatinine, post-operative pNGAL measurements may not be as useful for this purpose. C1 [Moledina, Dennis G.; Parikh, Chirag R.; Coca, Steven G.] Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA. [Moledina, Dennis G.; Parikh, Chirag R.; Coca, Steven G.] VA CT Healthcare Syst, West Haven, CT USA. [Moledina, Dennis G.; Parikh, Chirag R.; Coca, Steven G.] Yale Univ, Sch Med, Program Appl Translat Res, New Haven, CT 06510 USA. [Garg, Amit X.; Thiessen-Philbrook, Heather] Univ Western Ontario, Dept Med, Div Nephrol, London, ON, Canada. [Garg, Amit X.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Koyner, Jay L.] Univ Chicago, Dept Med, Nephrol Sect, Chicago, IL 60637 USA. [Patel, Uptal D.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Devarajan, Prasad] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. RP Parikh, CR (reprint author), Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA. EM chirag.parikh@yale.edu OI Moledina, Dennis/0000-0002-9537-9038 FU NIH [RO1HL085757, K24DK090203, U01DK082185]; Career Development Award from NIH [K23DK080132]; O'Brien Kidney Center Grant [P30 DK079310-07]; Institute for Clinical Evaluative Sciences (ICES) - Ontario Ministry of Health and Long-Term Care (MOHLTC); [R01DK096549] FX The study was supported by the NIH grant RO1HL085757 (CRP) to fund the TRIBE-AKI Consortium to study novel biomarkers of acute kidney injury in cardiac surgery. SGC has been supported by Career Development Award from the NIH (K23DK080132) and R01DK096549. CRP is also supported by NIH grant K24DK090203. CRP was supported by the P30 DK079310-07 O'Brien Kidney Center Grant. SGC, AXG, PD, and CRP are also members of the NIH-sponsored ASsess, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Consortium (U01DK082185). The plasma NGAL assays were donated by Biosite. Biosite, Inc., did not participate in the protocol development, analysis, or interpretation of the results. This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 3 Z9 3 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 JUN 8 PY 2015 VL 10 IS 6 AR UNSP e0129619 DI 10.1371/journal.pone.0129619 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1GM UT WOS:000355955300153 PM 26053382 ER PT J AU von Einem, B Wahler, A Schips, T Serrano-Pozo, A Proepper, C Boeckers, TM Rueck, A Wirth, T Hyman, BT Danzer, KM Thal, DR von Arnim, CAF AF von Einem, Bjoern Wahler, Anke Schips, Tobias Serrano-Pozo, Alberto Proepper, Christian Boeckers, Tobias M. Rueck, Angelika Wirth, Thomas Hyman, Bradley T. Danzer, Karin M. Thal, Dietmar R. von Arnim, Christine A. F. TI The Golgi-Localized gamma-Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid-beta Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1) SO PLOS ONE LA English DT Article ID SECRETASE CYTOSOLIC DOMAIN; FACTOR-II RECEPTOR; ALZHEIMERS-DISEASE; TRANS-GOLGI; VHS DOMAINS; CARBOXYL-TERMINUS; ACIDIC-CLUSTER; MUTATIONAL ANALYSIS; CYTOPLASMIC DOMAIN; SORTING-SIGNAL AB Proteolytic processing of amyloid-beta precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) is the initial step in the production of amyloid beta (A beta), which accumulates in senile plaques in Alzheimer's disease (AD). Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized.-ear-containing ARF-binding (GGA) proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in neurons, and to be decreased in AD brain, whereas little is known about GGA2. Since GGA1 impacts A beta generation by confining APP to the Golgi and perinuclear compartments, we tested whether all GGAs modulate BACE1 and APP transport and processing. We observed decreased levels of secreted APP alpha (sAPP alpha), sAPP beta, and A beta upon GGA overexpression, which could be reverted by knockdown. GGA-BACE1 co-immunoprecipitation was impaired upon GGA-GAE but not VHS domain deletion. Autoinhibition of the GGA1-VHS domain was irrelevant for BACE1 interaction. Our data suggest that all three GGAs affect APP processing via the GGA-GAE domain. C1 [von Einem, Bjoern; Wahler, Anke; Danzer, Karin M.; von Arnim, Christine A. F.] Univ Ulm, Inst Neurol, D-89081 Ulm, Germany. [Schips, Tobias; Wirth, Thomas] Univ Ulm, Inst Physiol Chem, D-89081 Ulm, Germany. [Serrano-Pozo, Alberto; Hyman, Bradley T.] Massachusetts Gen Hosp, Inst Neurodegenerat Dis, Charlestown, MA USA. [Proepper, Christian; Boeckers, Tobias M.] Univ Ulm, Inst Anat & Cell Biol, D-89081 Ulm, Germany. [Rueck, Angelika] Univ Ulm, Core Facil Laser Microscopy, D-89081 Ulm, Germany. [Thal, Dietmar R.] Univ Ulm, Inst Pathol, Lab Neuropathol, D-89081 Ulm, Germany. RP von Arnim, CAF (reprint author), Univ Ulm, Inst Neurol, Helmholtzstr 8-1, D-89081 Ulm, Germany. EM christine.arnim@uni-ulm.de FU Alzheimer Forschung Initiative e.V. (AFI) [05825]; AiF/IGF grant of Bundesministerium fur Wirtschaft [15727 N/1]; Ernst Schering Foundation FX This research was supported by grants to C.A.F. v.A from the Alzheimer Forschung Initiative e.V. (AFI) (grant number 05825) and from an AiF/IGF grant (grant number 15727 N/1) of the Bundesministerium fur Wirtschaft, as well as a Doctoral Fellowship to A.W. from the Ernst Schering Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 3 Z9 3 U1 1 U2 7 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 JUN 8 PY 2015 VL 10 IS 6 AR e0129047 DI 10.1371/journal.pone.0129047 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1GM UT WOS:000355955300079 PM 26053850 ER PT J AU Yang, C Yang, ZY Chen, XL Liu, T Gou, SM Chen, CZ Xiao, J Jin, X He, ZQ Dong, LM Zhang, YS Luo, N Wu, HS Wang, CY AF Yang, Chong Yang, Zhiyong Chen, Xinglin Liu, Tao Gou, Shanmiao Chen, Changzhong Xiao, Jun Jin, Xin He, Zhiqiang Dong, Liming Zhang, Yushun Luo, Na Wu, Heshui Wang, Chunyou TI Inverted U-Shaped Relationship between Central Venous Pressure and Intra-Abdominal Pressure in the Early Phase of Severe Acute Pancreatitis: A Retrospective Study SO PLOS ONE LA English DT Article ID ABDOMINAL COMPARTMENT SYNDROME; PREDICT FLUID RESPONSIVENESS; SURVIVING SEPSIS CAMPAIGN; RECEPTOR BLOCKADE; SEPTIC SHOCK; HYPERTENSION; RESUSCITATION; MANAGEMENT; GUIDELINES; CARE AB Objective Many studies have indicated that intra-abdominal pressure (IAP) is positively correlated with central venous pressure (CVP) in severe cases. However, although elevated IAP is common in patients with severe acute pancreatitis (SAP), its relationship with CVP remains unclear. Our study aimed to investigate the association of IAP with CVP in early-phase SAP patients. Methods In total, 116 SAP patients were included in this retrospective study. On the first day of hospitalization, blood samples were collected for biochemical examination and cytokine concentration monitoring. Additionally, a urinary catheter and right subclavian vein catheter were inserted for IAP and CVP measurement, respectively. Other routine clinical data were also recorded. Results Within 24 hours after hospitalization, CVP fluctuated and increased with increasing IAP up to 15.7 mmHg (P = 0.054) but decreased with increasing IAP when the IAP was > 15.7 mmHg (P < 0.001). After adjusting for abdominal perfusion pressure (APP) and mean arterial pressure (MAP), a similar distribution was observed. An inverted U-shaped trend between IAP and CVP was also present in the groups classified according to the patient's sex, local complications, ascites, and serum amylase levels. Conclusions CVP and IAP have an inverted U-shaped relationship, with a peak at an IAP of 15.7 mmHg in the early phase of SAP. After this peak, CVP decreases as IAP increases. These results have crucial implications for clinical fluid resuscitation in SAP patients. In particular, because one CVP value might be correlated with different IAP values in patients with the same CVP, the volume of fluid needed might be different. C1 [Yang, Chong; Yang, Zhiyong; Gou, Shanmiao; He, Zhiqiang; Dong, Liming; Zhang, Yushun; Wu, Heshui; Wang, Chunyou] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Pancreat Dis Inst, Wuhan 430074, Hubei Province, Peoples R China. [Yang, Chong] Sichuan Acad Med Sci, Organ Transplant Ctr, Chengdu, Sichuan Provinc, Peoples R China. [Yang, Chong] Sichuan Prov Peoples Hosp, Chengdu, Sichuan Provinc, Peoples R China. [Yang, Chong] Univ Elect Sci & Technol China, Sch Med, Chengdu 610054, Sichuan Provinc, Peoples R China. [Chen, Xinglin] Huazhong Univ Sci & Technol, Key Lab Geriatr, Minist Hlth, Dept Geriatr,Union Hosp,Tongji Med Coll, Wuhan 430074, Hubei Province, Peoples R China. [Xiao, Jun; Jin, Xin] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Surg Oncol Abdominal Dept,Canc Ctr, Wuhan 430074, Hubei Province, Peoples R China. [Chen, Changzhong] Dana Farber Canc Inst, Microarray Core Facil, Boston, MA 02115 USA. [Luo, Na] Univ Hong Kong, Ctr Appl English Studies, Hong Kong, Hong Kong, Peoples R China. RP Wu, HS (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Pancreat Dis Inst, Wuhan 430074, Hubei Province, Peoples R China. EM heshuiwu@163.com; chunyouwang52@126.com FU National Natural Science Foundation of China [81171840] FX This work was supported by a grant from the National Natural Science Foundation of China (No. 81171840). This funder did not participate in the development of the study or the manuscript, including study design, collection, analysis, or interpretation of the data; writing of the manuscript; or the decision to submit the paper for publication. NR 42 TC 1 Z9 1 U1 2 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 JUN 8 PY 2015 VL 10 IS 6 AR e0128493 DI 10.1371/journal.pone.0128493 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1GM UT WOS:000355955300042 PM 26053865 ER PT J AU Flanz, J AF Flanz, Jacob TI Accelerators for charged particle therapy SO MODERN PHYSICS LETTERS A LA English DT Article DE Hadron therapy; proton therapy; accelerator; beam delivery AB History has shown that energetic particles can be useful for medical applications. From the time, in 1895 when Roentgen discovered X-rays, and in 1913 when Coolidge developed the vacuum X-ray tube, energetic particles have been an important tool for medicine. Development of the appropriate tool for effective and safe radiotherapy requires an in-depth understanding of the application and constraints. Various solutions are possible and choices must be analyzed on the basis of the suitability for meeting the requirements. Some of the requirements of charged particle therapy are summarized and various accelerator options are described and discussed. C1 Harvard Univ, Dept Radiat Oncol, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. RP Flanz, J (reprint author), Harvard Univ, Dept Radiat Oncol, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. EM Flanz@hadron.mgh.harvard.edu NR 12 TC 1 Z9 2 U1 1 U2 8 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0217-7323 EI 1793-6632 J9 MOD PHYS LETT A JI Mod. Phys. Lett. A PD JUN 7 PY 2015 VL 30 IS 17 SI SI AR 1540020 DI 10.1142/S0217732315400209 PG 19 WC Physics, Nuclear; Physics, Particles & Fields; Physics, Mathematical SC Physics GA CI8IM UT WOS:000355016000004 ER PT J AU Mega, JL Stitziel, NO Smith, JG Chasman, DI Caulfield, MJ Devlin, JJ Nordio, F Hyde, CL Cannon, CP Sacks, FM Poulter, NR Sever, PS Ridker, PM Braunwald, E Melander, O Kathiresan, S Sabatine, MS AF Mega, Jessica L. Stitziel, Nathan O. Smith, J. Gustav Chasman, Daniel I. Caulfield, Mark J. Devlin, James J. Nordio, Francesco Hyde, Craig L. Cannon, Christopher P. Sacks, Frank M. Poulter, Neil R. Sever, Peter S. Ridker, Paul M. Braunwald, Eugene Melander, Olle Kathiresan, Sekar Sabatine, Marc S. TI Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials SO LANCET LA English DT Article ID RECURRENT MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; ARTERY-DISEASE; SUSCEPTIBILITY LOCI; RANDOMIZED-TRIALS; LDL CHOLESTEROL; CHROMOSOME 9P21; GRACE GENETICS; CARDIAC DEATH; POLYMORPHISMS AB Background Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. Methods A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48 421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1.34 (95% CI 1.22-1.47, p <0.0001) and that for the high genetic risk category was 1.72 (1.55-1.92, p<0.0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0.0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0.0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. C1 [Mega, Jessica L.; Nordio, Francesco; Cannon, Christopher P.; Braunwald, Eugene; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Mega, Jessica L.; Chasman, Daniel I.; Nordio, Francesco; Cannon, Christopher P.; Ridker, Paul M.; Braunwald, Eugene; Sabatine, Marc S.] Harvard Univ, Sch Med, Boston, MA USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden. [Smith, J. Gustav] Skane Univ Hosp, Lund, Sweden. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Genet, Boston, MA 02115 USA. [Caulfield, Mark J.] Queen Mary Univ London, William Harvey Res Inst, London, England. [Caulfield, Mark J.] Barts NIHR CV Biomed Res Inst, London, England. [Devlin, James J.] Quest Diagnost, Alameda, CA USA. [Hyde, Craig L.] Pfizer Res Lab, Groton, CT USA. [Sacks, Frank M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sacks, Frank M.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Poulter, Neil R.; Sever, Peter S.] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, Natl Heart & Lung Inst, London SW7 2AZ, England. RP Mega, JL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jmega@partners.org; nstitziel@wustl.edu OI Stitziel, Nathan/0000-0002-4963-8211 FU National Institutes of Health; AstraZeneca; Pfizer; Bristol-Myers Squibb; Sankyo; Swedish Research Council; Swedish Heart and Lung Foundation; European Research Council; Novo Nordisk Foundation; National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) [RC1 HL099634]; NIH; NHLBI [K08 HL114642]; NIHR FX National Institutes of Health.; JUPITER was supported by AstraZeneca; ASCOT was supported by Pfizer; CARE was supported by Bristol-Myers Squibb; and PROVE IT-TIMI 22 was supported by Bristol-Myers Squibb and Sankyo. The Malmo Diet and Cancer Study was funded by The Swedish Research Council, The Swedish Heart and Lung Foundation, the European Research Council, and the Novo Nordisk Foundation. Research reported in this publication was supported by National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) under award number RC1 HL099634. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NOS was supported in part by a career development award from the NIH and the NHLBI (grant K08 HL114642). This work was facilitated by the National Institute for Health Research (NIHR) Biomedical Research Unit at Barts (London, UK) and the NIHR Biomedical Research Centre at Imperial College (London, UK). MC, NP, and PS are recipients of NIHR Senior Investigator Awards. NR 43 TC 57 Z9 57 U1 6 U2 23 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 JUN 6 PY 2015 VL 385 IS 9984 BP 2264 EP 2271 DI 10.1016/S0140-6736(14)61730-X PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK1CR UT WOS:000355943500028 PM 25748612 ER PT J AU Mega, JL Walker, JR Ruff, CT Vandell, AG Nordio, F Deenadayalu, N Murphy, SA Lee, J Mercuri, MF Giugliano, RP Antman, EM Braunwald, E Sabatine, MS AF Mega, Jessica L. Walker, Joseph R. Ruff, Christian T. Vandell, Alexander G. Nordio, Francesco Deenadayalu, Naveen Murphy, Sabina A. Lee, James Mercuri, Michele F. Giugliano, Robert P. Antman, Elliott M. Braunwald, Eugene Sabatine, Marc S. TI Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial SO LANCET LA English DT Article ID ANTICOAGULATION-RELATED OUTCOMES; ATRIAL-FIBRILLATION; BLEEDING COMPLICATIONS; CYP2C9; ASSOCIATION; POLYMORPHISMS; VARIANTS; THERAPY; VKORC1; RISK AB Background Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who are at increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin. Methods ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2.0-3.0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1. The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov, number NCT00781391. Findings 14 348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61.7%) were classified as normal responders, 1711 (35.4%) as sensitive responders, and 140 (2.9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2.2%, IQR 0-20.2; 8.4%, 0-25.8; and 18.3%, 0-32.6; p(trend) <0.0001) and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1.31, 95% CI 1.05-1.64, p=0.0179; highly sensitive responders 2.66, 1.69-4.19, p<0.0001). Genotype added independent information beyond clinical risk scoring. During the first 90 days, when compared with warfarin, treatment with edoxaban reduced bleeding more so in sensitive and highly sensitive responders than in normal responders (higher-dose edoxaban p(interaction) = 0.0066; lower-dose edoxaban p(interaction) = 0.0036). After 90 days, the reduction in bleeding risk with edoxaban versus warfarin was similarly beneficial across genotypes. Interpretation CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin. C1 [Mega, Jessica L.; Ruff, Christian T.; Nordio, Francesco; Deenadayalu, Naveen; Murphy, Sabina A.; Giugliano, Robert P.; Antman, Elliott M.; Braunwald, Eugene; Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Div Cardiovasc Med, Boston, MA 02115 USA. [Vandell, Alexander G.; Lee, James; Mercuri, Michele F.] Daiichi Sankyo Pharma Dev, Edison, NJ USA. [Walker, Joseph R.] Celgene Corp, Summit, NJ USA. RP Mega, JL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jmega@partners.org; msabatine@partners.org FU Daiichi Sankyo FX Daiichi Sankyo. NR 40 TC 37 Z9 37 U1 1 U2 5 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 JUN 6 PY 2015 VL 385 IS 9984 BP 2280 EP 2287 DI 10.1016/S0140-6736(14)61994-2 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK1CR UT WOS:000355943500030 PM 25769357 ER PT J AU Ruff, CT Giugliano, RP Braunwald, E Morrow, DA Murphy, SA Kuder, JF Deenadayalu, N Jarolim, P Betcher, J Shi, MG Brown, K Patel, I Mercuri, M Antman, EM AF Ruff, Christian T. Giugliano, Robert P. Braunwald, Eugene Morrow, David A. Murphy, Sabina A. Kuder, Julia F. Deenadayalu, Naveen Jarolim, Petr Betcher, Joshua Shi, Minggao Brown, Karen Patel, Indravadan Mercuri, Michele Antman, Elliott M. TI Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial SO LANCET LA English DT Article ID NONVALVULAR ATRIAL-FIBRILLATION; ORAL ANTICOAGULANTS; WARFARIN; MANAGEMENT; STROKE; METAANALYSIS; RIVAROXABAN; DABIGATRAN; INTENSITY; THERAPY AB Background New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events. Methods We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1: 1: 1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2.0-3.0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30-50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov, number NCT00781391. Findings Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16.0-48.5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0.35-0.85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48.5 ng/mL [SD 45.8] to 34.6 ng/mL [30.9]) and 35% (from 24.5 ng/mL [22.7] to 16.0 ng/mL [14.5]) and mean anti-FXa activity by 25% (from 0.85 IU/mL [0.76] to 0.64 IU/mL [0.54]) and 20% (from 0.44 IU/mL [0.37] to 0.35 IU/mL [0.28]) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose p(interaction)=0.85, lower dose p(interaction)=0.99) and provided even greater safety (major bleeding: higher dose p(interaction) 0.02, lower dose p(interaction)=0.002). Interpretation These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism. C1 [Ruff, Christian T.; Giugliano, Robert P.; Braunwald, Eugene; Morrow, David A.; Murphy, Sabina A.; Kuder, Julia F.; Deenadayalu, Naveen; Jarolim, Petr; Antman, Elliott M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ruff, Christian T.; Giugliano, Robert P.; Braunwald, Eugene; Morrow, David A.; Murphy, Sabina A.; Kuder, Julia F.; Deenadayalu, Naveen; Jarolim, Petr; Antman, Elliott M.] Harvard Univ, Sch Med, Boston, MA USA. [Betcher, Joshua] Quintiles Inc, Res Triangle Pk, NC USA. [Shi, Minggao; Brown, Karen; Patel, Indravadan; Mercuri, Michele] Daiichi Sankyo Pharma Dev, Edison, NJ USA. RP Ruff, CT (reprint author), TIMI Study Grp, Boston, MA 02115 USA. EM cruff@partners.org FU Daiichi-Sankyo Pharma Development; Daiichi-Sankyo Development FX Daiichi-Sankyo Pharma Development.; The ENGAGE AF-TIMI 48 trial was funded by Daiichi-Sankyo Development. NR 20 TC 57 Z9 58 U1 1 U2 13 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 JUN 6 PY 2015 VL 385 IS 9984 BP 2288 EP 2295 DI 10.1016/S0140-6736(14)61943-7 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK1CR UT WOS:000355943500031 PM 25769361 ER PT J AU Xu, GJ Kula, T Xu, QK Li, MZ Vernon, SD Ndung'u, T Ruxrungtham, K Sanchez, J Brander, C Chung, RT O'Connor, KC Walker, B Larman, HB Elledge, SJ AF Xu, George J. Kula, Tomasz Xu, Qikai Li, Mamie Z. Vernon, Suzanne D. Ndung'u, Thumbi Ruxrungtham, Kiat Sanchez, Jorge Brander, Christian Chung, Raymond T. O'Connor, Kevin C. Walker, Bruce Larman, H. Benjamin Elledge, Stephen J. TI Comprehensive serological profiling of human populations using a synthetic human virome SO SCIENCE LA English DT Article ID VIRAL-INFECTIONS; UNITED-STATES; RISK-FACTORS; SEROPREVALENCE; HUMAN-HERPESVIRUS-8; PREVALENCE; DISCOVERY; DISEASE; GENOME; TYPE-1 AB The human virome plays important roles in health and immunity. However, current methods for detecting viral infections and antiviral responses have limited throughput and coverage. Here, we present VirScan, a high-throughput method to comprehensively analyze antiviral antibodies using immunoprecipitation and massively parallel DNA sequencing of a bacteriophage library displaying proteome-wide peptides from all human viruses. We assayed over 108 antibody-peptide interactions in 569 humans across four continents, nearly doubling the number of previously established viral epitopes. We detected antibodies to an average of 10 viral species per person and 84 species in at least two individuals. Although rates of specific virus exposure were heterogeneous across populations, antibody responses targeted strongly conserved "public epitopes" for each virus, suggesting that they may elicit highly similar antibodies. VirScan is a powerful approach for studying interactions between the virome and the immune system. C1 [Xu, George J.] Harvard Univ, Program Biophys, Cambridge, MA 02115 USA. [Xu, George J.] Harvard Massachusetts Inst Technol MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Xu, George J.; Kula, Tomasz; Xu, Qikai; Li, Mamie Z.; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Med, Div Genet, Boston, MA 02115 USA. [Xu, George J.; Kula, Tomasz; Xu, Qikai; Li, Mamie Z.; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kula, Tomasz] Harvard Univ, Program Biol & Biomed Sci, Cambridge, MA 02115 USA. [Vernon, Suzanne D.; Elledge, Stephen J.] Solve ME CFS Initiat, Los Angeles, CA 90036 USA. [Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Ndung'u, Thumbi; Walker, Bruce] Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Ndung'u, Thumbi; Walker, Bruce] MIT, Ragon Inst Massachusetts Gen Hosp, Cambridge, MA 02139 USA. [Ndung'u, Thumbi; Walker, Bruce] Harvard Univ, Cambridge, MA 02139 USA. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. [Ruxrungtham, Kiat] Chulalongkorn Univ, Fac Med, Dept Med, Vaccine & Cellular Immunol Lab, Bangkok 10330, Thailand. [Ruxrungtham, Kiat] Chulalongkorn Univ, Chula Vaccine Res Ctr, Bangkok 10330, Thailand. [Sanchez, Jorge] Asociac Civil IMPACTA Salud & Educ, Lima, Peru. [Brander, Christian] Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, AIDS Res Inst IrsiCaixa, Badalona, Spain. [Brander, Christian] Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, AIDS Unit, Badalona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. [Chung, Raymond T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [O'Connor, Kevin C.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Larman, H. Benjamin] Johns Hopkins Univ, Dept Pathol, Div Immunol, Baltimore, MD 21205 USA. RP Elledge, SJ (reprint author), Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Med, Div Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu FU NIH [R37AI067073, N01-AI-30024, N01-AI-15422, N01-A1-30024]; International AIDS Vaccine Initiative [UKZNRSA1001]; South African Research Chairs Initiative; Victor Daitz Foundation; International Early Career Scientist Award from the Howard Hughes Medical Institute; NIH-National Institute of Dental and Craniofacial Research [R01 DE018925-04]; HIVACAT program; CUTHIVAC [241904]; TRF Senior Research Scholar, the Thailand Research Fund; Chulalongkorn University Research Professor Program, Thailand; NSF Graduate Research Fellowships Program; [NIH DA033541]; [AI082630] FX We thank E. Unger and S. Buranapraditkun for providing reagents, K. Wucherpfennig (Harvard) and H. Ploegh (MIT) for critical reading of the manuscript, and TWIST Bioscience for providing access to their advanced oligonucleotide synthesis technology. The cohort in Durban, South Africa, was funded by the NIH (R37AI067073) and the International AIDS Vaccine Initiative (UKZNRSA1001). T.N. received additional funding from the South African Research Chairs Initiative, the Victor Daitz Foundation, and an International Early Career Scientist Award from the Howard Hughes Medical Institute. R.T.C. was funded by grants NIH DA033541 and AI082630. C.B. and J.S. were supported by NIH N01-AI-30024 and N01-AI-15422, NIH-National Institute of Dental and Craniofacial Research R01 DE018925-04, the HIVACAT program, and CUTHIVAC 241904. K.R. is supported by TRF Senior Research Scholar, the Thailand Research Fund; the Chulalongkorn University Research Professor Program, Thailand; and NIH grant N01-A1-30024. G.J.X. and T.K. were supported by the NSF Graduate Research Fellowships Program. S.J.E. and B.W. are Investigators with the Howard Hughes Medical Institute. G.J.X., T.K., H.B.L., and S.J.E. are inventors on a patent application (application no. PCT/US14/70902) filed by Brigham and Women's Hospital, Incorporated that covers the use of phage display libraries to detect antiviral antibodies. NR 37 TC 32 Z9 32 U1 10 U2 23 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 JUN 5 PY 2015 VL 348 IS 6239 AR aaa0698 DI 10.1126/science.aaa0698 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ6FY UT WOS:000355590500039 PM 26045439 ER PT J AU Chandrachud, U Walker, MW Simas, AM Heetveld, S Petcherski, A Klein, M Oh, H Wolf, P Zhao, WN Norton, S Haggarty, SJ Lloyd-Evans, E Cotman, SL AF Chandrachud, Uma Walker, Mathew W. Simas, Alexandra M. Heetveld, Sasja Petcherski, Anton Klein, Madeleine Oh, Hyejin Wolf, Pavlina Zhao, Wen-Ning Norton, Stephanie Haggarty, Stephen J. Lloyd-Evans, Emyr Cotman, Susan L. TI Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CEROID-LIPOFUSCINOSIS; INTRACELLULAR CALCIUM; BIOMETAL HOMEOSTASIS; ENDOCYTIC PATHWAY; BRAIN MICROSOMES; IMAGE-ANALYSIS; LYSOSOMAL PH; MOUSE MODEL; MITOCHONDRIAL; LINK AB Abnormal accumulation of undigested macromolecules, often disease-specific, is a major feature of lysosomal and neurodegenerative disease and is frequently attributed to defective autophagy. The mechanistic underpinnings of the autophagy defects are the subject of intense research, which is aided by genetic disease models. To gain an improved understanding of the pathways regulating defective autophagy specifically in juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), a neurodegenerative disease of childhood, we developed and piloted a GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) screening assay to identify, in an unbiased fashion, genotype-sensitive small molecule autophagy modifiers, employing a JNCL neuronal cell model bearing the most common disease mutation in CLN3. Thapsigargin, a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ pump inhibitor, reproducibly displayed significantly more activity in the mouse JNCL cells, an effect that was also observed in human-induced pluripotent stem cell-derived JNCL neural progenitor cells. The mechanism of thapsigargin sensitivity was Ca2+-mediated, and autophagosome accumulation in JNCL cells could be reversed by Ca2+ chelation. Interrogation of intracellular Ca2+ handling highlighted alterations in endoplasmic reticulum, mitochondrial, and lysosomal Ca2+ pools and in store-operated Ca2+ uptake in JNCL cells. These results further support an important role for the CLN3 protein in intracellular Ca2+ handling and in autophagic pathway flux and establish a powerful new platform for therapeutic screening. C1 [Chandrachud, Uma; Simas, Alexandra M.; Heetveld, Sasja; Petcherski, Anton; Klein, Madeleine; Oh, Hyejin; Wolf, Pavlina; Zhao, Wen-Ning; Norton, Stephanie; Haggarty, Stephen J.; Cotman, Susan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Walker, Mathew W.; Lloyd-Evans, Emyr] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. RP Cotman, SL (reprint author), Ctr Human Genet Res, Dept Neurol, 185 Cambridge St, Boston, MA 02114 USA. EM cotman@helix.mgh.harvard.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU National Institutes of Health from NINDS [R01NS073813]; National Institutes of Health from National Institute of Mental Health [R33MH087896]; Batten Disease Support and Research Association; National Tay-Sachs and Allied Diseases Association, Inc.; Tau Consortium; National Contest for Life Foundation (NCL Stiftung) fellowship; Finnish Foundation for JNCL Research fellowship; Knowledge Economy Skills Scholarship; Research Councils UK Fellowship; Basil O'Connor Starter Scholarship; Royal Society project grant FX This work was supported, in whole or in part, by National Institutes of Health Grants R01NS073813 from NINDS (to S. L. C.) and R33MH087896 from National Institute of Mental Health (to S. J. H.). This work was also supported by the Batten Disease Support and Research Association (to S. L. C.), the National Tay-Sachs and Allied Diseases Association, Inc. (to S. L. C.), the Tau Consortium (to S. J. H.), National Contest for Life Foundation (NCL Stiftung) fellowship (to A. P.), the Finnish Foundation for JNCL Research fellowship (to A. P.), a Knowledge Economy Skills Scholarship (to M. W. W.), a Research Councils UK Fellowship (to E. L. E.), a Basil O'Connor Starter Scholarship (to E. L. E.), and a Royal Society project grant (to E. L. E.) S. L. C. is a member of the Batten Disease Support and Research Association Advisory Board. P. W. is currently an employee of Sanofi. NR 61 TC 9 Z9 9 U1 2 U2 11 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 JUN 5 PY 2015 VL 290 IS 23 BP 14361 EP 14380 DI 10.1074/jbc.M114.621706 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ8MC UT WOS:000355754600009 PM 25878248 ER PT J AU Kim, WJ Wittner, BS Amzallag, A Brannigan, BW Ting, DT Ramaswamy, S Maheswaran, S Haber, DA AF Kim, Woo Jae Wittner, Ben S. Amzallag, Arnaud Brannigan, Brian W. Ting, David T. Ramaswamy, Sridhar Maheswaran, Shyamala Haber, Daniel A. TI The WTX Tumor Suppressor Interacts with the Transcriptional Corepressor TRIM28 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA METHYLATION; WILMS-TUMOR; RNAI SCREEN; PROTEIN; GENOME; GENE; INACTIVATION; EXPRESSION; REGULATOR; TIF1-BETA AB WTX encodes a tumor suppressor implicated in the pediatric kidney cancer Wilms tumor and in mesenchymal differentiation with potentially distinct functions in the cytoplasm, at the plasma membrane, and in the nucleus. Although modulating components of the WNT signaling pathway is a proposed function for cytoplasmic and membrane-bound WTX, its nuclear properties are not well understood. Here we report that the transcriptional corepressor TRIM28 is the major binding partner for nuclear WTX. WTX interacted with the coiled coil domain of TRIM28 required for its binding to Kruppel-associated box domains of transcription factors and for its chromatin recruitment through its own coiled coil and proline-rich domains. Knockdown of endogenous WTX reduced the recruitment of TRIM28 to a chromatinized reporter sequence and its ability to repress a target transcript. In mouse embryonic stem cells where TRIM28 plays a major role in repressing endogenous retroviruses and long interspersed elements, knockdown of either TRIM28 or WTX combined with single molecule RNA sequencing revealed a highly significant shared set of differentially regulated transcripts, including derepression of non-coding repetitive sequences and their neighboring protein encoding genes (p < 1e - 20). In mesenchymal precursor cells, depletion of WTX and TRIM28 resulted in analogous beta-catenin-independent defects in adipogenic and osteogenic differentiation, and knockdown of WTX reduced TRIM28 binding to Ppar gamma promoter. Together, the physical and functional interaction between WTX and TRIM28 suggests that the nuclear fraction of WTX plays a role in epigenetic silencing, an effect that may contribute to its function as a regulator of cellular differentiation and tumorigenesis. C1 [Ting, David T.; Ramaswamy, Sridhar; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Charlestown, MA 02129 USA. [Maheswaran, Shyamala] Massachusetts Gen Hosp, Ctr Canc, Dept Surg, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, CNY 7,Bldg 149, Charlestown, MA 02129 USA. EM Haber@helix.mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 FU Howard Hughes Medical Institute; American Cancer Society FX This work was supported by the Howard Hughes Medical Institute (to D. A. H.) and an American Cancer Society institutional research grant (to W. J. K.). NR 35 TC 1 Z9 1 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 JUN 5 PY 2015 VL 290 IS 23 BP 14381 EP 14390 DI 10.1074/jbc.M114.631945 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ8MC UT WOS:000355754600010 PM 25882849 ER PT J AU Habets, RAJ Groot, AJ Yahyanejad, S Tiyanont, K Blacklow, SC Vooijs, M AF Habets, Roger A. J. Groot, Arjan J. Yahyanejad, Sanaz Tiyanont, Kittichoat Blacklow, Stephen C. Vooijs, Marc TI Human NOTCH2 Is Resistant to Ligand-independent Activation by Metalloprotease Adam17 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MARGINAL ZONE LYMPHOMA; NEGATIVE REGULATORY REGION; SQUAMOUS-CELL CARCINOMA; PROTEOLYTIC ACTIVATION; T-ALL; CLEAVAGE; MUTATIONS; DOMAIN; DROSOPHILA; RECEPTORS AB Cell surface receptors of the NOTCH family of proteins are activated by ligand induced intramembrane proteolysis. Unfolding of the extracellular negative regulatory region (NRR), enabling successive proteolysis by the enzymes Adam10 and gamma-secretase, is rate-limiting in NOTCH activation. Mutations in the NOTCH1 NRR are associated with ligand-independent activation and frequently found in human T-cell malignancies. In mammals four NOTCH receptors and five Delta/Jagged ligands exist, but mutations in the NRR are only rarely reported for receptors other than NOTCH1. Using biochemical and functional assays, we compared the molecular mechanisms of ligand-independent signaling in NOTCH1 and the highly related NOTCH2 receptor. Both murine Notch1 and Notch2 require the metalloprotease protease Adam17, but not Adam10 during ligand-independent activation. Interestingly, the human NOTCH2 receptor is resistant to ligand-independent activation compared with its human homologs or murine orthologs. Taken together, our data reveal subtle but functionally important differences for the NRR among NOTCH paralogs and homologs. C1 [Habets, Roger A. J.; Groot, Arjan J.; Yahyanejad, Sanaz; Vooijs, Marc] Maastricht Univ, Dept Radiotherapy MaastRO GROW, Sch Dev Biol & Oncol, NL-6200 MD Maastricht, Netherlands. [Tiyanont, Kittichoat; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Vooijs, M (reprint author), Maastricht Univ, Dept Radiotherapy MaastRO GROW, Sch Dev Biol & Oncol, Univ Singel 50, NL-6229 ER Maastricht, Netherlands. EM marc.vooijs@maastrichtuniversity.nl FU European Research Council (ERC) under the European Community Seventh Framework Program (FP7) ERC [208259, 334987] FX This work was supported by the European Research Council (ERC) under the European Community Seventh Framework Program (FP7/2007-2013) ERC starting Grants 208259 and 334987 (to M. V.). NR 44 TC 5 Z9 5 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 5 PY 2015 VL 290 IS 23 BP 14705 EP 14716 DI 10.1074/jbc.M115.643676 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ8MC UT WOS:000355754600040 PM 25918160 ER PT J AU Guo, Y Hu, BF Huang, H Tsung, A Gaikwad, NW Xu, MS Jiang, MX Ren, SR Fan, J Billiar, TR Huang, M Xie, W AF Guo, Yan Hu, Bingfang Huang, Hai Tsung, Allan Gaikwad, Nilesh W. Xu, Meishu Jiang, Mengxi Ren, Songrong Fan, Jie Billiar, Timothy R. Huang, Min Xie, Wen TI Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; REDUCED-SIZE LIVER; NRF2 ACTIVATION; CELL-SURVIVAL; X-RECEPTOR; MICE; 17-BETA-ESTRADIOL; ANTIOXIDANT; MECHANISMS; INHIBITION AB Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2(-/-) mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST-/- males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST-/- mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen-responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury. C1 [Guo, Yan; Hu, Bingfang; Xu, Meishu; Jiang, Mengxi; Ren, Songrong; Xie, Wen] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA. [Guo, Yan; Hu, Bingfang; Xu, Meishu; Jiang, Mengxi; Ren, Songrong; Xie, Wen] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Huang, Hai; Tsung, Allan; Billiar, Timothy R.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15261 USA. [Xie, Wen] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Guo, Yan] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Pathol, Shanghai 200025, Peoples R China. [Hu, Bingfang; Huang, Min] Sun Yat Sen Univ, Inst Clin Pharmacol, Guangzhou 510275, Guangdong, Peoples R China. [Gaikwad, Nilesh W.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Gaikwad, Nilesh W.] Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. [Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Surg Res, Pittsburgh, PA 15240 USA. RP Huang, M (reprint author), Sun Yat Sen Univ, Inst Clin Pharmacol, Guangzhou 510006, Guangdong, Peoples R China. EM huangmin@mail.sysu.edu.cn; wex6@pitt.edu RI Huang, Hai/F-4286-2012; Regan, Clinton/E-6250-2012; Xie, Wen/M-1768-2016 OI Huang, Hai/0000-0001-7430-0119; FU National Institutes of Health [HD073070, DK099232, ES023438]; Joseph Koslow Endowed Professorship; Visiting Scholar Foundation of Shanghai Municipal Education Commission; China Scholarship Council [201206380045] FX This work was supported, in whole or in part, by National Institutes of Health Grants HD073070, DK099232, and ES023438, and by the Joseph Koslow Endowed Professorship (to W. X.).; Supported by the Visiting Scholar Foundation of Shanghai Municipal Education Commission.; Supported by China Scholarship Council Scholarship 201206380045. NR 37 TC 6 Z9 6 U1 1 U2 7 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 JUN 5 PY 2015 VL 290 IS 23 BP 14754 EP 14764 DI 10.1074/jbc.M115.642124 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ8MC UT WOS:000355754600044 PM 25922074 ER PT J AU Fogelgren, B Polgar, N Lui, VH Lee, AJ Tamashiro, KKA Napoli, JA Walton, CB Zuo, XF Lipschutz, JH AF Fogelgren, Ben Polgar, Noemi Lui, Vanessa H. Lee, Amanda J. Tamashiro, Kadee-Kalia A. Napoli, Josephine Andrea Walton, Chad B. Zuo, Xiaofeng Lipschutz, Joshua H. TI Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions SO PLOS ONE LA English DT Article ID BLADDER UMBRELLA CELLS; YEAST SECRETORY PATHWAY; CADHERIN GENE PROMOTER; CHRONIC-RENAL-FAILURE; PRIMARY CILIOGENESIS; GENITOURINARY TRACT; URETER DEVELOPMENT; DEVELOPING KIDNEY; PLASMA-MEMBRANE; PROTEIN SEC8 AB Most cases of congenital obstructive nephropathy are the result of ureteropelvic junction obstructions, and despite their high prevalence, we have a poor understanding of their etiology and scarcity of genetic models. The eight-protein exocyst complex regulates polarized exocytosis of intracellular vesicles in a large variety of cell types. Here we report generation of a conditional knockout mouse for Sec10, a central component of the exocyst, which is the first conditional allele for any exocyst gene. Inactivation of Sec10 in ureteric bud-derived cells using Ksp1.3-Cre mice resulted in severe bilateral hydronephrosis and complete anuria in newborns, with death occurring 6-14 hours after birth. Sec10(FL/FL); Ksp-Cre embryos developed ureteropelvic junction obstructions between E17.5 and E18.5 as a result of degeneration of the urothelium and subsequent overgrowth by surrounding mesenchymal cells. The urothelial cell layer that lines the urinary tract must maintain a hydrophobic luminal barrier again urine while remaining highly stretchable. This barrier is largely established by production of uroplakin proteins that are transported to the apical surface to establish large plaques. By E16.5, Sec10(FL/FL); Ksp-Cre ureter and pelvic urothelium showed decreased uroplakin-3 protein at the luminal surface, and complete absence of uroplakin-3 by E17.5. Affected urothelium at the UPJ showed irregular barriers that exposed the smooth muscle layer to urine, suggesting this may trigger the surrounding mesenchymal cells to overgrow the lumen. Findings from this novel mouse model show Sec10 is critical for the development of the urothelium in ureters, and provides experimental evidence that failure of this urothelial barrier may contribute to human congenital urinary tract obstructions. C1 [Fogelgren, Ben; Polgar, Noemi; Lui, Vanessa H.; Lee, Amanda J.; Tamashiro, Kadee-Kalia A.; Napoli, Josephine Andrea] Univ Hawaii Manoa, John A Burns Sch Med, Dept Anat Biochem & Physiol, Honolulu, HI 96822 USA. [Walton, Chad B.] Univ Hawaii Manoa, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Zuo, Xiaofeng; Lipschutz, Joshua H.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Lipschutz, Joshua H.] Ralph H Johnson Vet Affairs Med Ctr, Dept Med, Charleston, SC USA. RP Fogelgren, B (reprint author), Univ Hawaii Manoa, John A Burns Sch Med, Dept Anat Biochem & Physiol, Honolulu, HI 96822 USA. EM fogelgre@hawaii.edu OI Polgar, Noemi/0000-0002-8400-162X FU National Institutes of Health [K01DK087852, R03DK100738, P20GM103457-06A1-8293, R01DK069909, R21DK070980]; United States Department of Veteran's Affairs [I01 BX000820]; Satellite Healthcare Norman S. Coplon Extramural Research Grant; Hawaii Community Foundation [12ADVC-51347]; University of Alabama at Birmingham Hepato/Renal Fibrocystic Diseases Core Center [5P30DK074038]; March of Dimes: Basil O'Connor Starter Scholar Research Award [5-FY14-56]; University of Hawaii at Manoa Research Centers in Minority Institute, BRIDGES program [5G12MD007601] FX This work was supported by 1) National Institutes of Health: Grant # K01DK087852 to BF; http://www.nih.gov/. 2) National Institutes of Health: Grant # R03DK100738 to BF; http://www.nih.gov/. 3) National Institutes of Health: Grant # P20GM103457-06A1-8293 to BF; http://www.nih.gov/. 4) National Institutes of Health: Grant # R01DK069909 to JL; http://www.nih.gov/. 5) National Institutes of Health: Grant # R21DK070980 to JL; http://www.nih.gov/. 6) United States Department of Veteran's Affairs: Merit Award # I01 BX000820 to JL; http://www.research.va.gov/funding/. 7) Satellite Healthcare Norman S. Coplon Extramural Research Grant to JL; http://www.satellitehealth.com/about_satellite/philanthropy/coplon_grant s/. 8) Hawaii Community Foundation: Grant # 12ADVC-51347 to BF; http://www.hawaiicommunityfoundation.org/. 9) University of Alabama at Birmingham Hepato/Renal Fibrocystic Diseases Core Center: Pilot Award # 5P30DK074038 to BF; http://www.uab.edu/medicine/hrfdcc/. 10) March of Dimes: Basil O'Connor Starter Scholar Research Award #5-FY14-56 to BF; http://www.marchofdimes.org/. 11) University of Hawaii at Manoa Research Centers in Minority Institute, BRIDGES program: Pilot Award # 5G12MD007601 to BF; http://rcmi-bridges.jabsom.hawaii.edu/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 4 Z9 4 U1 2 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 JUN 5 PY 2015 VL 10 IS 6 AR UNSP e0129346 DI 10.1371/journal.pone.0129346 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7CR UT WOS:000355652200154 PM 26046524 ER PT J AU Moccia, M Liu, QS Guida, T Federico, G Brescia, A Zhao, Z Choi, HG Deng, XM Tan, L Wang, JH Billaud, M Gray, NS Carlomagno, F Santoro, M AF Moccia, Marialuisa Liu, Qingsong Guida, Teresa Federico, Giorgia Brescia, Annalisa Zhao, Zheng Choi, Hwan Geun Deng, Xianming Tan, Li Wang, Jinhua Billaud, Marc Gray, Nathanael S. Carlomagno, Francesca Santoro, Massimo TI Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase SO PLOS ONE LA English DT Article ID MEDULLARY-THYROID CANCER; CARCINOMA CELL-LINE; LUNG-CANCER; PONATINIB AP24534; POTENT INHIBITOR; GENE FUSION; BCR-ABL; MUTATIONS; RESISTANCE; ADENOCARCINOMA AB Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II- 41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoro-methyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II- 41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET. C1 [Moccia, Marialuisa; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Carlomagno, Francesca; Santoro, Massimo] Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy. [Moccia, Marialuisa; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Carlomagno, Francesca; Santoro, Massimo] CNR, Ist Endocrinol & Oncol Sperimentale, I-80125 Naples, Italy. [Liu, Qingsong; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Liu, Qingsong; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhao, Zheng] Chinese Acad Sci, High Field Magnet Lab, Hefei, Anhui, Peoples R China. [Billaud, Marc] CRI INSERM UJF U823, Inst Albert Bonniot, La Tronche, France. RP Santoro, M (reprint author), Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy. EM masantor@unina.it OI liu, qing song/0000-0002-7829-2547 FU Italian Association for Cancer Research (AIRC); FIRB Merit grant of MIUR; NIH grant [R01 CA172592] FX Support was provided by the Italian Association for Cancer Research (AIRC) and FIRB Merit grant of MIUR to MS, and NIH grant R01 CA172592 to NSG. NR 36 TC 1 Z9 1 U1 3 U2 14 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 JUN 5 PY 2015 VL 10 IS 6 AR e0128364 DI 10.1371/journal.pone.0128364 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7CR UT WOS:000355652200063 PM 26046350 ER PT J AU Oxlade, O Huang, CC Murray, M AF Oxlade, Olivia Huang, Chuan-Chin Murray, Megan TI Estimating the Impact of Reducing Under-Nutrition on the Tuberculosis Epidemic in the Central Eastern States of India: A Dynamic Modeling Study SO PLOS ONE LA English DT Article ID RISK; PRACTITIONERS; MALNUTRITION; PROGRESS; ENGLAND; WEIGHT; HEALTH; WALES AB Background Tuberculosis (TB) and under-nutrition are widespread in many low and middle-income countries. Momentum to prioritize under-nutrition has been growing at an international level, as demonstrated by the "Scaling Up Nutrition" movement. Low body mass index is an important risk factor for developing TB disease. The objective of this study was to project future trends in TB related outcomes under different scenarios for reducing under-nutrition in the adult population in the Central Eastern states of India. Methods A compartmental TB transmission model stratified by body mass index was parameterized using national and regional data from India. We compared TB related mortality and incidence under several scenarios that represented a range of policies and programs designed to reduce the prevalence of under-nutrition, based on the experience and observed trends in similar countries. Results The modeled nutrition intervention scenarios brought about reductions in TB incidence and TB related mortality in the Central Eastern Indian states ranging from 43% to 71% and 40% to 68% respectively, relative to the scenario of no nutritional intervention. Modest reductions in under-nutrition averted 4.8 (95% UR 0.5, 17.1) million TB cases and 1.6 (95% UR 0.5, 5.2) million TB related deaths over a period of 20 years of intervention, relative to the scenario of no nutritional intervention. Complete elimination of under-nutrition in the Central Eastern states averted 9.4 (95% UR 1.5, 30.6) million TB cases and 3.2 (95% UR 0.7-, 10.1) million TB related deaths, relative to the scenario of no nutritional intervention. Conclusion Our study suggests that intervening on under-nutrition could have a substantial impact on TB incidence and mortality in areas with high prevalence of under-nutrition, even if only small gains in under-nutrition can be achieved. Focusing on under-nutrition may be an effective way to reduce both rates of TB and other diseases associated with under-nutrition. C1 [Oxlade, Olivia; Huang, Chuan-Chin; Murray, Megan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Murray, Megan] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Murray, Megan] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. RP Murray, M (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM mmurray@hsph.harvard.edu FU Canadian Institute of Health Research [FRN 106987] FX OO received a post doctoral fellowship from the Canadian Institute of Health Research (FRN 106987). MM and CCH had no specific funding for this project. NR 47 TC 4 Z9 4 U1 1 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 JUN 5 PY 2015 VL 10 IS 6 AR e0128187 DI 10.1371/journal.pone.0128187 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7CR UT WOS:000355652200045 PM 26046649 ER PT J AU Thekkiniath, J Zabet-Moghaddam, M Kottapalli, KR Pasham, MR Francisco, SS Francisco, MS AF Thekkiniath, Jose Zabet-Moghaddam, Masoud Kottapalli, Kameswara Rao Pasham, Mithun R. Francisco, Susan San Francisco, Michael San TI Quantitative Proteomics of an Amphibian Pathogen, Batrachochytrium dendrobatidis, following Exposure to Thyroid Hormone SO PLOS ONE LA English DT Article ID FUNGUS BLASTOCLADIELLA-EMERSONII; EMERGING INFECTIOUS-DISEASE; HEAT-SHOCK-PROTEIN; CHYTRID FUNGUS; SACCHAROMYCES-CEREVISIAE; POPULATION DECLINES; CYTOSOLIC CALCIUM; L-6 MYOBLASTS; PLANT-CELLS; EXPRESSION AB Batrachochytrium dendrobatidis(Bd), a chytrid fungus, has increasingly been implicated as a major factor in the worldwide decline of amphibian populations. The fungus causes chytridiomycosis in susceptible species leading to massive die-offs of adult amphibians. Although Bd infects the keratinized mouthparts of tadpoles and negatively affects foraging behavior, these infections are non-lethal. An important morphogen controlling amphibian metamorphosis is thyroid hormone (T-3). Tadpoles may be infected with Bd and the fungus may be exposed to T-3 during metamorphosis. We hypothesize that exposure of Bd to T-3 may induce the expression of factors associated with host colonization and pathogenicity. We utilized a proteomics approach to better understand the dynamics of the Bd-T-3 interaction. Using liquid chromatography-mass spectrometry (LC-MS), we generated a data set of a large number of cytoplasmic and membrane proteins following exposure of Bd to T-3. From these data, we identified a total of 263 proteins whose expression was significantly changed following T-3 exposure. We provide evidence for expression of an array of proteins that may play key roles in both genomic and non-genomic actions of T-3 in Bd. Additionally, our proteomics study shows an increase in several proteins including proteases and a class of uncommon crinkler and crinkler-like effector proteins suggesting their importance in Bd pathogenicity as well as those involved in metabolism and energy transfer, protein fate, transport and stress responses. This approach provides insights into the mechanistic basis of the Bd-amphibian interaction following T-3 exposure. C1 [Thekkiniath, Jose] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Zabet-Moghaddam, Masoud; Kottapalli, Kameswara Rao; Francisco, Susan San] Texas Tech Univ, Ctr Biotechnol & Genom, Lubbock, TX 79402 USA. [Pasham, Mithun R.] Harvard Univ, Sch Med, Dept Cell Biol & Pediat, Boston, MA 02115 USA. [Pasham, Mithun R.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Francisco, Susan San; Francisco, Michael San] Texas Tech Univ, Dept Biol Sci, Lubbock, TX 79409 USA. RP Francisco, MS (reprint author), Texas Tech Univ, Dept Biol Sci, Lubbock, TX 79409 USA. EM Michael.sanfrancisco@ttu.edu FU Department of Biological Sciences FX We thank the Department of Biological Sciences for support during this work. NR 89 TC 0 Z9 0 U1 4 U2 14 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 JUN 5 PY 2015 VL 10 IS 6 AR e0123637 DI 10.1371/journal.pone.0123637 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7CR UT WOS:000355652200004 PM 26046527 ER PT J AU Jorgensen, TS Rasmussen, M Aarestrup, AK Ersboll, AK Jorgensen, SE Goodman, E Pedersen, TP Due, P Krolner, R AF Jorgensen, Thea Suldrup Rasmussen, Mette Aarestrup, Anne Kristine Ersboll, Annette Kjaer Jorgensen, Sanne Ellegaard Goodman, Elizabeth Pedersen, Trine Pagh Due, Pernille Krolner, Rikke TI The role of curriculum dose for the promotion of fruit and vegetable intake among adolescents: results from the Boost intervention SO BMC PUBLIC HEALTH LA English DT Article DE Implementation; Curriculum dose; School; Adolescents; Fruit and vegetables ID SCHOOL-BASED INTERVENTIONS; 5-A-DAY POWER PLUS; PRO CHILDREN; CONSUMPTION; PROGRAM; IMPLEMENTATION; NUTRITION; BEHAVIOR; HEALTH; VALIDITY AB Background: Multi-component interventions combining educational and environmental strategies have proved effective in increasing children and adolescents' fruit and vegetable intake. However such interventions are complex and difficult to implement and several studies report poor implementation. There is a need for knowledge on the role of dose for behaviour change and for assessment of intervention dose to avoid conclusions that intervention components which are not implemented are ineffective. This study aimed to examine 1) the association between dose of a class curriculum and adolescents' fruit and vegetable intake in a school-based multi-component intervention, 2) if gender and socioeconomic position modify this association. Methods: We carried out secondary analysis of data from intervention schools in the cluster-randomized Boost study targeting 13-year-olds' fruit and vegetable intake. Teacher-and student data on curriculum dose delivered and received were aggregated to the school-level and class-level (only possible for student data). We analysed the association between curriculum dose and students' (n 995) self-reported fruit and vegetable intake (24-h recall questionnaire) after finalization of the intervention using multi-level analyses. Potential moderation was examined by analyses stratified by gender and socioeconomic position. Results: Average dose received at class-level was significantly associated with students' fruit and vegetable intake (10 g (CI: 0.06, 20.33) per curricular activity received). In stratified analyses the association remained significant among boys only (14 g (CI: 2.84, 26.76) per curricular activity received). The average dose delivered and received at the school-level was not significantly associated with students' intake. Conclusions: We found a dose-response relationship between number of curricular activities received and adolescents' fruit and vegetable intake. The results indicate that curriculum dose received only mattered for promotion of fruit and vegetable intake among boys. Future studies should explore this gender difference in larger samples to guide the planning of school-based curricular interventions with regards to the optimal number of curricular activities required to promote behavioural change in subgroups with low fruit and vegetable intake at baseline. C1 [Jorgensen, Thea Suldrup; Rasmussen, Mette; Aarestrup, Anne Kristine; Jorgensen, Sanne Ellegaard; Due, Pernille; Krolner, Rikke] Univ Southern Denmark, Natl Inst Publ Hlth, Ctr Intervent Res Hlth Promot & Dis Prevent, DK-1353 Copenhagen K, Denmark. [Ersboll, Annette Kjaer; Pedersen, Trine Pagh] Univ Southern Denmark, Natl Inst Publ Hlth, DK-1353 Copenhagen K, Denmark. [Goodman, Elizabeth] Massachusetts Gen Hosp, Massachusetts Gen Hosp Children, Div Gen Acad Pediat, Boston, MA 02114 USA. RP Jorgensen, TS (reprint author), Univ Southern Denmark, Natl Inst Publ Hlth, Ctr Intervent Res Hlth Promot & Dis Prevent, Oster Farimagsgade 5A,2nd Floor, DK-1353 Copenhagen K, Denmark. EM thsj@niph.dk OI Ersboll, Annette Kjaer/0000-0002-9407-3387 FU TrygFonden; Copenhagen Food House; University of Southern Denmark; Nordea Foundation; NIH [DK046200]; Danish Cancer Society FX The authors thank TrygFonden and Copenhagen Food House for financially support. We would also like to thank the participating schools, students, parents, teachers and principals for participating in the Boost study. We also thank Nanna Lien, Mona Bjelland and Copenhagen Food House for extensive critical review of the Boost teaching material. We would like to express our gratitude to everyone who has allowed us to use extracts from their educational material in the Boost curriculum and to the teachers who critically reviewed drafts of the material.; This work was supported by TrygFonden (TSJ, AKA, SEJ, RK), University of Southern Denmark (AKE, ME, TSJ, AKA, PD), Nordea Foundation (TPP) and NIH (EG, grant DK046200 (in part)). The Boost study was funded by TrygFonden: The Boost study is part of Centre for Intervention Research in Health Promotion and Disease Prevention, National Institute of Public Health, University of Southern Denmark, Oster Farimagsgade 5A, 1353 Copenhagen K, Denmark. The Centre is funded by TrygFonden and the Danish Cancer Society. PhD scholarship TSJ is co-financed by University of Southern Denmark. Copenhagen Food House contributed financially to the development of the teaching material. The funders had no role in the design, analysis or writing of this article. NR 40 TC 0 Z9 0 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUN 5 PY 2015 VL 15 AR 536 DI 10.1186/s12889-015-1840-0 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK0QQ UT WOS:000355910100001 PM 26044311 ER PT J AU Mottron, L Duret, P Mueller, S Moore, RD d'Arc, BF Jacquemont, S Xiong, L AF Mottron, Laurent Duret, Pauline Mueller, Sophia Moore, Robert D. d'Arc, Baudouin Forgeot Jacquemont, Sebastien Xiong, Lan TI Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism SO MOLECULAR AUTISM LA English DT Review DE Autism spectrum; Sex ratio; Male bias; Synaptic plasticity; Regional plasticity; Perceptual associative cortex; Sexual dimorphism; Enhanced perceptual functioning ID FRAGILE-X-SYNDROME; DE-NOVO MUTATIONS; HIGH-FUNCTIONING AUTISM; LONG-TERM POTENTIATION; SPECTRUM DISORDER; VALPROIC ACID; MULTIPLE-SCLEROSIS; SYNAPTIC PLASTICITY; MENTAL-RETARDATION; PRENATAL EXPOSURE AB Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event. C1 [Mottron, Laurent; Duret, Pauline; d'Arc, Baudouin Forgeot] CETEDUM, Montreal, PQ, Canada. [Mottron, Laurent; Duret, Pauline; d'Arc, Baudouin Forgeot] Hop Riviere Prairies, Dept Psychiat, Montreal, PQ, Canada. [Mottron, Laurent; Duret, Pauline; d'Arc, Baudouin Forgeot; Xiong, Lan] Inst Univ Sante Mentale Montreal, Ctr Rech, Montreal, PQ, Canada. [Mottron, Laurent; Duret, Pauline; Moore, Robert D.; d'Arc, Baudouin Forgeot; Jacquemont, Sebastien; Xiong, Lan] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Duret, Pauline] Ecole Normale Super Lyon, Dept Biol, F-69364 Lyon 07, France. [Mueller, Sophia] Univ Hosp, Inst Clin Radiol, Munich, Germany. [Mueller, Sophia] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Mueller, Sophia] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Moore, Robert D.] Univ Montreal, Dept Hlth Sci, Montreal, PQ, Canada. [Moore, Robert D.] Univ Illinois, Coll Appl Hlth Sci, Urbana, IL 61801 USA. [Jacquemont, Sebastien] Ctr Hosp Univ St Justine, Ctr Rech, Montreal, PQ, Canada. [Jacquemont, Sebastien] Univ Lausanne, Univ Lausanne Hosp, Serv Med Genet, CH-1011 Lausanne, Switzerland. RP Mottron, L (reprint author), CETEDUM, Montreal, PQ, Canada. EM laurent.mottron@gmail.com RI Forgeot d'Arc, Baudouin/G-5774-2015 OI Forgeot d'Arc, Baudouin/0000-0001-7554-5361 FU Canadian Institute for Health Research (CIHR) Perception - language relationships in autism [MOP-130277] FX The authors would like to thank Christiane Belleville for clerical support and Alex Edelman and associates for editing the English version of the manuscript. This work was supported by a grant from the Canadian Institute for Health Research (CIHR) Perception - language relationships in autism, MOP-130277, awarded to LM. NR 219 TC 9 Z9 9 U1 7 U2 29 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD JUN 5 PY 2015 VL 6 AR 33 DI 10.1186/s13229-015-0024-1 PG 19 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA CK0QD UT WOS:000355908800001 PM 26052415 ER PT J AU Parmar, C Leijenaar, RTH Grossmann, P Velazquez, ER Bussink, J Rietveld, D Rietbergen, MM Haibe-Kains, B Lambin, P Aerts, HJWL AF Parmar, Chintan Leijenaar, Ralph T. H. Grossmann, Patrick Velazquez, Emmanuel Rios Bussink, Johan Rietveld, Derek Rietbergen, Michelle M. Haibe-Kains, Benjamin Lambin, Philippe Aerts, Hugo J. W. L. TI Radiomic feature clusters and Prognostic Signatures specific for Lung and Head & Neck cancer SO SCIENTIFIC REPORTS LA English DT Article ID TEXTURE ANALYSIS; CLASS DISCOVERY; TUMOR RESPONSE; SURVIVAL; PACKAGE; IMAGES; CT; CLASSIFICATION; OUTCOMES; STAGE AB Radiomics provides a comprehensive quantification of tumor phenotypes by extracting and mining large number of quantitative image features. To reduce the redundancy and compare the prognostic characteristics of radiomic features across cancer types, we investigated cancer-specific radiomic feature clusters in four independent Lung and Head & Neck (H&N) cancer cohorts (in total 878 patients). Radiomic features were extracted from the pre-treatment computed tomography (CT) images. Consensus clustering resulted in eleven and thirteen stable radiomic feature clusters for Lung and H&N cancer, respectively. These clusters were validated in independent external validation cohorts using rand statistic (Lung RS = 0.92, p < 0.001, H&N RS = 0.92, p < 0.001). Our analysis indicated both common as well as cancer-specific clustering and clinical associations of radiomic features. Strongest associations with clinical parameters: Prognosis Lung CI = 0.60 +/- 0.01, Prognosis H&N CI = 0.68 +/- 0.01; Lung histology AUC = 0.56 +/- 0.03, Lung stage AUC = 0.61 +/- 0.01, H&N HPV AUC = 0.58 +/- 0.03, H&N stage AUC = 0.77 +/- 0.02. Full utilization of these cancer-specific characteristics of image features may further improve radiomic biomarkers, providing a non-invasive way of quantifying and monitoring tumor phenotypic characteristics in clinical practice. C1 [Parmar, Chintan; Grossmann, Patrick; Velazquez, Emmanuel Rios; Aerts, Hugo J. W. L.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Parmar, Chintan; Leijenaar, Ralph T. H.; Lambin, Philippe] Maastricht Univ, Res Inst GROW, Radiat Oncol MAASTRO, NL-6200 MD Maastricht, Netherlands. [Parmar, Chintan] Indian Stat Inst, Machine Intelligence Unit, Kolkata, India. [Grossmann, Patrick; Aerts, Hugo J. W. L.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Bussink, Johan] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, Nijmegen, Netherlands. [Rietveld, Derek] Vrije Univ Amsterdam, Med Ctr, Dept Radiat Oncol, Amsterdam, Netherlands. [Rietbergen, Michelle M.] Vrije Univ Amsterdam, Med Ctr, Dept Otolaryngol Head & Neck Surg, Amsterdam, Netherlands. [Haibe-Kains, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Ontario Canc Inst, Toronto, ON, Canada. [Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Aerts, HJWL (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM Chintan_Parmar@dfci.harvard.edu; Hugo_Aerts@dfci.harvard.edu RI Bussink, Jan/N-3584-2014; Aerts, Hugo/P-6350-2015; Haibe-Kains, Benjamin/D-3702-2011 OI Aerts, Hugo/0000-0002-2122-2003; Haibe-Kains, Benjamin/0000-0002-7684-0079 FU National Institute of Health [NIH-USA U01 CA 143062-01, NIH-USA U01 CA 190234-01]; EU 7th framework program (EURECA); Kankeronderzoekfonds Limburg from Health Foundation Limburg; Dutch Cancer Society [KWF UM 2009-4454, KWF MAC 2013-6425]; EU 7th framework program (ARTFORCE) FX Authors 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 2009-4454, KWF MAC 2013-6425). NR 31 TC 35 Z9 35 U1 2 U2 28 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 JUN 5 PY 2015 VL 5 AR 11044 DI 10.1038/srep11044 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK0EI UT WOS:000355877900001 PM 26251068 ER PT J AU Tamae, D Mostaghel, E Montgomery, B Nelson, PS Balk, SP Kantoff, PW Taplin, ME Penning, TM AF Tamae, Daniel Mostaghel, Elahe Montgomery, Bruce Nelson, Peter S. Balk, Steven P. Kantoff, Philip W. Taplin, Mary-Ellen Penning, Trevor M. TI The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Castration resistant prostate cancer; Mass spectrometry; AKR1C3; DHEA-sulfate; Abiraterone acetate ID ANDROGEN-RECEPTOR GENE; DE-NOVO STEROIDOGENESIS; I CLINICAL-TRIAL; ABIRATERONE ACETATE; SPLICE VARIANTS; PHASE-I; KETOCONAZOLE THERAPY; DEPRIVATION THERAPY; INCREASED SURVIVAL; ADRENAL ANDROGENS AB Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de nova metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high-risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Delta(4)-androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (similar to 20 mu g/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5 alpha-dihydrotestosterone (DHT). The final step in conversion of Delta(4)-androstene-3,17-dione and 5 alpha-androstanedione to T and DHT, respectively, is catalyzed by AKRIC3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKRIC3 inhibition may be an effective combinatorial treatment strategy. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Tamae, Daniel; Penning, Trevor M.] Univ Penn, Perelman Sch Med, Ctr Canc Pharmacol, Philadelphia, PA 19104 USA. [Tamae, Daniel; Penning, Trevor M.] Univ Penn, Perelman Sch Med, Ctr Excellence Environm Toxicol, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA. [Mostaghel, Elahe; Montgomery, Bruce; Nelson, Peter S.] Univ Washington, Fred Hutchinson Canc Ctr, Seattle, WA 98109 USA. [Balk, Steven P.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kantoff, Philip W.; Taplin, Mary-Ellen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Penning, TM (reprint author), Dept Syst Pharmacol & Translat Therapeut, 1315 BRBII III,421 Curie Blvd, Philadelphia, PA 19104 USA. EM penning@upenn.edu OI Penning, Trevor/0000-0002-3937-1066 FU National Cancer Institute (NCI)/National Institutes of Health (NIH) Cancer Pharmacology Training Grant [R25 CA101871]; Prostate Cancer Foundation Challenge Award; National Institute of Environmental Health Sciences/NIH Center of Excellence in Environmental Toxicology [P30-ES013508]; NCI [P01-CA163227] FX Grant support was from the following funding sources: the National Cancer Institute (NCI)/National Institutes of Health (NIH) Cancer Pharmacology Training Grant (R25 CA101871) to D.T.; Prostate Cancer Foundation Challenge Award (S.P.B. and P.N.), AA clinical trial support Janssen Pharmaceuticals, TAPS clinical trial support; the National Institute of Environmental Health Sciences/NIH Center of Excellence in Environmental Toxicology (P30-ES013508), the NCI Grant (P01-CA163227) and a Prostate Cancer Foundation Challenge Award to T.M.P. NR 61 TC 14 Z9 14 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUN 5 PY 2015 VL 234 SI SI BP 332 EP 338 DI 10.1016/j.cbi.2014.12.012 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA CI8TG UT WOS:000355044000038 PM 25514466 ER PT J AU Safdar, N Odden, A Abad, CL Thapa, R Saint, S AF Safdar, Nasia Odden, Andrew Abad, Cybele L. Thapa, Rameet Saint, Sanjay TI In Sight and Out of Mind SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RUBELLA VACCINATION; MEASLES; POPULATION; CALIFORNIA; AUTISM; MUMPS C1 [Safdar, Nasia; Thapa, Rameet] Univ Wisconsin, Sch Med, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. [Safdar, Nasia; Thapa, Rameet] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Odden, Andrew; Saint, Sanjay] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Saint, Sanjay] Dept Vet Affairs Hlth Serv, Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Abad, Cybele L.] Univ Philippines, Philippine Gen Hosp, Dept Med, Manila, Philippines. RP Safdar, N (reprint author), Univ Wisconsin, Div Infect Dis, 1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu FU Doximity; Jvion FX Dr. Saint reports receiving fees for board membership from Doximity and Jvion. No other potential conflict of interest relevant to this article was reported. NR 13 TC 0 Z9 0 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 JUN 4 PY 2015 VL 372 IS 23 BP 2218 EP 2223 DI 10.1056/NEJMcps1413402 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CK1GK UT WOS:000355955100009 PM 26039603 ER PT J AU Wheeler, JM McMillan, PJ Hawk, M Iba, M Robinson, L Xu, GJ Dombroski, BA Jeong, D Dichter, MA Juul, H Loomis, E Raskind, M Leverenz, JB Trojanowski, JQ Lee, VMY Schellenberg, GD Kraemer, BC AF Wheeler, Jeanna M. McMillan, Pamela J. Hawk, Michele Iba, Michiyo Robinson, Linda Xu, George J. Dombroski, Beth A. Jeong, Doori Dichter, Marc A. Juul, Halvor Loomis, Elaine Raskind, Murray Leverenz, James B. Trojanowski, John Q. Lee, Virginia M. Y. Schellenberg, Gerard D. Kraemer, Brian C. TI High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE Tau; Aggregation; Hyperphosphorylation; Tauopathy ID ALZHEIMERS-DISEASE; MOUSE MODEL; MEMORY DEFICITS; PROTEIN; AGGREGATION; AXONOPATHY; DEMENTIA; ISOFORMS; TANGLES; BRAIN AB Introduction: Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer's disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease. Results: We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence. Conclusions: Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes. C1 [Wheeler, Jeanna M.; McMillan, Pamela J.; Robinson, Linda; Loomis, Elaine; Kraemer, Brian C.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [McMillan, Pamela J.; Raskind, Murray] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [McMillan, Pamela J.; Raskind, Murray; Kraemer, Brian C.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Hawk, Michele; Iba, Michiyo; Xu, George J.; Dombroski, Beth A.; Jeong, Doori; Trojanowski, John Q.; Lee, Virginia M. Y.; Schellenberg, Gerard D.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Dichter, Marc A.; Juul, Halvor] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Leverenz, James B.] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Cleveland, OH 44195 USA. [Kraemer, Brian C.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98104 USA. RP Schellenberg, GD (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM gerardsc@mail.med.UPENN.edu; kraemerb@uw.edu FU BLRD VA [I01 BX002619]; NIA NIH HHS [P50 AG005136, AG017586, P01 AG017586] NR 31 TC 2 Z9 2 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD JUN 4 PY 2015 VL 3 AR 33 DI 10.1186/s40478-015-0210-6 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CP9WK UT WOS:000360245800001 PM 26041339 ER PT J AU Hicks, SC Irizarry, RA AF Hicks, Stephanie C. Irizarry, Rafael A. TI quantro: a data-driven approach to guide the choice of an appropriate normalization method SO GENOME BIOLOGY LA English DT Article ID RNA-SEQ DATA; GENE-EXPRESSION; MICROARRAY DATA; DIFFERENTIAL EXPRESSION; ARRAY; MAINTENANCE; PACKAGE AB Normalization is an essential step in the analysis of high-throughput data. Multi-sample global normalization methods, such as quantile normalization, have been successfully used to remove technical variation. However, these methods rely on the assumption that observed global changes across samples are due to unwanted technical variability. Applying global normalization methods has the potential to remove biologically driven variation. Currently, it is up to the subject matter experts to determine if the stated assumptions are appropriate. Here, we propose a data-driven alternative. We demonstrate the utility of our method (quantro) through examples and simulations. A software implementation is available from http://www.bioconductor.org/packages/release/bioc/html/quantro.html. C1 [Hicks, Stephanie C.; Irizarry, Rafael A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hicks, Stephanie C.; Irizarry, Rafael A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Irizarry, RA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02115 USA. EM rafa@jimmy.harvard.edu OI Hicks, Stephanie/0000-0002-7858-0231 FU NIH R01 grant [GM083084, RR021967/GM103552] FX SCH and RAI were supported by NIH R01 grants GM083084 and RR021967/GM103552. NR 44 TC 7 Z9 7 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD JUN 4 PY 2015 VL 16 AR 117 DI 10.1186/s13059-015-0679-0 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CM6FE UT WOS:000357782700001 PM 26040460 ER PT J AU Nitzsche, B Frey, S Collins, LD Seeger, J Lobsien, D Dreyer, A Kirsten, H Stoffel, MH Fonov, VS Boltze, J AF Nitzsche, Bjoern Frey, Stephen Collins, Louis D. Seeger, Johannes Lobsien, Donald Dreyer, Antje Kirsten, Holger Stoffel, Michael H. Fonov, Vladimir S. Boltze, Johannes TI A stereotaxic, population-averaged T1w ovine brain atlas including cerebral morphology and tissue volumes SO FRONTIERS IN NEUROANATOMY LA English DT Article DE brain; atlas; tissue segmentation; structural MRI; sheep; stereotaxy; SPM ID VOXEL-BASED MORPHOMETRY; SURFACE-BASED ANALYSIS; LARGE-ANIMAL-MODEL; PROBABILISTIC ATLAS; MRI DATA; SHEEP; SEGMENTATION; REGISTRATION; ISCHEMIA; SPACE AB Standard stereotaxic reference systems play a key role in human brain studies. Stereotaxic coordinate systems have also been developed for experimental animals including non-human primates, dogs, and rodents. However, they are lacking for other species being relevant in experimental neuroscience including sheep. Here, we present a spatial, unbiased ovine brain template with tissue probability maps (TPM) that offer a detailed stereotaxic reference frame for anatomical features and localization of brain areas, thereby enabling inter-individual and cross-study comparability. Three-dimensional data sets from healthy adult Merino sheep (Ovis orientalis aries, 12 ewes and 26 neutered rams) were acquired on a 1.5 T Philips MRI using a T1w sequence. Data were averaged by linear and non-linear registration algorithms. Moreover, animals were subjected to detailed brain volume analysis including examinations with respect to body weight (BW), age, and sex. The created T1w brain template provides an appropriate population-averaged ovine brain anatomy in a spatial standard coordinate system. Additionally, TPM for gray (GM) and white (WM) matter as well as cerebrospinal fluid (CSF) classification enabled automatic prior-based tissue segmentation using statistical parametric mapping (SPM). Overall, a positive correlation of GM volume and BW explained about 15% of the variance of GM while a positive correlation between WM and age was found. Absolute tissue volume differences were not detected, indeed ewes showed significantly more GM per bodyweight as compared to neutered rams. The created framework including spatial brain template and TPM represent a useful tool for unbiased automatic image preprocessing and morphological characterization in sheep. Therefore, the reported results may serve as a starting point for further experimental and/or translational research aiming at in vivo analysis in this species. C1 [Nitzsche, Bjoern; Dreyer, Antje; Kirsten, Holger; Boltze, Johannes] Fraunhofer Inst Cell Therapy & Immunol, Dept Cell Therapy, Leipzig, Germany. [Nitzsche, Bjoern; Seeger, Johannes] Univ Leipzig, Fac Vet Med, Inst Anat Histol & Embryol, D-04109 Leipzig, Germany. [Frey, Stephen; Collins, Louis D.; Fonov, Vladimir S.] McGill Univ, Montreal Neurol Inst Hosp, McConnell Brain Imaging Ctr, Montreal, PQ, Canada. [Lobsien, Donald] Univ Hosp Leipzig, Dept Neuroradiol, Leipzig, Germany. [Kirsten, Holger] Univ Leipzig, Translat Ctr Regenerat Med, D-04109 Leipzig, Germany. [Kirsten, Holger] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Kirsten, Holger] Univ Leipzig, LIFE Ctr Leipzig Interdisciplinary Res Cluster Ge, D-04109 Leipzig, Germany. [Stoffel, Michael H.] Univ Bern, Vetsuisse Fac, Div Vet Anat, Bern, Switzerland. [Boltze, Johannes] Massachusetts Gen Hosp, Neurovasc Regulat Lab, Ctr Neurosci, Charlestown, MA USA. [Boltze, Johannes] Harvard Univ, Sch Med, Charlestown, MA USA. RP Nitzsche, B (reprint author), Fraunhofer Inst Cell Therapy & Immunol, Perlickstr 1, D-04103 Leipzig, Germany. EM bjoern.nitzsche@izi.fraunhofer.de RI Stoffel, Michael/I-6939-2015; OI Stoffel, Michael/0000-0002-4699-5125; Nitzsche, Bjorn/0000-0002-4759-0760 FU Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universitat Leipzig); European Union; European Regional Development Fund (ERFD); European Social Fund; Free State of Saxony FX HK was funded by the Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universitat Leipzig). LIFE is funded by means of the European Union, by the European Regional Development Fund (ERFD), the European Social Fund and by means of the Free State of Saxony within the framework of the excellence initiative. NR 69 TC 2 Z9 2 U1 8 U2 16 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD JUN 4 PY 2015 VL 9 AR 69 DI 10.3389/fnana.2015.00069 PG 14 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CL3EA UT WOS:000356831600001 PM 26089780 ER PT J AU Rostoker, R Abelson, S Genkin, I Ben-Shmuel, S Sachidanandam, R Scheinman, EJ Bitton-Worms, K Orr, ZS Caspi, A Tzukerman, M LeRoith, D AF Rostoker, Ran Abelson, Sagi Genkin, Inna Ben-Shmuel, Sarit Sachidanandam, Ravi Scheinman, Eyal J. Bitton-Worms, Keren Orr, Zila Shen Caspi, Avishay Tzukerman, Maty LeRoith, Derek TI CD24(+) cells fuel rapid tumor growth and display high metastatic capacity SO BREAST CANCER RESEARCH LA English DT Article ID CANCER STEM-CELLS; BREAST-CANCER; HETEROGENEITY; PROGRESSION; EXPRESSION; CARCINOMA; SURVIVAL; PROLIFERATION; TUMORIGENESIS; HIERARCHY AB Introduction: Breast tumors are comprised of distinct cancer cell populations which differ in their tumorigenic and metastatic capacity. Characterization of cell surface markers enables investigators to distinguish between cancer stem cells and their counterparts. CD24 is a well-known cell surface marker for mammary epithelial cells isolation, recently it was suggested as a potential prognostic marker in a wide variety of malignancies. Here, we demonstrate that CD24(+) cells create intra-tumor heterogeneity, and display highly metastatic properties. Methods: The mammary carcinoma Mvt1 cells were sorted into CD24(-) and CD24(+) cells. Both subsets were morphologically and phenotypically characterized, and tumorigenic capacity was assessed via orthotopic inoculation of each subset into the mammary fat pad of wild-type and MKR mice. The metastatic capacity of each subset was determined with the tail vein metastasis assay. The role of CD24 in tumorigenesis was further examined with shRNA technology. GFP-labeled cells were monitored in vivo for differentiation. The genetic profile of each subset was analyzed using RNA sequencing. Results: CD24(+) cells displayed a more spindle-like cytoplasm. The cells formed mammospheres in high efficiency and CD24(+) tumors displayed rapid growth in both WT and MKR mice, and were more metastatic than CD24(-) cells. Interestingly, CD24(-) KD in CD24(+) cells had no effect both in vitro and in vivo on the various parameters studied. Moreover, CD24(+) cells gave rise in vivo to the CD24(-) that comprised the bulk of the tumor. RNA-seq analysis revealed enrichment of genes and pathways of the extracellular matrix in the CD24(+) cells. Conclusion: CD24(+) cells account for heterogeneity in mammary tumors. CD24 expression at early stages of the cancer process is an indication of a highly invasive tumor. However, CD24 is not a suitable therapeutic target; instead we suggest here new potential targets accounting for early differentiated cancer cells tumorigenic capacity. C1 [Rostoker, Ran; Genkin, Inna; Ben-Shmuel, Sarit; Scheinman, Eyal J.; Bitton-Worms, Keren; Orr, Zila Shen; Caspi, Avishay; LeRoith, Derek] Technion Israel Inst Technol, Diabet & Metab Clin Res Ctr Excellence, Rambam Med Ctr, CRIR, IL-31096 Haifa, Israel. [Rostoker, Ran; Genkin, Inna; Ben-Shmuel, Sarit; Scheinman, Eyal J.; Bitton-Worms, Keren; Orr, Zila Shen; Caspi, Avishay; LeRoith, Derek] Technion Israel Inst Technol, Fac Med, Rambam Med Ctr, IL-31096 Haifa, Israel. [Abelson, Sagi; Tzukerman, Maty] Technion Israel Inst Technol, Lab Mol Med, Rambam Hlth Care Campus, IL-31096 Haifa, Israel. [Abelson, Sagi; Tzukerman, Maty] Technion Israel Inst Technol, Rappaport Fac Med & Res Inst, IL-31096 Haifa, Israel. [Sachidanandam, Ravi] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Sachidanandam, Ravi] James J Peters VA Med Ctr, New York, NY USA. [LeRoith, Derek] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. RP LeRoith, D (reprint author), Technion Israel Inst Technol, Diabet & Metab Clin Res Ctr Excellence, Rambam Med Ctr, CRIR, POB 9602, IL-31096 Haifa, Israel. EM derek.leroith@mssm.edu FU Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam; Israel Science Foundation; European Foundation for the Study of Diabetes and Cancer Program; Chesed Foundation New York; NCI [2R01CA128799-06A1] FX This work was supported by grants from the Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (to DLR), the Israel Science Foundation grant (to DLR), the European Foundation for the Study of Diabetes and Cancer Program (to DLR), Chesed Foundation New York (DLR) and the NCI grant (Grant 2R01CA128799-06A1) to DLR. NR 50 TC 6 Z9 7 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JUN 4 PY 2015 VL 17 AR 78 DI 10.1186/s13058-015-0589-9 PG 14 WC Oncology SC Oncology GA CL2KZ UT WOS:000356774000002 PM 26040280 ER PT J AU Zhou, TQ Lynch, RM Chen, L Acharya, P Wu, XL Doria-Rose, NA Joyce, MG Lingwood, D Soto, C Bailer, RT Ernandes, MJ Kong, R Longo, NS Louder, MK McKee, K O'Dell, S Schmidt, SD Tran, LL Yang, ZJ Druz, A Luongo, TS Moquin, S Srivatsan, S Yang, YP Zhang, BS Zheng, AQ Pancera, M Kirys, T Georgiev, IS Gindin, T Peng, HP Yang, AS Mullikin, JC Gray, MD Stamatatos, L Burton, DR Koff, WC Cohen, MS Haynes, BF Casazza, JP Connors, M Corti, D Lanzavecchia, A Sattentau, QJ Weiss, RA West, AP Bjorkman, PJ Scheid, JF Nussenzweig, MC Shapiro, L Mascola, JR Kwong, PD AF Zhou, Tongqing Lynch, Rebecca M. Chen, Lei Acharya, Priyamvada Wu, Xueling Doria-Rose, Nicole A. Joyce, M. Gordon Lingwood, Daniel Soto, Cinque Bailer, Robert T. Ernandes, Michael J. Kong, Rui Longo, Nancy S. Louder, Mark K. McKee, Krisha O'Dell, Sijy Schmidt, Stephen D. Tran, Lillian Yang, Zhongjia Druz, Aliaksandr Luongo, Timothy S. Moquin, Stephanie Srivatsan, Sanjay Yang, Yongping Zhang, Baoshan Zheng, Anqi Pancera, Marie Kirys, Tatsiana Georgiev, Ivelin S. Gindin, Tatyana Peng, Hung-Pin Yang, An-Suei Mullikin, James C. Gray, Matthew D. Stamatatos, Leonidas Burton, Dennis R. Koff, Wayne C. Cohen, Myron S. Haynes, Barton F. Casazza, Joseph P. Connors, Mark Corti, Davide Lanzavecchia, Antonio Sattentau, Quentin J. Weiss, Robin A. West, Anthony P., Jr. Bjorkman, Pamela J. Scheid, Johannes F. Nussenzweig, Michel C. Shapiro, Lawrence Mascola, John R. Kwong, Peter D. CA NISC Comparative Sequencing TI Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors SO CELL LA English DT Article ID NEUTRALIZING HIV-1 ANTIBODY; BINDING-SITE ANTIBODIES; B-CELL RECEPTORS; CRYSTAL-STRUCTURE; POTENT NEUTRALIZATION; MONOCLONAL-ANTIBODIES; CD4-BINDING SITE; RATIONAL DESIGN; ENVELOPE TRIMER; INFECTION AB The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and V-H-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by V-H-gene-restricted ontogenies. C1 [Zhou, Tongqing; Lynch, Rebecca M.; Chen, Lei; Acharya, Priyamvada; Wu, Xueling; Doria-Rose, Nicole A.; Joyce, M. Gordon; Lingwood, Daniel; Soto, Cinque; Bailer, Robert T.; Ernandes, Michael J.; Kong, Rui; Longo, Nancy S.; Louder, Mark K.; McKee, Krisha; O'Dell, Sijy; Schmidt, Stephen D.; Tran, Lillian; Yang, Zhongjia; Druz, Aliaksandr; Luongo, Timothy S.; Moquin, Stephanie; Srivatsan, Sanjay; Yang, Yongping; Zhang, Baoshan; Zheng, Anqi; Pancera, Marie; Kirys, Tatsiana; Georgiev, Ivelin S.; Casazza, Joseph P.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Zhou, Tongqing; Lynch, Rebecca M.; Chen, Lei; Acharya, Priyamvada; Wu, Xueling; Doria-Rose, Nicole A.; Joyce, M. Gordon; Lingwood, Daniel; Soto, Cinque; Bailer, Robert T.; Ernandes, Michael J.; Kong, Rui; Longo, Nancy S.; Louder, Mark K.; McKee, Krisha; O'Dell, Sijy; Schmidt, Stephen D.; Tran, Lillian; Yang, Zhongjia; Druz, Aliaksandr; Luongo, Timothy S.; Moquin, Stephanie; Srivatsan, Sanjay; Yang, Yongping; Zhang, Baoshan; Zheng, Anqi; Pancera, Marie; Kirys, Tatsiana; Georgiev, Ivelin S.; Casazza, Joseph P.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIH, Bethesda, MD 20892 USA. [Gindin, Tatyana; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Gindin, Tatyana; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA. [Peng, Hung-Pin; Yang, An-Suei] Acad Sinica, Genom Res Ctr, Taipei 11221, Taiwan. [Peng, Hung-Pin; Yang, An-Suei] Natl Yang Ming Univ, Inst Biomed Informat, Taipei 11221, Taiwan. [Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Gray, Matthew D.; Stamatatos, Leonidas] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02142 USA. [Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Microbiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Immunol, Chapel Hill, NC 27599 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Med, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Surg, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Pediat, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Immunol, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Ctr HIV AIDS Vaccine Immunol Immunogen Discovery, Durham, NC 27710 USA. [Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, Bethesda, MD 20892 USA. [Connors, Mark] NIH, Bethesda, MD 20892 USA. [Corti, Davide] Humabs BioMed SA, CH-6500 Bellinzona, Switzerland. [Corti, Davide; Lanzavecchia, Antonio] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland. [Sattentau, Quentin J.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RF, England. [Weiss, Robin A.] UCL, Div Infect Immun, London WC1E 6BT, England. [West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@nih.gov; pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010; Schmidt, Stephen/B-5398-2012 OI Zhou, Tongqing/0000-0002-3935-4637; FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; Division of AIDS, NIAID, National Institutes of Health [AI037526, AI072529, AI0678501, P01 AI094419, P01 AI100148, P01 AI104722, 1UM1 AI100663, UM1 AI100645]; Howard Hughes Medical Institute; Bill and Melinda Gates Foundation [38637, 1040753]; International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); UK Department for International Development (DFID); United States Agency for International Development (USAID) FX We thank members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript and B. Honig for structural biology mentorship. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panel. The authors acknowledge the contributions of the Center for HIV/AIDS Vaccine Discovery (CHAVI) Clinical Core Team. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, by the Howard Hughes Medical Institute (M.C.N. and P.J.B. are investigators), and by grants from the Division of AIDS, NIAID, National Institutes of Health (AI037526, AI072529, AI0678501, P01 AI094419, P01 AI100148, P01 AI104722, and 1UM1 AI100663 and UM1 AI100645), from the Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery Grant IDs 38637 and 1040753), and from the International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium. IAVI's work is made possible by support from many donors, including: the Bill and Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the UK Department for International Development (DFID); and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 50 TC 62 Z9 62 U1 2 U2 22 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 JUN 4 PY 2015 VL 161 IS 6 BP 1280 EP 1292 DI 10.1016/j.cell.2015.05.007 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CK0ZR UT WOS:000355935000009 PM 26004070 ER PT J AU Beerman, I Rossi, DJ AF Beerman, Isabel Rossi, Derrick J. TI Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease SO CELL STEM CELL LA English DT Review ID REGULATES HEMATOPOIETIC STEM; DNA METHYLATION CHANGES; REPRESSIVE COMPLEX 2; ADULT HIPPOCAMPAL NEUROGENESIS; ACUTE MYELOID-LEUKEMIA; LONG-TERM CULTURE; GENOME-WIDE MAPS; SELF-RENEWAL; PROGENITOR CELLS; MYELODYSPLASTIC SYNDROMES AB Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This Review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease. C1 [Beerman, Isabel; Rossi, Derrick J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Beerman, Isabel; Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Beerman, Isabel; Rossi, Derrick J.] Boston Childrens Hosp, Div Hematol Oncol, Program Cellular & Mol Med, Boston, MA 02116 USA. RP Rossi, DJ (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM derrick.rossi@childrens.harvard.edu FU NIH [RO1HL107630, R00AG029760, UO1DK072473-01]; Leona M. and Harry B. Helmsley Charitable Trust; New York Stem Cell Foundation; Harvard Stem Cell Institute FX We would like to thank Shinpei Yamaguchi for his helpful input and Rossi Lab colleagues for thoughtful discussion and figure input. D.J.R. is supported by grants from the NIH (RO1HL107630, R00AG029760, and UO1DK072473-01) as well as grants from The Leona M. and Harry B. Helmsley Charitable Trust, The New York Stem Cell Foundation, and The Harvard Stem Cell Institute. D.J.R. is New York Stem Cell Foundation Robertson Investigator. NR 160 TC 22 Z9 22 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUN 4 PY 2015 VL 16 IS 6 BP 613 EP 625 DI 10.1016/j.stem.2015.05.009 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CK0YR UT WOS:000355932300011 PM 26046761 ER PT J AU Villaruz, LC Huang, G Romkes, M Kirkwood, JM Buch, SC Nukui, T Flaherty, KT Lee, SJ Wilson, MA Nathanson, KL Benos, PV Tawbi, HA AF Villaruz, Liza C. Huang, Grace Romkes, Marjorie Kirkwood, John M. Buch, Shama C. Nukui, Tomoko Flaherty, Keith T. Lee, Sandra J. Wilson, Melissa A. Nathanson, Katherine L. Benos, Panayiotis V. Tawbi, Hussein A. TI MicroRNA expression profiling predicts clinical outcome of carboplatin/paclitaxel-based therapy in metastatic melanoma treated on the ECOG-ACRIN trial E2603 SO CLINICAL EPIGENETICS LA English DT Article DE Melanoma; MicroRNAs; Chemotherapy; Response; Biomarkers; Predictive ID FIBROBLAST-GROWTH-FACTOR; CUTANEOUS MALIGNANT-MELANOMA; RANDOMIZED PHASE-III; STAGE IV MELANOMA; DNA-DAMAGE; TUMOR-SUPPRESSOR; DOWN-REGULATION; PLEXIN B1; MUTATIONS; CANCER AB Background: Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18-20 % in unselected chemotherapy-naive patients. Molecular predictors of survival and response to CP-based chemotherapy in metastatic melanoma (MM) are critical to improving the therapeutic index. Intergroup trial E2603 randomized MM patients to CP with or without sorafenib. Expression data were collected from pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor tissues from 115 of 823 patients enrolled on E2603. The selected patients were balanced across treatment arms, BRAF status, and clinical outcome. We generated data using Nanostring array (microRNA (miRNA) expression) and DNA-mediated annealing, selection, extension and ligation (DASL)/Illumina microarrays (HT12 v4) (mRNA expression) with protocols optimized for FFPE samples. Integrative computational analysis was performed using a novel Tree-guided Recursive Cluster Selection (T-ReCS) [1] algorithm to select the most informative features/genes, followed by TargetScan miRNA target prediction (Human v6.2) and mirConnX [ 2] for network inference. Results: T-ReCS identified PLXNB1 as negatively associated with progression-free survival (PFS) and miR-659-3p as the primary miRNA associated positively with PFS. miR-659-3p was differentially expressed based on PFS but not based on treatment arm, BRAF or NRAS status. Dichotomized by median PFS (less vs greater than 4 months), miR-659-3p expression was significantly different. High miR-659-3p expression distinguished patients with responsive disease (complete or partial response) from patients with stable disease. miR-659-3p predicted gene targets include NFIX, which is a transcription factor known to interact with c-Jun and AP-1 in the context of developmental processes and disease. Conclusions: This novel integrative analysis implicates miR-659-3p as a candidate predictive biomarker for MM patients treated with platinum-based chemotherapy and may serve to improve patient selection. C1 [Villaruz, Liza C.; Romkes, Marjorie; Kirkwood, John M.; Tawbi, Hussein A.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Huang, Grace; Buch, Shama C.; Nukui, Tomoko; Benos, Panayiotis V.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Flaherty, Keith T.; Wilson, Melissa A.; Nathanson, Katherine L.] Univ Penn, Philadelphia, PA 19104 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, Sandra J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wilson, Melissa A.] NYU, New York, NY USA. RP Tawbi, HA (reprint author), Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. EM tawbih@upmc.edu OI Benos, Panayiotis/0000-0003-3172-3132 FU Public Health Service [CA180820, CA180794, CA180844, CA15488, CA18086]; UPCI Skin Cancer SPORE [P50 CA121973-02]; UPCI Cancer Biomarkers Facility [P30CA047904]; National Institutes of Health [R01LM012087]; Conquer Cancer Foundation of ASCO Young Investigator Award; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This study was conducted by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA180844, CA15488, and CA18086; the UPCI Skin Cancer SPORE (P50 CA121973-02) with the UPCI Cancer Biomarkers Facility (P30CA047904); the National Institutes of Health grant (R01LM012087) and the Conquer Cancer Foundation of ASCO Young Investigator Award and the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. NR 57 TC 3 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD JUN 4 PY 2015 VL 7 AR 58 DI 10.1186/s13148-015-0092-2 PG 9 WC Oncology SC Oncology GA CK2JL UT WOS:000356036500001 PM 26052356 ER PT J AU Aranda, F Bloy, N Pesquet, J Petit, B Chaba, K Sauvat, A Kepp, O Khadra, N Enot, D Pfirschke, C Pittet, M Zitvogel, L Kroemer, G Senovilla, L AF Aranda, F. Bloy, N. Pesquet, J. Petit, B. Chaba, K. Sauvat, A. Kepp, O. Khadra, N. Enot, D. Pfirschke, C. Pittet, M. Zitvogel, L. Kroemer, G. Senovilla, L. TI Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer SO ONCOGENE LA English DT Article ID MULTICENTER PHASE-II; CALRETICULIN EXPOSURE; VITAMIN-B6 METABOLISM; PLATINUM COMPLEXES; ANTICANCER DRUGS; DOSE EPIRUBICIN; DEATH; CHEMOTHERAPY; TUMOR; THERAPY AB cis-Diamminedichloroplatinum(II) (CDDP), which is mostly referred to as cisplatin, is a widely used antineoplastic. The efficacy of cisplatin can be improved by combining it with the vitamin B6 precursor pyridoxine. Here, we evaluated the putative synergistic interaction of CDDP with pyridoxine in the treatment of an orthotopic mouse model of non-small-cell lung cancer (NSCLC). CDDP and pyridoxine exhibited hyperadditive therapeutic effects. However, this synergy was only observed in the context of an intact immune system and disappeared when the otherwise successful drug combination was applied to the same NSCLC cancer implanted in the lungs of athymic mice (which lack T lymphocytes). Immunocompetent mice that had been cured from NSCLC by the combined regimen of CDDP plus pyridoxine became resistant against subcutaneous rechallenge with the same (but not with an unrelated) cancer cell line. In vitro, CDDP and pyridoxine did not only cause synergistic killing of NSCLC cells but also elicited signs of immunogenic cell death including an endoplasmic reticulum stress response and exposure of calreticulin at the surface of the NSCLC cells. NSCLC cells treated with CDDP plus pyridoxine in vitro elicited a protective anticancer immune response upon their injection into immunocompetent mice. Altogether, these results suggest that the combined regimen of cisplatin plus pyridoxine mediates immune-dependent antineoplastic effects against NSCLC. C1 [Aranda, F.; Bloy, N.; Pesquet, J.; Chaba, K.; Sauvat, A.; Kepp, O.; Khadra, N.; Enot, D.; Kroemer, G.; Senovilla, L.] Ctr Rech Cordeliers, INSERM U1138, Equipe Labellisee Pas Ligue Natl Canc 11, F-75006 Paris, France. [Aranda, F.; Bloy, N.; Pesquet, J.; Chaba, K.; Sauvat, A.; Kepp, O.; Khadra, N.; Enot, D.; Kroemer, G.] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Aranda, F.; Bloy, N.; Pesquet, J.; Sauvat, A.; Kepp, O.; Khadra, N.; Enot, D.; Kroemer, G.; Senovilla, L.] Metab & Cell Biol Platforms, Villejuif, France. [Bloy, N.; Zitvogel, L.] Univ Paris 11, Villejuif, France. [Petit, B.] INSERM, U1030, Villejuif, France. [Pfirschke, C.; Pittet, M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Pittet Lab, Boston, MA USA. [Zitvogel, L.; Senovilla, L.] INSERM, U1015, Villejuif, France. [Zitvogel, L.] Ctr Invest Clin Biotherapie CICBT 507, Villejuif, France. [Kroemer, G.] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France. RP Kroemer, G (reprint author), Ctr Rech Cordeliers, INSERM U1138, Equipe Labellisee Pas Ligue Natl Canc 11, 15 Rue Ecole Med, F-75006 Paris, France. EM kroemer@orange.fr; laurasenovilla@hotmail.com RI Aranda, Fernando/N-2112-2014 OI Aranda, Fernando/0000-0002-9364-474X FU Deutsche Forschungsgemeinschaft (DFG) [PF809/1-1]; Fondation Tourre; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); SIRIC Cancer Research and Personalized Medicine (CARPEM); Ligue contre le Cancer (equipe labelisee); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Canceropole Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Medicale (FRM); European Commission (ArtForce); European Research Council (ERC); LabEx Immuno-Oncology; Paris Alliance of Cancer Research Institutes (PACRI) FX We are indepted to Dr Gonin (Gustave Roussy) for help in mouse experiments. CP is supported by the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1. LS is supported by the Fondation Tourre, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) and the SIRIC Cancer Research and Personalized Medicine (CARPEM). GK is supported by the Ligue contre le Cancer (equipe labelisee); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Canceropole Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Medicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). NR 46 TC 8 Z9 8 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 4 PY 2015 VL 34 IS 23 BP 3053 EP 3062 DI 10.1038/onc.2014.234 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CK3EX UT WOS:000356100500010 PM 25065595 ER PT J AU Wei, F Ojo, D Lin, X Wong, N He, L Yan, J Xu, S Major, P Tang, D AF Wei, F. Ojo, D. Lin, X. Wong, N. He, L. Yan, J. Xu, S. Major, P. Tang, D. TI BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation SO ONCOGENE LA English DT Article ID DNA-DAMAGE RESPONSE; STRAND BREAK REPAIR; CELL SELF-RENEWAL; POLYCOMB GROUP PROTEINS; MYC TRANSGENIC MICE; GROUP GENE BMI1; GENOMIC INSTABILITY; MOLECULAR MARKER; PROSTATE-CANCER; HISTONE H2AX AB The BMI1 protein contributes to stem cell pluripotency and oncogenesis via multiple functions, including its newly identified role in DNA damage response (DDR). Although evidence clearly demonstrates that BMI1 facilitates the repair of double-stranded breaks via homologous recombination (HR), it remains unclear how BMI1 regulates checkpoint activation during DDR. We report here that BMI1 has a role in G2/M checkpoint activation in response to etoposide (ETOP) treatment. Ectopic expression of BMI1 in MCF7 breast cancer and DU145 prostate cancer cells significantly reduced ETOP-induced G2/M arrest. Conversely, knockdown of BMI1 in both lines enhanced the arrest. Consistent with ETOP-induced activation of the G2/M checkpoints via the ATM pathway, overexpression and knockdown of BMI1, respectively, reduced and enhanced ETOP-induced phosphorylation of ATM at serine 1981 (ATM pS1981). Furthermore, the phosphorylation of ATM targets, including gamma H2AX, threonine 68 (T68) on CHK2 (CHK2 pT68) and serine 15 (S15) on p53 were decreased in overexpression and increased in knockdown BMI1 cells in response to ETOP. In line with the requirement of NBS1 in ATM activation, we were able to show that BMI1 associates with NBS1 and that this interaction altered the binding of NBS1 with ATM. BMI1 consists of a ring finger (RF), helix-turn-helix-turn-helix-turn (HT), proline/serine (PS) domain and two nuclear localization signals (NLS). Although deletion of either RF or HT did not affect the association of BMI1 with NBS1, the individual deletions of PS and one NLS (KRMK) robustly reduced the interaction. Stable expression of these BMI1 mutants decreased ETOP-induced ATM pS1981 and CHK2 pT68, but not ETOP-elicited gamma H2AX in MCF7 cells. Furthermore, ectopic expression of BMI1 in non-transformed breast epithelial MCF10A cells also compromised ETOP-initiated ATM pS1981 and gamma H2AX. Taken together, we provide compelling evidence that BMI1 decreases ETOP-induced G2/M checkpoint activation via reducing NBS1-mediated ATM activation. C1 [Wei, F.; Ojo, D.; Lin, X.; Wong, N.; He, L.; Yan, J.; Xu, S.; Tang, D.] McMaster Univ, Dept Med, Div Nephrol, Hamilton, ON, Canada. [Wei, F.; Ojo, D.; Lin, X.; Wong, N.; He, L.; Yan, J.; Xu, S.; Tang, D.] Father Sean OSullivan Res Inst, Hamilton, ON, Canada. [Wei, F.; Ojo, D.; Lin, X.; Wong, N.; He, L.; Yan, J.; Xu, S.; Tang, D.] St Josephs Hosp, Hamilton Ctr Kidney Res, Hamilton, ON L8N 4A6, Canada. [Wei, F.] Inst Women & Childrens Hlth, Genet Lab, Shenzhen, Guangdong, Peoples R China. [He, L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Major, P.] McMaster Univ, Dept Oncol, Hamilton, ON, Canada. RP Tang, D (reprint author), St Josephs Hosp, Father Sean OSullivan Res Inst, T3310,50 Charlton Ave East, Hamilton, ON L8N 4A6, Canada. EM damut@mcmaster.ca FU CIHR grant [MOP-84381] FX This work was supported by a CIHR grant (MOP-84381) to D Tang. NR 64 TC 6 Z9 7 U1 4 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 4 PY 2015 VL 34 IS 23 BP 3063 EP 3075 DI 10.1038/onc.2014.235 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CK3EX UT WOS:000356100500011 PM 25088203 ER PT J AU Mesa, KR Rompolas, P Zito, G Myung, P Sun, TY Brown, S Gonzalez, DG Blagoev, KB Haberman, AM Greco, V AF Mesa, Kailin R. Rompolas, Panteleimon Zito, Giovanni Myung, Peggy Sun, Thomas Y. Brown, Samara Gonzalez, David G. Blagoev, Krastan B. Haberman, Ann M. Greco, Valentina TI Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool SO NATURE LA English DT Article ID REGRESSION CATAGEN; DERMAL PAPILLA; IN-VIVO; GENE; REGENERATION; CATENIN; ACTIVATION; APOPTOSIS; DYNAMICS; PROGENY AB Tissue homeostasis is achieved through a balance of cell production (growth) and elimination (regression)(1,2). In contrast to tissue growth, the cells and molecular signals required for tissue regression remain unknown. To investigate physiological tissue regression, we use the mouse hair follicle, which cycles stereotypically between phases of growth and regression while maintaining a pool of stem cells to perpetuate tissue regeneration(3). Here we show by intravital microscopy in live mice(4-6) that the regression phase eliminates the majority of the epithelial cells by two distinct mechanisms: terminal differentiation of suprabasal cells and a spatial gradient of apoptosis of basal cells. Furthermore, we demonstrate that basal epithelial cells collectively act as phagocytes to clear dying epithelial neighbours. Through cellular and genetic ablation we show that epithelial cell death is extrinsically induced through transforming growth factor (TGF)-beta activation and mesenchymal crosstalk. Strikingly, our data show that regression acts to reduce the stem cell pool, as inhibition of regression results in excess basal epithelial cells with regenerative abilities. This study identifies the cellular behaviours and molecular mechanisms of regression that counterbalance growth to maintain tissue homeostasis. C1 [Mesa, Kailin R.; Rompolas, Panteleimon; Myung, Peggy; Sun, Thomas Y.; Brown, Samara; Greco, Valentina] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Zito, Giovanni] Univ Palermo, Dept Biopathol & Med Biotechnol, I-90100 Palermo, Italy. [Myung, Peggy; Greco, Valentina] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Gonzalez, David G.; Haberman, Ann M.] Yale Univ, Sch Med, Dept Immunobiol, Dept Lab Med, New Haven, CT 06510 USA. [Blagoev, Krastan B.] Natl Sci Fdn, Arlington, VA 22230 USA. [Blagoev, Krastan B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA 02114 USA. [Greco, Valentina] Yale Univ, Sch Med, Yale Stem Cell Ctr, New Haven, CT 06510 USA. [Greco, Valentina] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA. RP Greco, V (reprint author), Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. EM valentina.greco@yale.edu OI Mesa, Kailin/0000-0003-4452-9048 FU National Institutes of Health (NIH) [5T32 GM007223]; American Cancer Society [RSG-12-059-02]; National Cancer Institute, NIH [2P50CA121974]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH [1R01AR063663-01]; New York Stem Cell Foundation; NIAMS Rheumatic Diseases Research Core Centers [5 P30 AR053495-07]; NSF FX We thank E. Fuchs for the K14-H2BGFP, Lef1-RFP and K14-GFPActin mice; M. Taketo for the Cttnb1fl(Ex3)/+ mice; A. Horwich and A. Mesa for critical feedback; M. Rendl for technical advice; M. Graham and X. Liu for technical support with electron microscopy; D. Egli for the H2BmCherry construct; and T. Nottoli for generating the K14-H2BmCherry mouse line. K.R.M. and S.B. were supported by the National Institutes of Health (NIH) Predoctoral Program in Cellular and Molecular Biology, grant no. 5T32 GM007223. K.R.M. is currently a National Science Foundation (NSF) Graduate Research Fellow. This work is supported by the American Cancer Society, grant no. RSG-12-059-02; Yale Spore Grant National Cancer Institute, NIH, grant no. 2P50CA121974; the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, grant no. 1R01AR063663-01; and by The New York Stem Cell Foundation. V.G. is a New York Stem Cell Foundation-Robertson Investigator. P.R. is a New York Stem Cell Foundation-Druckenmiller Fellow. A.M.H. is supported by NIAMS Rheumatic Diseases Research Core Centers grant no. 5 P30 AR053495-07. K.B.B. was supported by the NSF. The NSF had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views presented here are not those of the NSF and represent solely the views of the authors. NR 28 TC 14 Z9 14 U1 4 U2 15 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 JUN 4 PY 2015 VL 522 IS 7554 BP 94 EP U236 DI 10.1038/nature14306 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5QP UT WOS:000355543400036 PM 25849774 ER PT J AU Brown, RB Razzaque, MS AF Brown, Ronald B. Razzaque, Mohammed S. TI Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity SO BONEKEY REPORTS LA English DT Review ID FIBROBLAST-GROWTH-FACTOR; CHRONIC KIDNEY-DISEASE; NEUTRON-ACTIVATION ANALYSIS; MINERAL METABOLISM; DIETARY PHOSPHORUS; VITAMIN-D; PARATHYROID-HORMONE; CALCIUM/PHOSPHORUS RATIO; CARDIOVASCULAR-DISEASE; VASCULAR CALCIFICATION AB Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1 alpha(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders. C1 [Brown, Ronald B.] Kansas State Univ, Dept Hospitality Management & Dietet, Coll Human Ecol, Manhattan, KS 66506 USA. [Razzaque, Mohammed S.] Forsyth Inst, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. [Razzaque, Mohammed S.] VPS Healthcare, Div Res & Dev, Abu Dhabi, U Arab Emirates. RP Razzaque, MS (reprint author), Forsyth Inst, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM mrazzaque@forsyth.org NR 102 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2047-6396 J9 BONEKEY REP JI BoneKEy Rep. PD JUN 3 PY 2015 VL 4 AR 705 DI 10.1038/bonekey.2015.74 PG 7 WC Orthopedics SC Orthopedics GA DL5QG UT WOS:000375691200001 PM 26131357 ER PT J AU Xia, CJ Stolle, D Gidengil, E Fellows, LK AF Xia, Chenjie Stolle, Dietlind Gidengil, Elisabeth Fellows, Lesley K. TI Lateral Orbitofrontal Cortex Links Social Impressions to Political Choices SO JOURNAL OF NEUROSCIENCE LA English DT Article DE decision-making; frontal lobes; human; neuropolitics; neuropsychology; social neuroscience ID VENTROMEDIAL PREFRONTAL CORTEX; MULTIATTRIBUTE DECISION-MAKING; 1ST IMPRESSIONS; FACIAL ATTRACTIVENESS; ELECTION OUTCOMES; MECHANISMS; INFERENCES; EMOTION; SYSTEMS; FACES AB Recent studies of political behavior suggest that voting decisions can be influenced substantially by "first-impression" social attributions based on physical appearance. Separate lines of research have implicated the orbitofrontal cortex (OFC) in the judgment of social traits on the one hand and economic decision-making on the other, making this region a plausible candidate for linking social attributions to voting decisions. Here, we asked whether OFC lesions in humans disrupted the ability to judge traits of political candidates or affected how these judgments influenced voting decisions. Seven patients with lateral OFC damage, 18 patients with frontal damage sparing the lateral OFC, and 53 matched healthy participants took part in a simulated election paradigm, in which they voted for real-life (but unknown) candidates based only on photographs of their faces. Consistent with previous work, attributions of "competence" and "attractiveness" based on candidate appearance predicted voting behavior in the healthy control group. Frontal damage did not affect substantially the ability to make competence or attractiveness judgments, but patients with damage to the lateral OFC differed from other groups in how they applied this information when voting. Only attractiveness ratings had any predictive power for voting choices after lateral OFC damage, whereas other frontal patients and healthy controls relied on information about both competence and attractiveness in making their choice. An intact lateral OFC may not be necessary for judgment of social traits based on physical appearance, but it seems to be crucial in applying this information in political decision-making. C1 [Xia, Chenjie; Fellows, Lesley K.] Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Stolle, Dietlind; Gidengil, Elisabeth] McGill Univ, Dept Polit Sci, Ctr Study Democrat Citizenship, Montreal, PQ H3A 2T7, Canada. [Xia, Chenjie] Massachusetts Gen Hosp, Gerontol Res Unit, Charlestown, MA 02129 USA. [Xia, Chenjie] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Xia, Chenjie] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Fellows, LK (reprint author), Montreal Neurol Inst, Dept Neurol & Neurosurg, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. EM lesley.fellows@mcgill.ca FU Quebec Fund for Research, Society, and Culture; Canadian Institutes of Health Research Grant [MOP 97821]; Montreal Neurological Institute; University of Pennsylvania FX This work was supported by operating grants from the Quebec Fund for Research, Society, and Culture (E.G.) and Canadian Institutes of Health Research Grant MOP 97821 (L.K.F.). We thank Michael Spezio for generously sharing the stimulus set and for helpful discussions in the initial stages of this project. Ongoing support for the patient registries from the Montreal Neurological Institute and the University of Pennsylvania is gratefully acknowledged. Arlene Berg, Eileen Cardillo, and Kaitlyn Shannon provided useful research assistance. Finally, we thank the participants, particularly the patients and their families, without whom this work would not be possible. NR 45 TC 3 Z9 3 U1 4 U2 15 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 JUN 3 PY 2015 VL 35 IS 22 BP 8507 EP 8514 DI 10.1523/JNEUROSCI.0526-15.2015 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CN2JV UT WOS:000358247900013 PM 26041918 ER PT J AU Ma, KH Hung, HA Srinivasan, R Xie, HF Orkin, SH Svaren, J AF Ma, Ki H. Hung, Holly A. Srinivasan, Rajini Xie, Huafeng Orkin, Stuart H. Svaren, John TI Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE chromatin; histone; injury; myelin; polycomb; Schwann ID SCHWANN-CELL DIFFERENTIATION; EMBRYONIC STEM-CELLS; SONIC HEDGEHOG; NEURAL CREST; HISTONE METHYLATION; BINDING-PROTEIN; NEUROFIBROMA FORMATION; MOUSE DEVELOPMENT; DESERT HEDGEHOG; EZH2 AB Myelination of peripheral nerves by Schwann cells requires coordinate regulation of gene repression as well as gene activation. Several chromatin remodeling pathways critical for peripheral nerve myelination have been identified, but the functions of histone methylation in the peripheral nerve have not been elucidated. To determine the role of histone H3 Lys27 methylation, we have generated mice with a Schwann cell-specific knock-out of Eed, which is an essential subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 Lys27. Analysis of this mutant revealed no significant effects on early postnatal development of myelin. However, its loss eventually causes progressive hypermyelination of small-diameter axons and apparent fragmentation of Remak bundles. These data identify the PRC2 complex as an epigenomic modulator of mature myelin thickness, which is associated with changes in Akt phosphorylation. Interestingly, we found that Eed inactivation causes derepression of several genes, e.g., Sonic hedgehog (Shh) and Insulin-like growth factor-binding protein 2 (Igfbp2), that become activated after nerve injury, but without activation of a primary regulator of the injury program, c-Jun. Analysis of the activated genes in cultured Schwann cells showed that Igfbp2 regulates Akt activation. Our results identify an epigenomic pathway required for establishing thickness of mature myelin and repressing genes that respond to nerve injury. C1 [Ma, Ki H.; Hung, Holly A.; Srinivasan, Rajini; Svaren, John] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Ma, Ki H.; Hung, Holly A.] Univ Wisconsin, Cellular & Mol Pathol Grad Program, Madison, WI 53705 USA. [Svaren, John] Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53705 USA. [Xie, Huafeng; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Xie, Huafeng; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Xie, Huafeng; Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Svaren, J (reprint author), Waisman Ctr Mental Retardat & Human Dev, 1500 Highland Ave, Madison, WI 53705 USA. EM jpsvaren@wisc.edu OI Svaren, John/0000-0003-2963-7921 FU National Institutes of Health [NS075269]; P30 Core Grant [HD03352] FX This work was supported by the National Institutes of Health: NS075269 to J. S. and P30 Core Grant HD03352. We thank Marie Adams for performance and preliminary analysis of Illumina sequencing, Xiao-yu Liu for assistance in ChIP-Seq/microarray analysis, Christopher Huppenbauer for technical support in 3D deconvolution imaging, Steve Scherer for guidance inEManalysis, and Albee Messing and Larry Wrabetz for generously providing the P0-Cre mice. NR 93 TC 6 Z9 6 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 3 PY 2015 VL 35 IS 22 BP 8640 EP 8652 DI 10.1523/JNEUROSCI.2257-14.2015 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CN2JV UT WOS:000358247900024 PM 26041929 ER PT J AU Gulati, T Won, SJ Ramanathan, DS Wong, CC Bodepudi, A Swanson, RA Ganguly, K AF Gulati, Tanuj Won, Seok Joon Ramanathan, Dhakshin S. Wong, Chelsea C. Bodepudi, Anitha Swanson, Raymond A. Ganguly, Karunesh TI Robust Neuroprosthetic Control from the Stroke Perilesional Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain-machine interface; electrophysiology; plasticity; stroke ID BRAIN-COMPUTER INTERFACES; PRIMARY MOTOR CORTEX; MACHINE INTERFACE; CORTICAL CONTROL; IPSILATERAL ARM; AREA V4; RECOVERY; MOVEMENTS; NEURONS; REHABILITATION AB Intracortical brain-machine interfaces (BMIs) may eventually restore function in those with motor disability after stroke. However, current research into the development of intracortical BMIs has focused on subjects with largely intact cortical structures, such as those with spinal cord injury. Although the stroke perilesional cortex (PLC) has been hypothesized as a potential site for a BMI, it remains unclear whether the injured motor cortical network can support neuroprosthetic control directly. Using chronic electrophysiological recordings in a rat stroke model, we demonstrate here the PLC's capacity for neuroprosthetic control and physiological plasticity. We initially found that the perilesional network demonstrated abnormally increased slow oscillations that also modulated neural firing. Despite these striking abnormalities, neurons in the perilesional network could be modulated volitionally to learn neuroprosthetic control. The rate of learning was surprisingly similar regardless of the electrode distance from the stroke site and was not significantly different from intact animals. Moreover, neurons achieved similar task-related modulation and, as an ensemble, formed cell assemblies with learning. Such control was even achieved in animals with poor motor recovery, suggesting that neuroprosthetic control is possible even in the absence of motor recovery. Interestingly, achieving successful control also reduced locking to abnormal oscillations significantly. Our results thus suggest that, despite the disrupted connectivity in the PLC, it may serve as an effective target for neuroprosthetic control in those with poor motor recovery after stroke. C1 [Gulati, Tanuj; Won, Seok Joon; Ramanathan, Dhakshin S.; Wong, Chelsea C.; Bodepudi, Anitha; Swanson, Raymond A.; Ganguly, Karunesh] San Francisco VA Med Ctr, Neurol & Rehabil Serv, San Francisco, CA 94158 USA. [Ramanathan, Dhakshin S.] San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA 94158 USA. [Gulati, Tanuj; Won, Seok Joon; Wong, Chelsea C.; Bodepudi, Anitha; Swanson, Raymond A.; Ganguly, Karunesh] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Ramanathan, Dhakshin S.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Ganguly, K (reprint author), San Francisco VA Med Ctr, Neurol & Rehabil Serv, 1700 Owens St, San Francisco, CA 94158 USA. EM karunesh.ganguly@ucsf.edu FU Department of Veterans Affairs [B6674]; Burroughs Wellcome Fund [1009855]; American Heart/Stroke Association [0875016N]; SFVAMC; NCIRE; UCSF Department of Neurology; Advanced Research Fellowship from the VA FX This work is supported by the Department of Veterans Affairs (Grant B6674 to K.G.), the Burroughs Wellcome Fund (Grant 1009855 to K.G.), the American Heart/Stroke Association (Grant 0875016N to K.G.), and by start-up funds from the SFVAMC, NCIRE, and UCSF Department of Neurology; an Advanced Research Fellowship from the VA to D.R. NR 63 TC 6 Z9 6 U1 0 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 JUN 3 PY 2015 VL 35 IS 22 BP 8653 EP 8661 DI 10.1523/JNEUROSCI.5007-14.2015 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CN2JV UT WOS:000358247900025 PM 26041930 ER PT J AU Bellmunt, J Werner, L Leow, JJ Mullane, SA Fay, AP Riester, M Van Hummelen, P Taplin, ME Choueiri, TK Van Allen, E Rosenberg, J AF Bellmunt, Joaquim Werner, Lillian Leow, Jeffrey J. Mullane, Stephanie A. Fay, Andre P. Riester, Markus Van Hummelen, Paul Taplin, Mary-Ellen Choueiri, Toni K. Van Allen, Eliezer Rosenberg, Jonathan TI Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors SO PLOS ONE LA English DT Article ID BLADDER-CANCER; PIK3CA MUTATION; CELL CARCINOMA; FGFR3; FREQUENT; TARGET; AMPLIFICATION; THERAPY; RAS AB Background An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS) in patients with advanced urothelial carcinoma (UC) treated with platinum-based chemotherapy. Patients and Methods DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE) invasive high-grade UC samples and were screened for mutations, copy number variation (CNV) and gene expression analysis. Clinical data were available from 85 cases. Mutations were analyzed by mass-spectrometry based on genotyping platform (Oncomap 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio >= 0.4, or <= 0.6 were defined as either having copy number gain or loss and significantly recurrent CNV across the set of samples were determined using a GISTIC analysis. Expression analysis on selected relevant UC genes was conducted using Nanostring. To define the co-occurrence pattern of mutations and CNV, we grouped genomic events into 5 core signal transduction pathways: 1) TP53 pathway, 2) RTK/RAS/RAF pathway, 3) PI3K/AKT/mTOR pathway, 4) WNT/CTNNB1, 5) RB1 pathway. Cox regression was used to assess pathways abnormalities with survival outcomes. Results 35 samples (41%) harbored mutations on at least one gene: TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). 66% of patients had some sort of CNV. PIK3CA/AKT/mTOR pathway alteration (mutations+CNV) had the greatest impact on OS (p=0.055). At a gene level, overexpression of CTNNB1 (p=0.0008) and PIK3CA (p=0.02) were associated with shorter OS. Mutational status on PIK3CA was not associated with survival. Among other individually found genomic alterations, TP53 mutations (p=0.07), mTOR gain (p=0.07) and PTEN overexpression (p=0.08) have a marginally significant negative impact on OS. Conclusions Our study suggests that targeted therapies focusing on the PIK3CA/AKT/mTOR pathway genomic alterations can generate the greatest impact in the overall patient population of high-grade advanced UC. C1 [Bellmunt, Joaquim; Leow, Jeffrey J.; Mullane, Stephanie A.; Fay, Andre P.; Taplin, Mary-Ellen; Choueiri, Toni K.; Van Allen, Eliezer] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Lank Ctr Genitourinary Onco, Boston, MA 02115 USA. [Werner, Lillian; Riester, Markus] Harvard Univ, Sch Med, Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Van Hummelen, Paul] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Rosenberg, Jonathan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Bellmunt, J (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Lank Ctr Genitourinary Onco, Boston, MA 02115 USA. EM joaquim_bellmunt@dfci.harvard.edu OI Rosenberg, Jonathan/0000-0003-2637-4249 FU Spanish Health Ministry Grant "Fondo de Investigacion Sanitaria" [PI061513]; RTICC grants [06/0020/19]; Pla Director d'Oncologia de Catalunya (XBTC); Friends of Dana-Farber; Retired Professional Fire Fighters Cancer Fund; Whole Foods Golf Classic FX This work has been supported by PI061513 (Spanish Health Ministry Grant "Fondo de Investigacion Sanitaria") and RTICC 06/0020/19 grants. Fundacio Cellex (Barcelona) provided a generous donation to the Group of Molecular Therapeutics and Biomarkers, Hospital del Mar. The Tumor Bank of the Department of Pathology of Hospital del Mar (RD09/0076/0036) and the Xarxa de Bancs de Tumors sponsored by Pla Director d'Oncologia de Catalunya (XBTC) provided tissue samples. This study was also possible thanks to a Grant from Friends of Dana-Farber, the Retired Professional Fire Fighters Cancer Fund, and the generous support of Whole Foods Golf Classic for bladder cancer research in memoriam of Christopher Snell. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 8 Z9 8 U1 1 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 JUN 3 PY 2015 VL 10 IS 6 AR e0124711 DI 10.1371/journal.pone.0124711 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7ST UT WOS:000355700700004 PM 26039708 ER PT J AU Castiglioni, A Corna, G Rigamonti, E Basso, V Vezzoli, M Monno, A Almada, AE Mondino, A Wagers, AJ Manfredi, AA Rovere-Querini, P AF Castiglioni, Alessandra Corna, Gianfranca Rigamonti, Elena Basso, Veronica Vezzoli, Michela Monno, Antonella Almada, Albert E. Mondino, Anna Wagers, Amy J. Manfredi, Angelo A. Rovere-Querini, Patrizia TI FOXP3(+) T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; GROWTH-FACTOR-I; MUSCULAR-DYSTROPHY; GAMMA-CHAIN; MDX MICE; INFLAMMATION; DIFFERENTIATION; RECEPTOR; CD4(+); MYOGENESIS AB Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a promyogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2(-/-) gamma-chain(-/-) mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4(+)CD25(+)FOXP3(+) cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue. C1 [Castiglioni, Alessandra; Corna, Gianfranca; Rigamonti, Elena; Vezzoli, Michela; Monno, Antonella; Manfredi, Angelo A.; Rovere-Querini, Patrizia] San Raffaele Sci Inst, Div Regenerat Med Stem Cells & Gene Therapy, I-20132 Milan, Italy. [Castiglioni, Alessandra; Corna, Gianfranca; Rigamonti, Elena; Basso, Veronica; Vezzoli, Michela; Monno, Antonella; Mondino, Anna; Manfredi, Angelo A.; Rovere-Querini, Patrizia] Vita Salute San Raffaele Univ, Milan, Italy. [Castiglioni, Alessandra; Almada, Albert E.; Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Castiglioni, Alessandra; Almada, Albert E.; Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Castiglioni, Alessandra; Almada, Albert E.; Wagers, Amy J.] Howard Hughes Med Inst, Cambridge, MA USA. [Castiglioni, Alessandra; Almada, Albert E.; Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA USA. [Castiglioni, Alessandra; Almada, Albert E.; Wagers, Amy J.] Harvard Univ, Sch Med, Paul F Glenn Lab Biol Mech Aging, Boston, MA USA. [Basso, Veronica; Mondino, Anna] San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, I-20132 Milan, Italy. RP Castiglioni, A (reprint author), San Raffaele Sci Inst, Div Regenerat Med Stem Cells & Gene Therapy, I-20132 Milan, Italy. EM acastiglioni@fas.harvard.edu FU Italian Ministry of Health; Association Francaise contre les Myopathies [15440]; AIRC - Associazione Italiana per la Ricerca sul Cancro; Ministero dell'Istruzione, dell'Universita' e della Ricerca; Burroughs Wellcome Fund; NIH [1R01 AG033053, 5U01 HL100402, P30 DK036836]; National Institutes of Health (NIH) FX This work was supported by the Italian Ministry of Health (Fondo per gli Investimenti della Ricerca di Base-IDEAS to P.R.-Q. and Ricerca Finalizzata to A.A.M. and P.R.-Q.) the Association Francaise contre les Myopathies (Grant 15440 to P.R.-Q.) the AIRC - Associazione Italiana per la Ricerca sul Cancro (to A.A.M.) and Ministero dell'Istruzione, dell'Universita' e della Ricerca (to A.A.M.). A.E. A., Ph.D., holds a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund. NIH 1R01 AG033053 and 5U01 HL100402 supported A.J.W., and NIH P30 DK036836 supported the Joslin Diabetes Center Flow Cytometry Core. A.J.W. is an Early Career Scientist of the Howard Hughes Medical Institute. Research described here was supported in part by funding from the National Institutes of Health (NIH). Content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH or other funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 17 Z9 17 U1 6 U2 14 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 JUN 3 PY 2015 VL 10 IS 6 AR e0128094 DI 10.1371/journal.pone.0128094 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7ST UT WOS:000355700700088 PM 26039259 ER PT J AU Kim, W Conery, AL Rajamuthiah, R Fuchs, BB Ausubel, FM Mylonakis, E AF Kim, Wooseong Conery, Annie L. Rajamuthiah, Rajmohan Fuchs, Beth Burgwyn Ausubel, Frederick M. Mylonakis, Eleftherios TI Identification of an Antimicrobial Agent Effective against Methicillin-Resistant Staphylococcus aureus Persisters Using a Fluorescence-Based Screening Strategy SO PLOS ONE LA English DT Article ID NEMATODE CAENORHABDITIS-ELEGANS; PSEUDOMONAS-AERUGINOSA; CYSTIC-FIBROSIS; ANTIBACTERIAL AGENTS; ANTIBIOTICS; INFECTION; COLONIZATION; BIOFILMS; MRSA; METAANALYSIS AB Persisters are a subpopulation of normal bacterial cells that show tolerance to conventional antibiotics. Persister cells are responsible for recalcitrant chronic infections and new antibiotics effective against persisters would be a major development in the treatment of these infections. Using the reporter dye SYTOX Green that only stains cells with permeabilized membranes, we developed a fluorescence-based screening assay in a 384-well format for identifying compounds that can kill methicillin-resistant Staphylococcus aureus (MRSA) persisters. The assay proved robust and suitable for high throughput screening (Z -factor: >0.7). In screening a library of hits from a previous screen, which identified compounds that had the ability to block killing of the nematode Caenorhabditis by MRSA, we discovered that the low molecular weight compound NH125, a bacterial histidine kinase inhibitor, kills MRSA persisters by causing cell membrane permeabilization, and that 5 mu g/mL of the compound can kill all cells to the limit of detection in a 10(8) CFU/mL culture of MRSA persisters within 3h. Furthermore, NH125 disrupts 50% of established MRSA biofilms at 20 mu g/mL and completely eradicates biofilms at 160 mu g/mL. Our results suggest that the SYTOX Green screening assay is suitable for large-scale projects to identify small molecules effective against MRSA persisters and should be easily adaptable to a broad range of pathogens that form persisters. Since NH125 has strong bactericidal properties against MRSA persisters and high selectivity to bacteria, we believe NH125 is a good anti-MRSA candidate drug that should be further evaluated. C1 [Kim, Wooseong; Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Mylonakis, Eleftherios] Brown Univ, Alpert Med Sch, Rhode Isl Hosp, Div Infect Dis, Providence, RI 02912 USA. [Conery, Annie L.; Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Ausubel, Frederick M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA. RP Mylonakis, E (reprint author), Brown Univ, Alpert Med Sch, Rhode Isl Hosp, Div Infect Dis, Providence, RI 02912 USA. EM emylonakis@lifespan.org RI Kim, Wooseong/A-9256-2017 OI Kim, Wooseong/0000-0002-4597-8374 FU National Institutes of Health grant [P01 AI083214, U54 AI057159] FX This study was supported by National Institutes of Health grant P01 AI083214 to EM and FMA and grant U54 AI057159 to NERCE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 6 Z9 6 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2015 VL 10 IS 6 AR e0127640 DI 10.1371/journal.pone.0127640 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7ST UT WOS:000355700700069 PM 26039584 ER PT J AU Barhoumi, A Salvador-Culla, B Kohane, DS AF Barhoumi, Aoune Salvador-Culla, Borja Kohane, Daniel S. TI NIR-Triggered Drug Delivery by Collagen-Mediated Second Harmonic Generation SO ADVANCED HEALTHCARE MATERIALS LA English DT Article DE drug delivery; near-IR; nonlinear optics; photocleavage; second harmonic generation ID PHOTOREMOVABLE PROTECTING GROUPS; HARMONIC-GENERATION; REACTION-MECHANISMS; CROSS-LINKING; NANOPARTICLES; LIGHT; CHEMOTHERAPY; MODULATION; MICROSCOPY; CONVERSION C1 [Barhoumi, Aoune; Salvador-Culla, Borja; Kohane, Daniel S.] Harvard Univ, Sch Med, Div Crit Care Med, Dept Anesthesiol,Boston Childrens Hosp, Boston, MA 02115 USA. [Barhoumi, Aoune; Salvador-Culla, Borja; Kohane, Daniel S.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Salvador-Culla, Borja] Harvard Univ, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Kohane, DS (reprint author), Harvard Univ, Sch Med, Div Crit Care Med, Dept Anesthesiol,Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM Daniel.kohane@childrens.harvard.edu FU Sanofi [6923561] FX This work was supported by Sanofi Grant 6923561 (to R.L. and D.S.K.). NR 30 TC 7 Z9 7 U1 3 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD JUN 3 PY 2015 VL 4 IS 8 BP 1159 EP 1163 DI 10.1002/adhm.201400768 PG 5 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA CJ8JJ UT WOS:000355746000004 PM 25728310 ER PT J AU Clarke, S AF Clarke, Sarah TI BMJ CONFIDENTIAL Sarah Clarke: Determined and convivial SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Biographical-Item C1 [Clarke, Sarah] Papworth Hosp, Cambridge, England. [Clarke, Sarah] British Cardiovasc Soc, London, England. [Clarke, Sarah] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Clarke, S (reprint author), Papworth Hosp, Cambridge, England. NR 0 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 JUN 3 PY 2015 VL 350 AR h2878 DI 10.1136/bmj.h2878 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CK0TY UT WOS:000355919100003 PM 26040795 ER PT J AU Hass, J Walton, E Wright, C Beyer, A Scholz, M Turner, J Liu, JY Smolka, MN Roessner, V Sponheim, SR Gollub, RL Calhoun, VD Ehrlich, S AF Hass, Johanna Walton, Esther Wright, Carrie Beyer, Andreas Scholz, Markus Turner, Jessica Liu, Jingyu Smolka, Michael N. Roessner, Veit Sponheim, Scott R. Gollub, Randy L. Calhoun, Vince D. Ehrlich, Stefan TI Associations between DNA methylation and schizophrenia-related intermediate phenotypes - A gene set enrichment analysis SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE DNA methylarion; GSEA; Intermediate phenotype; MicroRNA targets; Schizophrenia ID ESTROGEN-RECEPTOR-ALPHA; WHITE-MATTER INTEGRITY; GENOME-WIDE ASSOCIATION; DORSOLATERAL PREFRONTAL CORTEX; MAJOR MENTAL-ILLNESS; WORKING-MEMORY; DIFFUSION TENSOR; BRAIN STRUCTURE; AUDITORY HALLUCINATIONS; PSYCHIATRIC-DISORDERS AB Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data 01 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identity markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (ERIIA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hass, Johanna; Walton, Esther; Roessner, Veit; Ehrlich, Stefan] Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Translat Dev Neurosci Sect, D-01307 Dresden, Germany. [Wright, Carrie] Univ New Mexico, Hlth Sci Ctr, Dept Neurosci, Albuquerque, NM 87131 USA. [Beyer, Andreas] Tech Univ Dresden, Ctr Biotechnol, D-01307 Dresden, Germany. [Beyer, Andreas] Univ Cologne, CECAD, D-50931 Cologne, Germany. [Scholz, Markus] Univ Leipzig, IMISE, D-04109 Leipzig, Germany. [Scholz, Markus] Univ Leipzig, LIFE Leipzig Interdisciplinary Res Cluster Genet, D-04109 Leipzig, Germany. [Wright, Carrie; Turner, Jessica; Liu, Jingyu; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Turner, Jessica] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Smolka, Michael N.] Tech Univ Dresden, Fac Med, Dept Psychiat, D-01307 Dresden, Germany. [Sponheim, Scott R.] Univ Minnesota, Dept Psychiat, Minneapolis VA Hlth Care Syst, Minneapolis, MN 55455 USA. [Gollub, Randy L.; Ehrlich, Stefan] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gollub, Randy L.; Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Liu, Jingyu; Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Ehrlich, S (reprint author), Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Translat Dev Neurosci Sect, Fetscherstr 74, D-01307 Dresden, Germany. EM transden.lab@uniklinikum-dresden.de OI Ehrlich, Stefan/0000-0003-2132-4445; Beyer, Andreas/0000-0002-3891-2123; Walton, Esther/0000-0002-0935-2200; Liu, Jingyu/0000-0002-1724-7523 FU National Institutes of Health [NIH/NCRR P41RR14075, NIBIB 2R01EB000840, COBRE 5P20RR021938/P20GM103472]; U.S. Department of Energy [DE-FG02-99ER62764]; Mind Research Network; Morphometry BIRN [1U24, RR021382A]; Function BIRN [U24RR021992-01, NIH.NCRR MO1 RR025758-01]; NARSAD Young Investigator Grant; Deutsche Forschungsgemeinschaft [EH 367/5-1] FX This work was supported by the National Institutes of Health (NIH/NCRR P41RR14075, NIBIB 2R01EB000840 and COBRE 5P20RR021938/P20GM103472), U.S. Department of Energy (DE-FG02-99ER62764), The Mind Research Network, Morphometry BIRN (1U24, RR021382A), Function BIRN (U24RR021992-01, NIH.NCRR MO1 RR025758-01), NARSAD Young Investigator Grant (SE), and the Deutsche Forschungsgemeinschaft (EH 367/5-1; Research Fellowship to SE). All funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. NR 126 TC 8 Z9 8 U1 4 U2 72 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUN 3 PY 2015 VL 59 BP 31 EP 39 DI 10.1016/j.pnpbp.2015.01.006 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CB9WP UT WOS:000349984900004 PM 25598502 ER PT J AU Gold, PW Pavlatou, MG Michelson, D Mouro, CM Kling, MA Wong, ML Licinio, J Goldstein, SA AF Gold, P. W. Pavlatou, M. G. Michelson, D. Mouro, C. M. Kling, M. A. Wong, M-L Licinio, J. Goldstein, S. A. TI Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID SYMPATHETIC-NERVOUS-SYSTEM; SEROTONIN-REUPTAKE INHIBITORS; MINERAL DENSITY; MAJOR DEPRESSION; BIOCHEMICAL MANIFESTATIONS; WOMEN; RISK; INTERLEUKIN-6; NEUROBIOLOGY; FRACTURES AB Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age. C1 [Gold, P. W.; Pavlatou, M. G.] NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. [Michelson, D.] Merck, Whitehouse Stn, NJ USA. [Mouro, C. M.; Goldstein, S. A.] Univ Michigan, Orthopaed Res Labs, Ann Arbor, MI 48109 USA. [Kling, M. A.] Philadelphia VA Med Ctr, Behav Hlth Serv, Philadelphia, PA USA. [Kling, M. A.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Wong, M-L; Licinio, J.] Australian Natl Univ, John Curtin Sch Med Res, Dept Translat Med, Canberra, ACT 2601, Australia. RP Gold, PW (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, 10 Ctr Dr,Room 2D46, Bethesda, MD 20892 USA. EM philipgold@mail.nih.gov OI Kling, Mitchel/0000-0002-2232-1409 FU Clinical Neuroendocrinology Branch, National Institute of Mental Health, NIH [AR34399]; Whittaker Foundation; National Institute of Aging, NIA [T32 AG00114]; GAANN FX We acknowledge the substantial contributions of Erica Smith and Cameron Mouro for conducting many of the MicroCT and mechanical tests. We also acknowledge Mark Stock and Rick Zanecki for their technical assistance. This work was supported by funding from the Clinical Neuroendocrinology Branch, National Institute of Mental Health, NIH AR34399, the Whittaker Foundation and a Multidisciplinary Research Training Grant in Aging from the National Institute of Aging, NIA T32 AG00114 and a GAANN Fellowship. NR 29 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUN 2 PY 2015 VL 5 AR e576 DI 10.1038/tp.2015.38 PG 6 WC Psychiatry SC Psychiatry GA DA2WQ UT WOS:000367658300003 PM 26035060 ER PT J AU Zheng, X Demirci, FY Barmada, MM Richardson, GA Lopez, OL Sweet, RA Kamboh, MI Feingold, E AF Zheng, X. Demirci, F. Y. Barmada, M. M. Richardson, G. A. Lopez, O. L. Sweet, R. A. Kamboh, M. I. Feingold, E. TI Genome-wide copy-number variation study of psychosis in Alzheimer's disease SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID LAST 2 DECADES; PROTEIN PHOSPHATASE-2A; VARIATION ASSOCIATION; IDENTIFIES VARIANTS; SIGNALING PATHWAYS; TUMOR-SUPPRESSOR; COMMON VARIANTS; BETA-CATENIN; ADULT BRAIN; ONSET AB About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is similar to 61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD - P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD - P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD - P controls (P = 0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio = 0.42; P = 7.2E - 10). We also observed suggestive associations of duplications with AD+P in the SET (P = 1.95E - 06), JAG2 (P = 5.01E - 07) and ZFPM1 (P = 2.13E - 07) genes and marginal association of a deletion in CNTLN (P = 8.87E - 04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies. C1 [Zheng, X.; Feingold, E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Zheng, X.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27514 USA. [Demirci, F. Y.; Barmada, M. M.; Kamboh, M. I.; Feingold, E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Richardson, G. A.; Sweet, R. A.; Kamboh, M. I.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Richardson, G. A.; Kamboh, M. I.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Lopez, O. L.; Sweet, R. A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Lopez, O. L.; Sweet, R. A.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 4, Pittsburgh, PA USA. RP Zheng, X (reprint author), Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27514 USA. EM xiaojinz@email.unc.edu OI Demirci, F. Yesim/0000-0001-6907-9843; Kamboh, M. Ilyas/0000-0002-3453-1438; Barmada, M Michael/0000-0002-3604-6460; Feingold, Eleanor/0000-0003-2898-6484 FU National Institute on Aging [AG030653, AG041718, AG005133, AG027224]; NIMH [T32 MH015169] FX This study was supported by the National Institute on Aging grants AG030653, AG041718 (MIK), AG005133 (OLL) and AG027224 (RAS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Department of Veterans Affairs or the United States Government. This work was conducted in partial fulfillment of requirements for the first author's doctoral degree, supported by NIMH Grant T32 MH015169 (GAR, Program Director). NR 66 TC 3 Z9 3 U1 6 U2 11 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 JUN 2 PY 2015 VL 5 AR e574 DI 10.1038/tp.2015.64 PG 9 WC Psychiatry SC Psychiatry GA DA2WQ UT WOS:000367658300001 PM 26035058 ER PT J AU Leroy, P Tham, A Wong, H Tenney, R Chen, C Stiner, R Balmes, JR Paquet, AC Arjomandi, M AF Leroy, Pascale Tham, Andrea Wong, Hofer Tenney, Rachel Chen, Chun Stiner, Rachel Balmes, John R. Paquet, Agnes C. Arjomandi, Mehrdad TI Inflammatory and Repair Pathways Induced in Human Bronchoalveolar Lavage Cells with Ozone Inhalation SO PLOS ONE LA English DT Article ID LARGE GENE LISTS; AIRWAY INFLAMMATION; EPITHELIAL INJURY; APOPTOTIC CELLS; CROSS-LINKING; IN-VITRO; LUNG; OSTEOPONTIN; EXPOSURE; MICE AB Background Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury. Methods To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o-cell line scratch assay]. Results Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an alpha 9 beta 1 integrin-dependent manner. Conclusions Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury. C1 [Leroy, Pascale; Tham, Andrea; Tenney, Rachel; Stiner, Rachel; Arjomandi, Mehrdad] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Wong, Hofer; Balmes, John R.; Arjomandi, Mehrdad] Univ Calif San Francisco, Div Occupat & Environm Med, Human Exposure Lab, San Francisco, CA 94143 USA. [Wong, Hofer; Balmes, John R.; Arjomandi, Mehrdad] Univ Calif San Francisco, Div Pulm Crit Care Allergy & Immunol & Sleep Med, San Francisco, CA 94143 USA. [Chen, Chun] Univ Calif San Francisco, Dept Med, Lung Biol Ctr, San Francisco, CA 94143 USA. [Balmes, John R.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Paquet, Agnes C.] CNRS, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France. RP Arjomandi, M (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM mehrdad.arjomandi@ucsf.edu FU National Institute of Health/NHLBI [K23 HL083099]; Stromedix, Inc.; Five Prime Therapeutics, Inc.; National Institute of Health/NCRR/OD UCSF-CTSI [KL2 RR024130, UL1 RR024131]; California Air Resources Board (CARB) [04-322]; Northern California Institute for Research and Education; University of California San Francisco Cardiovascular Research Institute Faculty Development Funds FX This work was supported by: 1) National Institute of Health/NHLBI K23 HL083099 (Arjomandi); 2) Stromedix, Inc. unrestricted research gift (Arjomandi); 3) Five Prime Therapeutics, Inc. investigator-initiated grant (Arjomandi); 4) National Institute of Health/NCRR/OD UCSF-CTSI Grant Number KL2 RR024130 and UL1 RR024131; 5) California Air Resources Board (CARB Contract # 04-322; Balmes); 6) Northern California Institute for Research and Education (Arjomandi); and 7) University of California San Francisco Cardiovascular Research Institute Faculty Development Funds (Arjomandi). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 2 Z9 2 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 JUN 2 PY 2015 VL 10 IS 6 AR e0127283 DI 10.1371/journal.pone.0127283 PG 28 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7SJ UT WOS:000355699100010 PM 26035830 ER PT J AU Myung, W Lee, GH Won, HH Fava, M Mischoulon, D Nyer, M Kim, DK Heo, JY Jeon, HJ AF Myung, Woojae Lee, Geung-Hee Won, Hong-Hee Fava, Maurizio Mischoulon, David Nyer, Maren Kim, Doh Kwan Heo, Jung-Yoon Jeon, Hong Jin TI Paraquat Prohibition and Change in the Suicide Rate and Methods in South Korea SO PLOS ONE LA English DT Article ID SRI-LANKA; MEANS RESTRICTION; ECONOMIC-CRISIS; PREVENTION; INTOXICATION; ASSOCIATION; SWITZERLAND; HOMICIDE; IMPACT; ADULTS AB The annual suicide rate in South Korea is the highest among the developed countries. Paraquat is a highly lethal herbicide, commonly used in South Korea as a means for suicide. We have studied the effect of the 2011 paraquat prohibition on the national suicide rate and method of suicide in South Korea. We obtained the monthly suicide rate from 2005 to 2013 in South Korea. In our analyses, we adjusted for the effects of celebrity suicides, and economic, meteorological, and seasonal factors on suicide rate. We employed change point analysis to determine the effect of paraquat prohibition on suicide rate over time, and the results were verified by structural change analysis, an alternative statistical method. After the paraquat prohibition period in South Korea, there was a significant reduction in the total suicide rate and suicide rate by poisoning with herbicides or fungicides in all age groups and in both genders. The estimated suicide rates during this period decreased by 10.0% and 46.1% for total suicides and suicides by poisoning of herbicides or fungicides, respectively. In addition, method substitution effect of paraquat prohibition was found in suicide by poisoning by carbon monoxide, which did not exceed the reduction in the suicide rate of poisoning with herbicides or fungicides. In South Korea, paraquat prohibition led to a lower rate of suicide by paraquat poisoning, as well as a reduction in the overall suicide rate. Paraquat prohibition should be considered as a national suicide prevention strategy in developing and developed countries alongside careful observation for method substitution effects. C1 [Myung, Woojae; Kim, Doh Kwan; Heo, Jung-Yoon; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. [Myung, Woojae; Lee, Geung-Hee] Korea Natl Open Univ, Dept Informat Stat, Seoul, South Korea. [Myung, Woojae; Won, Hong-Hee] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Samsung Biomed Res Inst, Seoul, South Korea. [Fava, Maurizio; Mischoulon, David; Nyer, Maren; Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA 02115 USA. [Jeon, Hong Jin] Samsung Adv Inst Hlth Sci & Technol, Dept Clin Res Design & Evaluat, Seoul, South Korea. [Jeon, Hong Jin] Samsung Adv Inst Hlth Sci & Technol, Dept Med Device Management & Res, Seoul, South Korea. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. EM jeonhj@skku.edu RI Kim, Doh Kwan/F-4616-2014 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0013064]; Korea Health Technology R&D Project (HJJ) through the Korea Health Industry Development Institute (KHIDI); Samsung Medical Center Clinical Research Development Program (CRDP) [SMO1131461] FX This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0013064, HJJ) and a grant of the Korea Health Technology R&D Project (HJJ) through the Korea Health Industry Development Institute (KHIDI). This study was also supported by the Samsung Medical Center Clinical Research Development Program (CRDP) Grant SMO1131461 (HJJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 2 PY 2015 VL 10 IS 6 AR e0128980 DI 10.1371/journal.pone.0128980 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7SJ UT WOS:000355699100060 PM 26035175 ER PT J AU Adegbola, AA Cox, GF Bradshaw, EM Hafler, DA Gimelbrant, A Chess, A AF Adegbola, Abidemi A. Cox, Gerald F. Bradshaw, Elizabeth M. Hafler, David A. Gimelbrant, Alexander Chess, Andrew TI Monoallelic expression of the human FOXP2 speech gene SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE random monoallelic expression; FOXP2; speech; language developmental verbal; dyspraxia ID X-CHROMOSOME INACTIVATION; PRADER-WILLI-SYNDROME; PARKINSONS-DISEASE; LANGUAGE DISORDER; ALZHEIMER-DISEASE; OLFACTORY-BULB; RETT-SYNDROME; MUTATION; LOCUS; PHENOTYPE AB The recent descriptions of widespread random monoallelic expression (RMAE) of genes distributed throughout the autosomal genome indicate that there are more genes subject to RMAE on autosomes than the number of genes on the X chromosome where X-inactivation dictates RMAE of X-linked genes. Several of the autosomal genes that undergo RMAE have independently been implicated in human Mendelian disorders. Thus, parsing the relationship between allele-specific expression of these genes and disease is of interest. Mutations in the human forkhead box P2 gene, FOXP2, cause developmental verbal dyspraxia with profound speech and language deficits. Here, we show that the human FOXP2 gene undergoes RMAE. Studying an individual with developmental verbal dyspraxia, we identify a deletion 3 Mb away from the FOXP2 gene, which impacts FOXP2 gene expression in cis. Together these data suggest the intriguing possibility that RMAE impacts the haploinsufficiency phenotypes observed for FOXP2 mutations. C1 [Adegbola, Abidemi A.; Chess, Andrew] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Adegbola, Abidemi A.] Ctr Autism, Philadelphia, PA 19131 USA. [Cox, Gerald F.] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Cox, Gerald F.] Boston Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. [Cox, Gerald F.] Genzyme, Dept Clin Dev, Cambridge, MA 02142 USA. [Bradshaw, Elizabeth M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Hafler, David A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Hafler, David A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Gimelbrant, Alexander] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Gimelbrant, Alexander] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chess, Andrew] Mt Sinai Sch Med, Friedman Brain Inst, Dept Genet & Genom Sci, Fishberg Dept Neurosci, New York, NY 10029 USA. RP Chess, A (reprint author), Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. EM andrew.chess@mssm.edu FU National Institutes of Health; Brain and Behavior Foundation Young Investigator Award; Pew Scholar award FX We thank present and past members of the A.C. laboratory for helpful discussions. This work was supported by grants from the National Institutes of Health (to A.C.), by a Brain and Behavior Foundation Young Investigator Award (to A.A.A.), and by a Pew Scholar award (to A.G.). NR 56 TC 6 Z9 6 U1 9 U2 14 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 JUN 2 PY 2015 VL 112 IS 22 BP 6848 EP 6854 DI 10.1073/pnas.1411270111 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9OO UT WOS:000355832200040 PM 25422445 ER PT J AU Tong, J Sadreyev, RI Pei, JM Kinch, LN Grishin, NV AF Tong, Jing Sadreyev, Ruslan I. Pei, Jimin Kinch, Lisa N. Grishin, Nick V. TI Using homology relations within a database markedly boosts protein sequence similarity search SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE homology detection; remote sequence; similarity search; homology network; protein modeling; similarity score ID DISTANTLY RELATED PROTEINS; HIDDEN MARKOV-MODELS; STATISTICAL SIGNIFICANCE; PSI-BLAST; GENERATION; CASP10; INFORMATION; PREDICTIONS; ALIGNMENTS; PROFILES AB Inference of homology from protein sequences provides an essential tool for analyzing protein structure, function, and evolution. Current sequence-based homology search methods are still unable to detect many similarities evident from protein spatial structures. In computer science a search engine can be improved by considering networks of known relationships within the search database. Here, we apply this idea to protein-sequence-based homology search and show that it dramatically enhances the search accuracy. Our new method, COMPADRE (COmparison of Multiple Protein sequence Alignments using Database RElationships) assesses the relationship between the query sequence and a hit in the database by considering the similarity between the query and hit's known homologs. This approach increases detection quality, boosting the precision rate from 18% to 83% at half-coverage of all database homologs. The increased precision rate allows detection of a large fraction of protein structural relationships, thus providing structure and function predictions for previously uncharacterized proteins. Our results suggest that this general approach is applicable to a wide variety of methods for detection of biological similarities. The web server is available at prodata.swmed.edu/compadre. C1 [Tong, Jing; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Dept Mol Biophys, Dallas, TX 75390 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Pei, Jimin; Kinch, Lisa N.; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. RP Grishin, NV (reprint author), Univ Texas SW Med Ctr Dallas, Dept Mol Biophys, Dallas, TX 75390 USA. EM grishin@chop.swmed.edu FU National Institutes of Health [GM094575]; Welch Foundation [I-1505] FX The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing grid resources that have contributed to the research results reported within this paper. This work was supported in part by the National Institutes of Health (GM094575 to N.V.G.) and the Welch Foundation (I-1505 to N.V.G.). NR 32 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 JUN 2 PY 2015 VL 112 IS 22 BP 7003 EP 7008 DI 10.1073/pnas.1424324112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9OO UT WOS:000355832200066 PM 26038555 ER PT J AU Sawyer, EK Liao, CC Qi, HX Balaram, P Matrov, D Kaas, JH AF Sawyer, Eva Kille Liao, Chia-Chi Qi, Hui-Xin Balaram, Pooja Matrov, Denis Kaas, Jon H. TI Subcortical barrelette-like and barreloid-like structures in the prosimian galago (Otolemur garnetti) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vibrissa; barrel cortex; trigeminal; somatosensory maps; primate ID SPINAL TRIGEMINAL NUCLEUS; SOMATOSENSORY THALAMUS; BRAIN-STEM; FUNCTIONAL-ORGANIZATION; MYSTACIAL VIBRISSAE; CORTICAL BARRELS; AFFERENT INPUTS; CEREBRAL-CORTEX; MOUSE; RAT AB Galagos are prosimian primates that resemble ancestral primates more than most other extant primates. As in many other mammals, the facial vibrissae of galagos are distributed across the upper and lower jaws and above the eye. In rats and mice, the mystacial macrovibrissae are represented throughout the ascending trigeminal pathways as arrays of cytoarchitecturally distinct modules, with each module having a nearly one-to-one relationship with a specific facial whisker. The macrovibrissal representations are termed barrelettes in the trigeminal somatosensory brainstem, barreloids in the ventroposterior medial subnucleus of the thalamus, and barrels in primary somatosensory cortex. Despite the presence of facial whiskers in all nonhuman primates, barrel-like structures have not been reported in primates. By staining for cytochrome oxidase, Nissl, and vesicular glutamate transporter proteins, we show a distinct array of barrelette-like and barreloid-like modules in the principal sensory nucleus, the spinal trigeminal nucleus, and the ventroposterior medial subnucleus of the galago, Otolemur garnetti. Labeled terminals of primary sensory neurons in the brainstem and cell bodies of thalamocortically projecting neurons demonstrate that barrelette-like and barreloid-like modules are located in areas of these somatosensory nuclei that are topographically consistent with their role in facial touch. Serendipitously, the plane of section that best displays the barreloid-like modules reveals a remarkably distinct homunculus-like patterning which, we believe, is one of the clearest somatotopic maps of an entire body surface yet found. C1 [Sawyer, Eva Kille] Vanderbilt Univ, Neurosci Grad Program, Nashville, TN 37240 USA. [Liao, Chia-Chi; Qi, Hui-Xin; Kaas, Jon H.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Balaram, Pooja] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Balaram, Pooja] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Matrov, Denis] Natl Inst Physiol Sci, Dept Dev Physiol, Aichi 4448585, Japan. [Matrov, Denis] Univ Tartu, Dept Psychol, EE-50411 Tartu, Estonia. RP Kaas, JH (reprint author), Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. EM jon.h.kaas@vanderbilt.edu FU NIH [NS016446, NS084706] FX We thank Laura Trice for help with histological procedures and Mary Feurtado, Daniel Miller, Jamie Reed, Emily Rockoff, and Iwona Stepniewaska for surgical assistance. This work was funded by NIH Grants NS016446 (to J.H.K.) and NS084706-02 (to E.K.S.). NR 49 TC 1 Z9 1 U1 0 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 JUN 2 PY 2015 VL 112 IS 22 BP 7079 EP 7084 DI 10.1073/pnas.1506646112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9OO UT WOS:000355832200079 PM 26038561 ER PT J AU Franzosa, EA Huang, K Meadow, JF Gevers, D Lemon, KP Bohannan, BJM Huttenhower, C AF Franzosa, Eric A. Huang, Katherine Meadow, James F. Gevers, Dirk Lemon, Katherine P. Bohannan, Brendan J. M. Huttenhower, Curtis TI Identifying personal microbiomes using metagenomic codes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE forensic genetics; microbial ecology; metagenomics; human microbiome; strain variation ID HUMAN GUT MICROBIOME; GENOMIC RESEARCH; SKIN MICROBIOME; ENTEROTYPES; DIVERSITY; ECOLOGY; SCIENCE; DISEASE; PRIVACY; AGE AB Community composition within the human microbiome varies across individuals, but it remains unknown if this variation is sufficient to uniquely identify individuals within large populations or stable enough to identify them over time. We investigated this by developing a hitting set-based coding algorithm and applying it to the Human Microbiome Project population. Our approach defined body site-specific metagenomic codes: sets of microbial taxa or genes prioritized to uniquely and stably identify individuals. Codes capturing strain variation in clade-specific marker genes were able to distinguish among 100s of individuals at an initial sampling time point. In comparisons with follow-up samples collected 30-300 d later, similar to 30% of individuals could still be uniquely pinpointed using metagenomic codes from a typical body site; coincidental (false positive) matches were rare. Codes based on the gut microbiome were exceptionally stable and pinpointed >80% of individuals. The failure of a code to match its owner at a later time point was largely explained by the loss of specific microbial strains (at current limits of detection) and was only weakly associated with the length of the sampling interval. In addition to highlighting patterns of temporal variation in the ecology of the human microbiome, this work demonstrates the feasibility of microbiome-based identifiability-a result with important ethical implications for microbiome study design. The datasets and code used in this work are available for download from huttenhower.sph.harvard.edu/idability. C1 [Franzosa, Eric A.; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Franzosa, Eric A.; Huang, Katherine; Gevers, Dirk; Huttenhower, Curtis] Broad Inst, Genome Sequencing & Anal Program, Microbial Syst & Communities, Cambridge, MA 02142 USA. [Meadow, James F.; Bohannan, Brendan J. M.] Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA. [Lemon, Katherine P.] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. [Lemon, Katherine P.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Huttenhower, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM chuttenh@hsph.harvard.edu FU National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200900018C]; NIH National Human Genome Research Institute (NHGRI) Grant [U54HG004969]; NIH National Institute of General Medical Sciences Grant [P50GM098911]; NIH NIAID Grant [R01 AI101018]; Danone Research Grant [PLF-5972-GD]; NIH NHGRI Grant [R01HG005969]; Army Research Office Grant [W911NF-11-1-0473]; National Science Foundation Faculty Early Career Development Grant [DBI-1053486] FX We thank N. Segata for assistance profiling MetaPhlAn marker genes, L. J. McIver and A. Shafquat for reviewing online materials, and T. L. Tickle, R. D. Franzosa, and the three anonymous reviewers for helpful comments. This work was funded in part by National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) Contract HHSN272200900018C (to D.G.), NIH National Human Genome Research Institute (NHGRI) Grant U54HG004969 (to the Broad Institute and D.G.), NIH National Institute of General Medical Sciences Grant P50GM098911 (to B.J.M.B.), NIH NIAID Grant R01 AI101018 (to K.P.L.), Danone Research Grant PLF-5972-GD (to Wendy Garrett and C.H.), NIH NHGRI Grant R01HG005969 (to C.H.), Army Research Office Grant W911NF-11-1-0473 (to C.H.), and National Science Foundation Faculty Early Career Development Grant DBI-1053486 (to C.H.). NR 35 TC 51 Z9 54 U1 11 U2 56 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 JUN 2 PY 2015 VL 112 IS 22 BP E2930 EP E2938 DI 10.1073/pnas.1423854112 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9OO UT WOS:000355832200014 PM 25964341 ER PT J AU Romeo, GR Abrahamson, MJ AF Romeo, Giulio R. Abrahamson, Martin J. TI The 2015 Standards for Diabetes Care: Maintaining a Patient-Centered Approach SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID RISK C1 Joslin Diabet Ctr, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Abrahamson, MJ (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM martin.abrahamson@joslin.harvard.edu NR 10 TC 4 Z9 4 U1 0 U2 3 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 JUN 2 PY 2015 VL 162 IS 11 BP 785 EP 786 DI 10.7326/M15-0385 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CJ5ZH UT WOS:000355572300006 PM 25798733 ER PT J AU Huybrechts, KF Bateman, BT Palmsten, K Desai, RJ Patorno, E Gopalakrishnan, C Levin, R Mogun, H Hernandez-Diaz, S AF Huybrechts, Krista F. Bateman, Brian T. Palmsten, Kristin Desai, Rishi J. Patorno, Elisabetta Gopalakrishnan, Chandrasekar Levin, Raisa Mogun, Helen Hernandez-Diaz, Sonia TI Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SEROTONIN-REUPTAKE INHIBITORS; HUMAN UMBILICAL ARTERIES; NITRIC-OXIDE; MATERNAL USE; OUTCOMES; ADJUSTMENT; PGF2-ALPHA; DELIVERY; INFANT; SCORES AB IMPORTANCE The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006. OBJECTIVE To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy. DESIGN AND SETTING Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010. PARTICIPANTS A total of 3 789 330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use. MAIN OUTCOMES AND MEASURES Recorded diagnosis of PPHN during the first 30 days after delivery. RESULTS A total of 128 950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102 179 (2.7%) used an SSRI and 26 771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10 000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10 000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10 000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74). CONCLUSIONS AND RELEVANCE Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies. C1 [Huybrechts, Krista F.; Bateman, Brian T.; Desai, Rishi J.; Patorno, Elisabetta; Gopalakrishnan, Chandrasekar; Levin, Raisa; Mogun, Helen] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Huybrechts, Krista F.; Bateman, Brian T.; Patorno, Elisabetta] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Bateman, Brian T.; Palmsten, Kristin] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02114 USA. [Hernandez-Diaz, Sonia] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Huybrechts, KF (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. EM khuybrechts@partners.org FU Agency for Healthcare Research and Quality [R01 HS018533]; National Institute of Mental Health [K01MH099141]; National Institute of Child Health and Human Development [K08HD075831]; Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development [T32HD060454] FX This study was supported by grant R01 HS018533 from the Agency for Healthcare Research and Quality. Dr Huybrechts was supported by career development grant K01MH099141 from the National Institute of Mental Health. Dr Bateman was supported by career development grant K08HD075831 from the National Institute of Child Health and Human Development. Dr Palmsten was supported by training grant T32HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development. NR 39 TC 31 Z9 33 U1 1 U2 5 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 JUN 2 PY 2015 VL 313 IS 21 BP 2142 EP 2151 DI 10.1001/jama.2015.5605 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CJ4CC UT WOS:000355430900014 PM 26034955 ER PT J AU Simon, NM AF Simon, Naomi M. TI Increasing Support for the Treatment of Complicated Grief in Adults of All Ages SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIAL; DISORDER AB IMPORTANCE Complicated grief (CG) is a debilitating condition, most prevalent in elderly persons. However, to our knowledge, no full-scale randomized clinical trial has studied CG in this population. OBJECTIVE To determine whether complicated grief treatment (CGT) produces greater improvement in CG and depressive symptoms than grief-focused interpersonal psychotherapy (IPT). DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial enrolling 151 individuals 50 years or older (mean [SD] age, 66.1 [8.9] years) scoring at least 30 on the Inventory of Complicated Grief (ICG). Participants were recruited from the New York metropolitan area from August 20, 2008, through January 7, 2013, and randomized to receive CGT or IPT. The main outcome was assessed at 20 weeks after baseline, with interim measures collected at 8, 12, and 16 weeks after baseline. INTERVENTIONS Sixteen sessions of CGT (n = 74) or IPT (n = 77) delivered approximately weekly. MAIN OUTCOMES AND MEASURES Rate of treatment response, defined as a rating from an independent evaluator of much or very much improved on the Improvement subscale of the Clinical Global Impression Scale. RESULTS Both treatments produced improvement in CG symptoms. Response rate for CGT (52 individuals [70.5%]) was more than twice that for IPT (24 [32.0%]) (relative risk, 2.20 [95% CI, 1.51-3.22]; P <.001), with the number needed to treat at 2.56. Secondary analyses of CG severity and CG symptom and impairment questionnaire measures confirmed that CGT conferred a significantly greater change in illness severity (22 individuals [35.2%] in the CGT group vs 41 [64.1%] in the IPT group were still at least moderately ill [P =.001]), rate of CG symptom reduction (1.05 ICG points per week for CGT vs 0.75 points per week for IPT [t(633) = 3.85; P <.001]), and the rate of improvement in CG impairment (0.63 work and Social Adjustment Scale points per week with CGT and 0.39 points per week with IPT [t(503) = 2.87; P =.004]). Results were not moderated by participant age. CONCLUSIONS AND RELEVANCE Complicated grief treatment produced clinically and statistically significantly greater response rates for CG symptoms than a proven efficacious treatment for depression (IPT). Results strongly support the need for physicians and other health care providers to distinguish CG from depression. Given the growing elderly population, the high prevalence of bereavement in aging individuals, and the marked physical and psychological impact of CG, clinicians need to know how to treat CG in older adults. C1 [Simon, Naomi M.] Massachusetts Gen Hosp, Complicated Grief Program, Boston, MA 02114 USA. [Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, One Bowdoin Sq,Sixth Floor, Boston, MA 02114 USA. EM nsimon@partners.org FU American Foundation for Suicide Prevention; Department of Defense; Highland Street Foundation; National Institutes of Health FX The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Simon reported having received research grants from the American Foundation for Suicide Prevention, Department of Defense, Highland Street Foundation, and National Institutes of Health; having served in a speaking, education, or consulting role for Massachusetts General Hospital Psychiatry Academy and Pfizer Pharmacuticals; and her spouse having equity in Dandreon, G Zero, and Gatekeeper. NR 10 TC 1 Z9 1 U1 1 U2 12 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 JUN 2 PY 2015 VL 313 IS 21 BP 2172 EP 2173 DI 10.1001/jama.2015.105 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CJ4CC UT WOS:000355430900017 PM 26034957 ER PT J AU Schwartz, GG Abt, M Bao, W DeMicco, D Kallend, D Miller, M Mundl, H Olsson, AG AF Schwartz, Gregory G. Abt, Markus Bao, Weihang DeMicco, David Kallend, David Miller, Michael Mundl, Hardi Olsson, Anders G. TI Fasting Triglycerides Predict Recurrent Ischemic Events in Patients With Acute Coronary Syndrome Treated With Statins SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE lipids; myocardial infarction; unstable angina ID DENSITY-LIPOPROTEIN-CHOLESTEROL; ACUTE MYOCARDIAL-INFARCTION; OF-FUNCTION MUTATIONS; HEART-DISEASE; NONFASTING TRIGLYCERIDES; CARDIOVASCULAR EVENTS; VASCULAR-DISEASE; RISK-FACTOR; TRIAL; WOMEN AB BACKGROUND Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dalOUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p < 0.001). The hazard ratio in the highest/lowest quintile (> 175/<= 80 mg/dl) was 1.50 (95% confidence interval: 1.05 to 2.15). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p = 0.03), with a hazard ratio of 1.51 (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/<= 135 mg/dl). The relationship of triglycerides to risk was independent of lowdensity lipoprotein cholesterol in both studies. CONCLUSIONS Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (C) 2015 by the American College of Cardiology Foundation. C1 [Schwartz, Gregory G.] Denver VA Med Ctr, Cardiol Sect, Denver, CO 80220 USA. [Schwartz, Gregory G.] Univ Colorado, Sch Med, Denver, CO 80202 USA. [Abt, Markus; Kallend, David; Mundl, Hardi] F Hoffmann La Roche, Pharma Dev, Basel, Switzerland. [Bao, Weihang; DeMicco, David] Pfizer Inc, New York, NY USA. [Miller, Michael] Univ Maryland, Sch Med, Div Cardiovasc Med, Baltimore, MD 21201 USA. [Olsson, Anders G.] Stockholm Heart Ctr, Stockholm, Sweden. [Olsson, Anders G.] Linkoping Univ, Linkoping, Sweden. RP Schwartz, GG (reprint author), Denver VA Med Ctr, Cardiol Sect 111B, 1055 Clermont St, Denver, CO 80220 USA. EM Gregory.Schwartz@va.gov RI 刘, 李陆/H-8469-2015 FU F. Hoffmann-La Roche Ltd.; Pfizer; Anthera; Resverlogix; Roche; Sanofi; Amgen; AstraZeneca; Karobio; Merck FX The dal-OUTCOMES trial was funded by F. Hoffmann-La Roche Ltd. The MIRACL trial was funded by Pfizer. Dr. Schwartz, through his institution, has received research grants from Anthera, Pfizer, Resverlogix, Roche, and Sanofi. Dr. Abt is an employee of F. Hoffmann-La Roche, Ltd. Drs. Bao and DeMicco are employees of Pfizer. Drs. Kallend and Mundl were employees of F. Hoffmann-La Roche at the time the dal-OUTCOMES study was performed and data collected. Dr. Miller has served as a consultant for Amarin, AstraZeneca, Pronova, and Zydus. Dr. Olsson has received research grants from Amgen, AstraZeneca, Karobio, Merck, Pfizer, Roche, and Sanofi; and has received consultation fees from AstraZeneca, Karobio, Merck, Pfizer, and Roche. Dr. Kallend is currently affiliated with The Medicines Company, Zurich, Switzerland. Dr. Mundl is currently affiliated with Bayer Pharmaceuticals, Berlin, Germany. NR 30 TC 38 Z9 38 U1 0 U2 9 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 JUN 2 PY 2015 VL 65 IS 21 BP 2267 EP 2275 DI 10.1016/j.jacc.2015.03.544 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CJ0VH UT WOS:000355196300001 PM 26022813 ER PT J AU Groarke, JD Nohria, A AF Groarke, John D. Nohria, Anju TI Anthracycline Cardiotoxicity A New Paradigm for an Old Classic SO CIRCULATION LA English DT Editorial Material DE Editorials; anthracyclines; cardiotoxicity ID CHILDHOOD-CANCER SURVIVORS; INDUCED CARDIOMYOPATHY; PRACTICE GUIDELINES; AMERICAN-SOCIETY; HEART-FAILURE; CHEMOTHERAPY; DYSFUNCTION; THERAPY; ECHOCARDIOGRAPHY; ASSOCIATION C1 [Groarke, John D.; Nohria, Anju] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Groarke, John D.; Nohria, Anju] Dana Farber Canc Inst, Cardiooncol Program, Boston, MA 02115 USA. [Groarke, John D.; Nohria, Anju] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Nohria, A (reprint author), Brigham & Womens Hosp, Cardiooncol Program, 75 Francis St, Boston, MA USA. EM anohria@partners.org NR 20 TC 7 Z9 7 U1 1 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 JUN 2 PY 2015 VL 131 IS 22 BP 1946 EP 1949 DI 10.1161/CIRCULATIONAHA.115.016704 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ8PW UT WOS:000379474600007 PM 25948539 ER PT J AU Menda, SA Lowry, EA Porco, TC Stamper, RL Rubin, MR Han, Y AF Menda, Shivali A. Lowry, Eugene A. Porco, Travis C. Stamper, Robert L. Rubin, Michel R. Han, Ying TI Ex-PRESS outcomes using mitomycin-C, Ologen alone, Ologen with 5-fluorouracil SO INTERNATIONAL OPHTHALMOLOGY LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; COLLAGEN MATRIX IMPLANTS; TRABECULECTOMY; GLAUCOMA; PHACOTRABECULECTOMY AB To compare the complication rate and effectiveness of mitomycin C (MMC), Ologen alone, and Ologen with 5-fluorouracil (5-FU) as adjunctives with Ex-PRESS mini shunt for medically uncontrolled glaucoma. Retrospective comparative study of 59 Ex-PRESS mini shunt trabeculectomy operations coupled with Ologen implantation alone, transient MMC application or Ologen implantation with 5-FU as adjunctive treatment. Eight eyes (7 patients) received Ologen alone, 37 eyes (34 patients) received MMC, and 14 eyes (14 patients) received Ologen with 5-FU as adjunctive therapy. Baseline characteristics, adjunctive used during operation, along with outcomes including intraocular pressure (IOP), number of anti-hypertensive drops, visual acuity, and complications were documented and compared. The primary outcome was IOP at 12 months. Variables were compared with r x c Fisher tests. The Ologen only group had a significantly higher IOP at 12 months (20.5 +/- A 10.23 mmHg) compared with Ologen combined with 5-FU (12.2 +/- A 1.47 mmHg) or MMC (13.8 +/- A 4.37 mmHg) (p = 0.015, linear mixed model). The Ologen only cohort also had a higher re-operation rate (p = 0.01, Fisher's Exact Test) and higher rate of bleb leak (p = 0.02, Fisher's Exact Test). Visual acuity was similar among all three groups. 5-FU with Ologen is as effective as MMC in maintaining IOP following Ex-PRESS shunt surgery at 1 year. However, Ologen alone may not be as effective as the other two adjunctive agents. C1 [Menda, Shivali A.; Lowry, Eugene A.; Porco, Travis C.; Stamper, Robert L.; Rubin, Michel R.; Han, Ying] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Porco, Travis C.] Univ Calif San Francisco, Francis I Proctor Fdn, San Francisco, CA 94143 USA. [Porco, Travis C.] UCSF, Div Prevent Med & Publ Hlth, Dept Epidemiol & Biostat, San Francisco, CA USA. [Han, Ying] San Francisco Vet Adm Med Ctr, Dept Ophthalmol, San Francisco, CA USA. RP Lowry, EA (reprint author), Univ Calif San Francisco, Dept Ophthalmol, 10 Koret Way, San Francisco, CA 94143 USA. EM gene.lowry@ucsf.edu NR 17 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-5701 EI 1573-2630 J9 INT OPHTHALMOL JI Int. Ophthalmol. PD JUN PY 2015 VL 35 IS 3 BP 357 EP 363 DI 10.1007/s10792-014-9955-3 PG 7 WC Ophthalmology SC Ophthalmology GA CH2AZ UT WOS:000353827300008 PM 24920197 ER PT J AU Betz, ME Arias, SA Miller, M Barber, C Espinola, JA Sullivan, AF Manton, AP Miller, I Camargo, CA Boudreaux, ED AF Betz, Marian E. Arias, Sarah A. Miller, Matthew Barber, Catherine Espinola, Janice A. Sullivan, Ashley F. Manton, Anne P. Miller, Ivan Camargo, Carlos A., Jr. Boudreaux, Edwin D. TI Change in Emergency Department Providers' Beliefs and Practices After Use of New Protocols for Suicidal Patients SO PSYCHIATRIC SERVICES LA English DT Article ID SELF-HARM; MEANS RESTRICTION; MENTAL-HEALTH; FOLLOW-UP; PREVENTION; RISK; ATTITUDES; VISITS; CARE; OPPORTUNITY AB Objective: The study examined changes in self-reported attitudes and practices related to suicide risk assessment among providers at emergency departments (EDs) during a three-phase quasi-experimental trial involving implementation of ED protocols for suicidal patients. Methods: A total of 1,289 of 1,828 (71% response rate) eligible providers at eight EDs completed a voluntary, anonymous survey at baseline, after introduction of universal suicide screening, and after introduction of suicide prevention resources (nurses) and a secondary risk assessment tool (physicians). Results: Among participants, the median age was 40 years old, 64% were female, and there were no demographic differences across study phases; 68% were nurses, and 32% were attending physicians. Between phase 1 and phase 3, increasing proportions of nurses reported screening for suicide (36% and 95%, respectively, p<. 001) and increasing proportions of physicians reported further assessment of suicide risk (63% and 80%, respectively, p<. 01). Although increasing proportions of providers said universal screening would result in more psychiatric consultations, decreasing proportions said it would slow down clinical care. Increasing proportions of nurses reported often or almost always asking suicidal patients about firearm access (18% 269%, depending on the case), although these numbers remained low relative to ideal practice. Between 35% and 87% of physicians asked about firearms, depending on the case, and these percentages did not change significantly over the study phases. Conclusions: These findings support the feasibility of implementing universal screening for suicide in EDs, assuming adequate resources, but providers should be educated to ask suicidal patients about firearm access. C1 [Betz, Marian E.] Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO USA. [Arias, Sarah A.; Miller, Ivan] Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Arias, Sarah A.; Miller, Ivan] Brown Univ, Sch Med, Providence, RI 02912 USA. [Miller, Matthew; Barber, Catherine] Harvard Univ, Sch Publ Hlth, Harvard Injury Control Res Ctr, Boston, MA 02115 USA. [Espinola, Janice A.; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Espinola, Janice A.; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Manton, Anne P.] Cape Cod Hosp, Ctr Behav Hlth, Hyannis, MA USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. RP Betz, ME (reprint author), Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO USA. EM marian.betz@ucdenver.edu OI Boudreaux, Edwin/0000-0002-3223-6371; Arias, Sarah/0000-0003-1832-8824 FU National Institute of Mental Health (NIMH) [U01MH088278]; American Foundation for Suicide Prevention FX This project was supported by award U01MH088278 from the National Institute of Mental Health (NIMH) and by a Young Investigator Award from the American Foundation for Suicide Prevention. The authors acknowledge the time and effort of the site coinvestigators, research coordinators and research assistants at the eight participating sites. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or the National Institutes of Health. NR 37 TC 10 Z9 10 U1 1 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUN PY 2015 VL 66 IS 6 BP 625 EP 631 DI 10.1176/appi.ps.201400244 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DE5RL UT WOS:000370689100013 PM 25726978 ER PT J AU Abramson, JS AF Abramson, Jeremy S. TI Transformative Clinical Trials in Non-Hodgkin and Hodgkin Lymphomas SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Hematologic-Oncology CY SEP 17-20, 2014 CL Houston, TX DE Diffuse Large B-cell Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; Novel Agents; Peripheral T-cell Lymphoma ID B-CELL LYMPHOMA; SINGLE-AGENT LENALIDOMIDE; PHASE-II GAUGUIN; BRENTUXIMAB VEDOTIN; OPEN-LABEL; FOLLICULAR LYMPHOMA; OBINUTUZUMAB GA101; 1ST-LINE TREATMENT; INDOLENT LYMPHOMA; FRONTLINE THERAPY AB Dramatic progress in the understanding of underlying disease biology and the development of novel therapeutics has yielded a revolution that is poised to transform the face of lymphoma treatment across a broad spectrum of histologies. Ongoing randomized clinical trials are poised to unseat long-entrenched standards of care in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and Hodgkin lymphoma. Emerging treatment approaches are reviewed, including optimization of existing chemoimmunotherapy platforms, development of chemotherapy-sparing immunotherapy for follicular lymphoma, biologically targeted therapy for subsets of diffuse large B-cell lymphoma, and incorporation of novel agents into the treatment of mantle cell lymphoma and peripheral T-cell lymphoma. Novel therapies in early stage trials with future promise of redefining standards of care are also reviewed for non-Hodgkin and Hodgkin lymphomas, including small molecule pathway inhibitors and advances in immunotherapy. (C) 2015 Elsevier Inc. All rights reserved. C1 [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA 02114 USA. [Abramson, Jeremy S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Abramson, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Yawkey 9A,55 Fruit St, Boston, MA 02114 USA. EM jabramson@mgh.harvard.edu FU Millennium; Infinity; Gilead; Pharmacyclics FX Consulting fees from Millennium, Infinity, Gilead, Pharmacyclics. NR 60 TC 0 Z9 0 U1 1 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 EI 2152-2669 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD JUN PY 2015 VL 15 SU 1 BP S141 EP S146 DI 10.1016/j.clml.2015.02.006 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA DE5MY UT WOS:000370676300025 PM 26297267 ER PT J AU Brown, JJR Byrd, JC O'Brien, S Barrientos, JC Kay, NE Reddy, NM Coutre, S Tam, CS Mulligan, S Jaeger, U Devereux, S Barr, PM Furman, R Kipps, T Cymbalista, F Fardis, M McGreivy, J Clow, F James, DF Hilmen, P AF Brown, J. Jennifer R. Byrd, John C. O'Brien, Susan Barrientos, Jacqueline C. Kay, Neil E. Reddy, Nishitha M. Coutre, Steven Tam, Constantine S. Mulligan, Stephen Jaeger, Ulrich Devereux, Stephen Barr, Paul M. Furman, Richard Kipps, Thomas Cymbalista, Florence Fardis, Maria McGreivy, Jesse Clow, Fong James, Danelle F. Hilmen, Peter TI Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATE (TM) (PCYC-1112) Trial SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Meeting Abstract C1 [Brown, J. Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Byrd, John C.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [O'Brien, Susan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Barrientos, Jacqueline C.] North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA. [Kay, Neil E.] Mayo Clin, Rochester, MN USA. [Reddy, Nishitha M.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Coutre, Steven] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Tam, Constantine S.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Tam, Constantine S.] St Vincents Hosp, Melbourne, Vic, Australia. [Mulligan, Stephen] Royal N Shore Hosp, Sydney, NSW, Australia. [Jaeger, Ulrich] Med Univ Vienna, Vienna, Austria. [Devereux, Stephen] Kings Coll Hosp London, NHS Fdn Trust, London, England. [Barr, Paul M.] Univ Rochester, Ctr Canc, Rochester, NY USA. [Furman, Richard] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. [Kipps, Thomas] Moores UCSD Canc Ctr, San Diego, CA USA. [Cymbalista, Florence] Hop Avicenne, Paris, France. [Fardis, Maria; McGreivy, Jesse; Clow, Fong; James, Danelle F.] Pharmacyclics Inc, Sunnyvale, CA USA. [Hilmen, Peter] Leeds Teaching Hosp, St James Inst Oncol, Leeds, W Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 EI 2152-2669 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD JUN PY 2015 VL 15 SU 1 MA 304 BP S204 EP S204 PG 1 WC Oncology; Hematology SC Oncology; Hematology GA DE5MY UT WOS:000370676300088 ER PT J AU DeAngelo, DJ Sekeres, MA Ottmann, OG Sanz, MA Naoe, T Taube, T Belsack, V Ge, MM Dohner, H AF DeAngelo, Daniel J. Sekeres, Mikkael A. Ottmann, Oliver G. Sanz, Miguel A. Naoe, Tomoki Taube, Tillmann Belsack, Valerie Ge, Miaomiao Doehner, Hartmut TI Phase III randomized trial of volasertib combined with low-dose cytarabine (LDAC) versus placebo plus LDAC in patients aged >= 65 years with previously untreated, acute myeloid leukemia (AML) ineligible for intensive remission induction therapy SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Meeting Abstract C1 [DeAngelo, Daniel J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sekeres, Mikkael A.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Ottmann, Oliver G.] Goethe Univ Frankfurt, D-60054 Frankfurt, Germany. [Sanz, Miguel A.] Univ Hosp La Fe, Valencia, Spain. [Naoe, Tomoki] Natl Hosp Org, Nagoya Med Ctr, Nagoya, Aichi, Japan. [Taube, Tillmann] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. [Belsack, Valerie] SCS Boehringer Ingelheim Comm V, Brussels, Belgium. [Ge, Miaomiao] Boehringer Ingelheim Corp, Ridgefield, CT USA. [Doehner, Hartmut] Univ Hosp Ulm, Ulm, Germany. NR 0 TC 0 Z9 0 U1 2 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 EI 2152-2669 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD JUN PY 2015 VL 15 SU 1 MA 229 BP S194 EP S194 PG 1 WC Oncology; Hematology SC Oncology; Hematology GA DE5MY UT WOS:000370676300072 ER PT J AU Boyd, JE Juanamarga, J Hashemi, P AF Boyd, Jennifer E. Juanamarga, Josephine Hashemi, Parisa TI Stigma of Taking Psychiatric Medications Among Psychiatric Outpatient Veterans SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article DE social stigma; stigmatization; psychotropic drugs; outpatients; veterans ID ILLNESS ISMI SCALE; MENTAL-ILLNESS; INTERNALIZED STIGMA; MILITARY; DEPRESSION; PEOPLE AB Objective: Service members and veterans underutilize mental health services due to stigma. The study investigated stigma of taking psychiatric medications, and its relationship to internalized stigma of mental illness, gender, age, service era, duration of taking medications, and their perceived helpfulness. Method: Of the 200 veterans completing an anonymous questionnaire in an outpatient mental health waiting room, data are presented on the 159 who reported taking psychiatric medications. Results: Medication stigma was related to internalized stigma and was common: over one half reported feeling uncomfortable disclosing or feeling judged, and about one fifth reported feeling embarrassed. Medication stigma was not related to gender, duration, or helpfulness. Younger age was associated with feeling judged, and more recent service era was associated with shame. Conclusions and Implications for Practice: Medication stigma among veterans is common and warrants further study. Discomfort disclosing and feeling judged might be particularly worthy targets of discussion in shared decisions about medication. C1 [Boyd, Jennifer E.; Juanamarga, Josephine; Hashemi, Parisa] San Francisco VA Med Ctr, Mental Hlth Serv, 4150 Clement St 116A, San Francisco, CA 94121 USA. [Boyd, Jennifer E.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Boyd, JE (reprint author), San Francisco VA Med Ctr, Mental Hlth Serv, 4150 Clement St 116A, San Francisco, CA 94121 USA. EM jennifer.boyd@va.gov NR 12 TC 1 Z9 1 U1 2 U2 6 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X EI 1559-3126 J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD JUN PY 2015 VL 38 IS 2 SI SI BP 132 EP 134 DI 10.1037/prj0000122 PG 3 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA DE1NE UT WOS:000370392900006 PM 25821981 ER PT J AU Harris, JI Farchmin, L Stull, L Boyd, J Schumacher, M Drapalski, AL AF Harris, J. Irene Farchmin, Leah Stull, Laura Boyd, Jennifer Schumacher, Marianne Drapalski, Amy L. TI Prediction of Changes in Self-Stigma Among Veterans Participating in Partial Psychiatric Hospitalization: The Role of Disability Status and Military Cohort SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article DE internalized stigma; research; Veterans; partial hospitalization; serious mental illness ID RANDOMIZED CONTROLLED-TRIAL; MENTAL-HEALTH PROBLEMS; INTERNALIZED STIGMA; REDUCE STIGMA; ILLNESS; SCHIZOPHRENIA; PEOPLE; RECOVERY; CONSEQUENCES; ASSOCIATIONS AB Objective: Interventions addressing internalized stigma are a new area of research, and it is important to identify the types of clientele who derive benefit from existing interventions. Method: Information was provided by 235 veterans attending a partial psychiatric hospitalization program, regarding their levels of internalized stigma on admission and discharge from a 3-week program that included interventions targeting internalized stigma. Results: Upon discharge, veterans receiving disability benefits demonstrated less reduction in internalized stigma than those not receiving disability benefits. Time of service moderated the relationship between disability status and change in internalized stigma, such that veterans serving in the more recent Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) cohort who received disability benefits had a more difficult time resolving internalized stigma. Further analyses suggested that OEF/OIF/OND cohort veterans receiving disability benefits have more difficulty developing effective stigma resistance, and more difficulty resolving stigma-related alienation, than other veterans. Conclusions and Implications for Practice: Based on this research, particular attention should be devoted to internalized stigma among OEF/OIF/OND veterans. C1 [Harris, J. Irene; Farchmin, Leah] Minneapolis Vet Affairs Hlth Care Syst, Mental & Behav Hlth VA, Minneapolis, MN 55417 USA. [Harris, J. Irene] Univ Minnesota, Counseling Psychol & Psychiat, Minneapolis, MN 55455 USA. [Farchmin, Leah] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Stull, Laura] Anderson Univ, Dept Psychol, Anderson, IN USA. [Boyd, Jennifer] San Francisco VA Med Ctr, Mental Hlth Serv VA, San Francisco, CA USA. [Boyd, Jennifer] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Schumacher, Marianne] Minneapolis Vet Affairs Hlth Care Syst, Mental & Behav Hlth, Minneapolis, MN USA. [Drapalski, Amy L.] Vet Affairs Capitol Hlth Care Network VISN 5, Mental Illness Res Educ & Clin Ctr, Baltimore, MD USA. RP Harris, JI (reprint author), Minneapolis Vet Affairs Hlth Care Syst, Mental & Behav Hlth VA, Minneapolis, MN 55417 USA.; Harris, JI (reprint author), Minneapolis VA Hlth Cam Syst, Psychol, Mailstop 116B,One Vet Dr, Minneapolis, MN 55417 USA. EM jeanette.harris2@va.gov FU VISN 5 Mental Illness Research, Education, and Clinical Center; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX Support for the manuscript was provided by the VISN 5 Mental Illness Research, Education, and Clinical Center. This material is based upon work supported (or supported in part) by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. The contents of the publication/presentation do not represent the views of the Department of Veterans Affairs or the United States Government. NR 42 TC 2 Z9 2 U1 2 U2 7 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X EI 1559-3126 J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD JUN PY 2015 VL 38 IS 2 SI SI BP 179 EP 185 DI 10.1037/prj0000118 PG 7 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA DE1NE UT WOS:000370392900013 PM 25799300 ER PT J AU Grapsa, J Nunes, MCP Tan, TC Cabrita, IZ Coulter, T Smith, BCF Dawson, D Gibbs, JSR Nihoyannopoulos, P AF Grapsa, Julia Nunes, Maria Carmo Pereira Tan, Timothy C. Cabrita, Ines Zimbarra Coulter, Taryn Smith, Benjamin C. F. Dawson, David Gibbs, J. Simon R. Nihoyannopoulos, Petros TI Echocardiographic and Hemodynamic Predictors of Survival in Precapillary Pulmonary Hypertension Seven-Year Follow-Up SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE echocardiography; pericardial effusion; pulmonary hypertension; right ventricular function; survival analysis ID RIGHT-VENTRICULAR FUNCTION; ARTERIAL-HYPERTENSION; TRICUSPID REGURGITATION; EUROPEAN ASSOCIATION; PROGNOSTIC-FACTORS; MANAGEMENT; PRESSURE; REGISTRY; HEART; TIME AB Background-In this study, we looked at the prognostic value of echocardiographic and hemodynamic measures in a large cohort of patients with precapillary pulmonary hypertension before and after initiation of treatment. Methods and Results-Data were collected prospectively in a cohort of consecutive patients with precapillary pulmonary hypertension referred between 2002 and 2011. A range of clinical and echocardiographic variables were collected and stored on a database to assess predictors of survival. Invasive hemodynamic data including pulmonary artery pressure, pulmonary vascular resistance, capillary wedge pressure, and cardiac index were also obtained at baseline in all patients. Outcome was defined as mortality because of cardiovascular-related death. The study cohort comprised 777 patients (514 women) with precapillary pulmonary hypertension. A total of 195 (25%) died. In multivariable analysis, moderate or severe tricuspid regurgitation (hazard ratio [HR], 26.537; 95% confidence interval, 11.536-61.044; P< 0.001), right ventricular myocardial performance index (HR, 3.421; 95% confidence interval, 1.777-6.584; P< 0.001), and the presence of pericardial effusion (HR, 1.38; 95% confidence interval, 1.023-1.862; P= 0.035) were independent predictors of mortality. High pulmonary vascular resistance and right atrial pressure by invasive hemodynamic measurements were independent predictors of mortality (HR, 1.084; 95% confidence interval, 1.041-1.130, and 1.079, respectively; 95% confidence interval, 1.049-1.111; P< 0.001 for both), whereas patients with a higher cardiac index had better survival overall (HR, 0.384; 95% confidence interval, 0.307-0.481; P< 0.001). Conclusions-Right ventricular dysfunction, moderate-severe tricuspid regurgitation, low cardiac index, and raised right atrial pressure were associated with poor survival for both pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertensive disease patients. The severity of tricuspid regurgitation, myocardial performance index, presence of pericardial effusion, pulmonary vascular resistance, cardiac index, and right atrial pressure may be used to stratify risk of death. C1 [Grapsa, Julia; Coulter, Taryn; Smith, Benjamin C. F.; Dawson, David; Nihoyannopoulos, Petros] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Cardiol, Du Cane Rd, London W12 0NN, England. [Nunes, Maria Carmo Pereira; Tan, Timothy C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiol, Boston, MA USA. [Cabrita, Ines Zimbarra; Gibbs, J. Simon R.] Imperial Coll Healthcare NHS Trust, Hammersmith Hosp, Natl Pulm Hypertens Serv, London, England. RP Nihoyannopoulos, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Cardiol, Du Cane Rd, London W12 0NN, England. EM petros@imperial.ac.uk OI smith, benjamin/0000-0003-1218-7290 FU National Institute for Health Research under the Biomedical Research Centre Scheme FX This study was supported by the National Institute for Health Research under the Biomedical Research Centre Scheme. NR 47 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JUN PY 2015 VL 8 IS 6 AR e002107 DI 10.1161/CIRCIMAGING.114.002107 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DD1WT UT WOS:000369714500001 ER PT J AU Sung, S Nonyane, BAS Lee, H Kimball, AB AF Sung, Sarah Nonyane, Bareng A. S. Lee, Hang Kimball, Alexa B. TI Academia and the Millennials: Trending Career Choices of Graduating Dermatology Residents 1999-2012 SO JOURNAL OF DRUGS IN DERMATOLOGY LA English DT Letter C1 [Sung, Sarah] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Nonyane, Bareng A. S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Lee, Hang] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sung, S (reprint author), Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. EM sarah.clark.m@gmail.com OI Nonyane, Bareng/0000-0001-5633-7487 NR 5 TC 1 Z9 1 U1 1 U2 2 PU JOURNAL OF DRUGS IN DERMATOLOGY PI NEW YORK PA 377 PARK AVE SOUTH, 6TH FLOOR, NEW YORK, NY 10016 USA SN 1545-9616 J9 J DRUGS DERMATOL JI J. Drugs Dermatol. PD JUN PY 2015 VL 14 IS 6 BP 549 EP 550 PG 2 WC Dermatology SC Dermatology GA DD8ZC UT WOS:000370214400004 PM 26091378 ER PT J AU Haywood, C Lanzkron, S Hughes, M Brown, R Saha, S Beach, MC AF Haywood, Carlton, Jr. Lanzkron, Sophie Hughes, Mark Brown, Rochelle Saha, Somnath Beach, Mary Catherine TI The Association of Clinician Characteristics with their Attitudes Toward Patients with Sickle Cell Disease: Secondary Analyses of a Randomized Controlled Trial SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE Sickle cell disease; clinician attitudes; healthcare disparities ID HIGH HOSPITAL UTILIZATION; PAIN MANAGEMENT; HEALTH-CARE; PROVIDERS CONTRIBUTE; PHYSICIANS; TRUST; RACE; PERCEPTIONS; DISPARITIES; DEPENDENCE AB Background: A high level of evidence exists to suggest that negative attitudes held by clinicians toward persons with sickle cell disease serve as important barriers to the delivery of high quality care to this patient population. Little is known. though. about the characteristics of clinicians that may be predictive of these negative attitudes. Methods: During spring and summer 2009, we conducted a randomized controlled trial to test an intervenlion to improve clinician attitudes toward persons with sickle cell disease. Participating clinicians completed questionnaires regarding their demographic characteristics and their attitudes toward sic kle cell patienls. Principal clinician charac teristics of interest included their race, professio nal discipline (nurse/ physic ian), and the amount of their recent exposure to sickle cell patients in pain. Secondary analyses from this trial are presented here. Main Findings: Asian clinicians reported more negative allitudes towards these palients than did Black or White clinicians, nurses reported more negative altitudes lhan physicians. and clinicians w ith the greatest levels of recent exposure to sickle cell patients in pain reported more nega tive attitudes than did clinicians with lower levels of recent exposure. Conclusions: Our findings could facilitate the development of tailored educational resources needed to improve the quality of care delivered to persons with sickle cell disease, a national priority for sickle cell efforts. C1 [Haywood, Carlton, Jr.; Hughes, Mark; Beach, Mary Catherine] Johns Hopkins Sch Med, Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. [Lanzkron, Sophie; Brown, Rochelle] Johns Hopkins Sch Med, Baltimore, MD USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Gen Internal Med Sect, Div Gen Internal Med & Geriatr, Portland, OR 97201 USA. RP Haywood, C (reprint author), Johns Hopkins Berman Inst Bioeth, 1809 Ashland Ave,Deering Hall,Room 210, Baltimore, MD 21205 USA. EM chaywoodjr@jhu.edu FU Osler Center for Excellence institutional award; Johns Hopkins Clinical Research Scholars Program [5KL2RR025006-03]; National Heart, Lung, and Blood Institute [1 KOI HL108832-01]; Agency for Healthcare Research and Quality [K08 HS013903-05]; Blaustein Scholars through the Johns Hopkins Berman Institute of Bioethics FX This work was supported by an Osler Center for Excellence institutional award. Dr. Haywood's effort on this project was supported by the Johns Hopkins Clinical Research Scholars Program (5KL2RR025006-03), as well as by a grant from the National Heart, Lung, and Blood Institute (1 KOI HL108832-01). Dr. Beach's effort on this project was supported by a grant from the Agency for Healthcare Research and Quality (K08 HS013903-05). Drs. Beach and Hughes were also supported as Blaustein Scholars through the Johns Hopkins Berman Institute of Bioethics. NR 44 TC 1 Z9 1 U1 4 U2 5 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 EI 1943-4693 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUN PY 2015 VL 107 IS 2 BP 89 EP 96 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DC4EX UT WOS:000369174400012 PM 27269495 ER PT J AU Dowling, MB MacIntire, IC White, JC Narayan, M Duggan, MJ King, DR Raghavan, SR AF Dowling, Matthew B. MacIntire, Ian C. White, Joseph C. Narayan, Mayur Duggan, Michael J. King, David R. Raghavan, Srinivasa R. TI Sprayable Foams Based on an Amphiphilic Biopolymer for Control of Hemorrhage Without Compression SO ACS BIOMATERIALS SCIENCE & ENGINEERING LA English DT Article DE noncompressible hemorrhage; hydrophobically modified chitosan; liquid foam; rheology; hydrophobic interactions ID HYDROPHOBICALLY-MODIFIED CHITOSAN; NONCOMPRESSIBLE TORSO HEMORRHAGE; DYNAMIC SURFACE-TENSION; FIBRIN SEALANT FOAM; EPIDEMIOLOGY; INJURY; TRAUMA; BATTLEFIELD; RHEOLOGY; EFFICACY AB Hemorrhage (severe blood loss) from traumatic injury is a leading cause of death for soldiers in combat and for young civilians. In some cases, hemorrhage can be stopped by applying compression of a tourniquet or bandage at the injury site. However, the majority of hemorrhages that prove fatal are "non-compressible", such as those due to an internal injury in the truncal region. Currently, there is no effective way to treat such injuries. In this initial study, we demonstrate that a sprayable polymer-based foam can be effective at treating bleeding from soft tissue without the need for compression. When the foam is sprayed into an open cavity created by injury, it expands and forms a self-supporting barrier that counteracts the expulsion of blood from the cavity. The active material in this foam is the amphiphilic biopolymer, hydrophobically modified chitosan (hmC), which physically connects blood cells into clusters via hydrophobic interactions (the hemostatic mechanism of hmC is thus distinct from the natural clotting cascade, and it works even with heparinized or citrated blood). The amphiphilic nature of hmC also allows it to serve as a stabilizer for the bubbles in the foam. We tested the hmC-based hemostatic foam for its ability to arrest bleeding from an injury to the liver in pigs. Hemostasis was achieved within minutes after application of the hmC foams (without the need for external compression). The total blood loss was 90% lower with the hmC foam relative to controls. C1 [Dowling, Matthew B.; Raghavan, Srinivasa R.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [MacIntire, Ian C.; White, Joseph C.; Raghavan, Srinivasa R.] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Narayan, Mayur] Univ Maryland, Sch Med, R Adams Cowley Shock Trauma Ctr, Baltimore, MD 21202 USA. [Duggan, Michael J.; King, David R.] Massachusetts Gen Hosp, Dept Emergency Surg Trauma & Crit Care, Boston, MA USA. RP Dowling, MB (reprint author), Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. EM mdowlin2@gmail.com; sraghava@umd.edu FU NSF SBIR program [IIP-114277] FX This work was funded by an award from the NSF SBIR program (IIP-114277). NR 31 TC 1 Z9 1 U1 8 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-9878 J9 ACS BIOMATER SCI ENG JI ACS Biomater. Sci. Eng. PD JUN PY 2015 VL 1 IS 6 BP 440 EP 447 DI 10.1021/acsbiomaterials.5b00067 PG 8 WC Materials Science, Biomaterials SC Materials Science GA DC6RO UT WOS:000369347500011 ER PT J AU Huffman, KM Cohen, ME Ko, CY Hall, BL AF Huffman, Kristopher M. Cohen, Mark E. Ko, Clifford Y. Hall, Bruce Lee TI A Comprehensive Evaluation of Statistical Reliability in ACS NSQIP Profiling Models SO ANNALS OF SURGERY LA English DT Article DE ACS NSQIP; hospital profiling; reliability; surgical quality ID HOSPITAL QUALITY MEASURE; SURGICAL QUALITY; RISK AB Objective: To assess statistical reliability of hospital profiling models in ACS NSQIP (American College of Surgeons' National Surgical Quality Improvement Program). Background: The ACS NSQIP January 2013 Semiannual Report provided risk-adjusted hospital quality assessments for 137 models. Methods: Median reliability and percentage of hospitals achieving acceptable reliability were computed for each model. Average median reliability was computed across models with common outcomes. Results: Median reliability varied across the 137 models, from a high of 0.91 for "All Cases Morbidity" to a low of 0.005 for "Procedure-Targeted Total Hip Arthroplasty Surgical Site Infection." Generally, reliability was greatest for models with larger sample sizes and higher outcome event rates. Among "Essentials" models, 72% attained a median reliability of 0.40 or more, and 24% of 0.70 or more. Among "Procedure-Targeted" models, 29% attained a median reliability of 0.40 or more, and 3% of 0.70 or more. Percentage of hospitals achieving an acceptable reliability of 0.40 ranged from 98% for "All Cases Morbidity" to 0% for "Procedure-Targeted Pancreatectomy Mortality." For Essentials models, average median reliability for each outcome, except mortality, was more than 0.40. However, for Procedure-Targeted models the average median was less than 0.40. Conclusions: For a large proportion of ACS NSQIP Essentials models, statistical reliability is adequate for assessing surgical quality and differentiating hospital performance. The Procedure-Targeted program is evolving in terms of statistical reliability, with promising results to date. These results also argue for broader discussions of statistical reliability in performance assessments for the profession. C1 [Huffman, Kristopher M.; Cohen, Mark E.; Ko, Clifford Y.; Hall, Bruce Lee] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Hall, Bruce Lee] Washington Univ, Dept Surg, St Louis, MO USA. [Hall, Bruce Lee] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce Lee] Washington Univ, Olin Business Sch, St Louis, MO USA. [Hall, Bruce Lee] John Cochran Vet Affairs Med Ctr, St Louis, MO USA. [Hall, Bruce Lee] BJC Healthcare, St Louis, MO USA. RP Huffman, KM (reprint author), Amer Coll Surg, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM khuffman@facs.org NR 11 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUN PY 2015 VL 261 IS 6 BP 1108 EP 1113 DI 10.1097/SLA.0000000000000913 PG 6 WC Surgery SC Surgery GA DD0LN UT WOS:000369611600040 PM 25211276 ER PT J AU Borsook, D Kussman, B George, E Becerra, L Burke, D AF Borsook, David Kussman, Barry George, Edward Becerra, Lino Burke, Dennis TI Surgically Induced Neuropathic Pain: Understanding the Perioperative Process Reply SO ANNALS OF SURGERY LA English DT Letter ID CRPS C1 [Borsook, David] Boston Childrens Hosp, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Borsook, D (reprint author), Boston Childrens Hosp, Boston, MA USA. NR 11 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUN PY 2015 VL 261 IS 6 BP E162 EP E163 DI 10.1097/SLA.0000000000000391 PG 2 WC Surgery SC Surgery GA DD0LN UT WOS:000369611600016 PM 24299687 ER PT J AU Merkow, RP Hall, BL Ko, CY AF Merkow, Ryan P. Hall, Bruce L. Ko, Clifford Y. TI Validity and Feasibility of the American College of Surgeons Colectomy Composite Outcome Quality Measure Reply SO ANNALS OF SURGERY LA English DT Letter ID SURGICAL QUALITY C1 [Merkow, Ryan P.; Hall, Bruce L.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Merkow, Ryan P.] Univ Chicago, Pritzker Sch Med, Dept Surg, Chicago, IL 60637 USA. [Hall, Bruce L.] Washington Univ, Barnes Jewish Hosp, Sch Med, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO USA. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, Dept Surg, St Louis, MO USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Merkow, RP (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. EM RMerkow@facs.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUN PY 2015 VL 261 IS 6 BP E158 EP E159 DI 10.1097/SLA.0000000000000405 PG 2 WC Surgery SC Surgery GA DD0LN UT WOS:000369611600012 PM 24263330 ER PT J AU Jeffery, AD AF Jeffery, Alvin D. TI Methodological Challenges in Examining the Impact of Healthcare Predictive Analytics on Nursing-Sensitive Patient Outcomes SO CIN-COMPUTERS INFORMATICS NURSING LA English DT Article DE Computer assisted; Clinical decision; Decision making; Models; Nursing; Research design; Statistical; Support systems ID DECISION-SUPPORT-SYSTEMS; PRACTITIONER PERFORMANCE; CLINICAL DETERIORATION; EXTERNAL VALIDATION; PRESSURE ULCERS; RISK-ASSESSMENT; BIG DATA; MODELS; TRIAL; INFECTIONS AB The expansion of real-time analytic abilities within current electronic health records has led to innovations in predictive modeling and clinical decision support systems. However, the ability of these systems to influence patient outcomes is currently unknown. Even though nurses are the largest profession within the healthcare workforce, little research has been performed to explore the impact of clinical decision support on their decisions and the patient outcomes associated with them. A scoping literature review explored the impact clinical decision support systems containing healthcare predictive analytics have on four nursing-sensitive patient outcomes (pressure ulcers, failure to rescue, falls, and infections). While many articles discussed variable selection and predictive model development/validation, only four articles examined the impact on patient outcomes. The novelty of predictive analytics and the inherent methodological challenges in studying clinical decision support impact are likely responsible for this paucity of literature. Major methodological challenges include (1) multilevel nature of intervention, (2) treatment fidelity, and (3) adequacy of clinicians' subsequent behavior. There is currently insufficient evidence to demonstrate efficacy of healthcare predictive analytics-enhanced clinical decision support systems on nursing-sensitive patient outcomes. Innovative research methods and a greater emphasis on studying this phenomenon are needed. C1 [Jeffery, Alvin D.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN USA. [Jeffery, Alvin D.] Cincinnati Childrens Hosp Med Ctr, Ctr Profess Excellence, Cincinnati, OH 45229 USA. RP Jeffery, AD (reprint author), 3333 Burnet Ave,MLC 8006, Cincinnati, OH 45229 USA. EM alvinjeffery@gmail.com FU US Department of Veterans Affairs, Office of Academic Affiliations FX This work was supported, in part, by the US Department of Veterans Affairs, Office of Academic Affiliations. NR 34 TC 0 Z9 0 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1538-2931 EI 1538-9774 J9 CIN-COMPUT INFORM NU JI CIN-Comput. Inform. Nurs. PD JUN PY 2015 VL 33 IS 6 BP 258 EP 264 DI 10.1097/CIN.0000000000000154 PG 7 WC Computer Science, Interdisciplinary Applications; Medical Informatics; Nursing SC Computer Science; Medical Informatics; Nursing GA DD0RV UT WOS:000369628000004 PM 25899442 ER PT J AU Greene, M Covinsky, KE Valcour, V Miao, YH Madamba, J Lampiris, H Cenzer, IS Martin, J Deeks, SG AF Greene, Meredith Covinsky, Kenneth E. Valcour, Victor Miao, Yinghui Madamba, Joy Lampiris, Harry Cenzer, Irena Stijacic Martin, Jeffrey Deeks, Steven G. TI Geriatric Syndromes in Older HIV-Infected Adults SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE aging; frailty; function ID IMMUNODEFICIENCY-VIRUS-INFECTION; INDEPENDENT RISK-FACTOR; DRUG-DRUG INTERACTIONS; ANTIRETROVIRAL THERAPY; HOMELESS ADULTS; PREVENTION TRIALS; FRAILTY; FALLS; IMPAIRMENT; PREVALENCE AB Background: Geriatric syndromes such as falls, frailty, and functional impairment are multifactorial conditions used to identify vulnerable older adults. Limited data exist on these conditions in older HIV-infected adults, and no studies have comprehensively examined these conditions. Methods: Geriatric syndromes including falls, urinary incontinence, functional impairment, frailty, sensory impairment, depression, and cognitive impairment were measured in a cross-sectional study of HIV-infected adults aged 50 years and older who had an undetectable viral load on antiretroviral therapy. We examined both HIV and nonHIV- related predictors of geriatric syndromes including sociodemographics, number of comorbidities and nonantiretroviral medications, and HIV-specific variables in multivariate analyses. Results: We studied 155 participants with a median age of 57 (interquartile range: 54-62) and 94% were men. Prefrailty (56%), difficulty with instrumental activities of daily living (46%), and cognitive impairment (47%) were the most frequent geriatric syndromes. Lower CD4 nadir incidence rate ratio [IRR: 1.16, 95% (confidence interval) CI: 1.06 to 1.26], non-white race (IRR: 1.38, 95% CI: 1.10 to 1.74), and increasing number of comorbidities (IRR: 1.09, 95% CI: 1.03 to 1.15) were associated with increased risk of having more geriatric syndromes. Conclusions: Geriatric syndromes are common in older HIVinfected adults. Treatment of comorbidities and early initiation of antiretroviral therapy may help to prevent development of these agerelated complications. Clinical care of older HIV-infected adults should consider incorporation of geriatric principles. C1 [Greene, Meredith; Covinsky, Kenneth E.; Valcour, Victor; Miao, Yinghui; Cenzer, Irena Stijacic] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Greene, Meredith; Covinsky, Kenneth E.; Miao, Yinghui; Cenzer, Irena Stijacic] San Francisco VA Med Ctr, Sect Geriatr & Palliat Med, San Francisco, CA USA. [Valcour, Victor] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [Madamba, Joy; Deeks, Steven G.] Univ Calif San Francisco, Dept Med, Div HIV AIDS, San Francisco, CA USA. [Lampiris, Harry] Univ Calif San Francisco, Div Infect Dis, Dept Med, San Francisco, CA USA. [Martin, Jeffrey] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lampiris, Harry] San Francisco VA Med Ctr, Infect Dis Sect, San Francisco, CA USA. RP Greene, M (reprint author), 4150 Clement St UC Box 181-G, San Francisco, CA 94121 USA. EM meredith.greene@ucsf.edu FU National Institutes of Health; University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research [P30-AI027763]; S.D. Bechtel Jr. Foundation Program for the Aging Century; NIAID [K24AI069994]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; CFAR Network of Integrated Systems [R24 AI067039]; National Institutes of Health [5-T32-AG000212] FX Supported by a grant from the National Institutes of Health, University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research, P30-AI027763, the S.D. Bechtel Jr. Foundation Program for the Aging Century, NIAID (K24AI069994), the UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131), and the CFAR Network of Integrated Systems (R24 AI067039). M.G. receives salary support from the National Institutes of Health (5-T32-AG000212). S.G.D., J.M., and K.E.C. each currently hold grants from the National Institutes of Health. V.V. currently holds grants from the National Institutes of Health and has served as a consultant and paid lecturer for IAS-USA. NR 53 TC 16 Z9 16 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2015 VL 69 IS 2 BP 161 EP 167 DI 10.1097/QAI.0000000000000556 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC5GW UT WOS:000369250500012 PM 26009828 ER PT J AU Weisberg, DF Gordon, KS Barry, DT Becker, WC Crystal, S Edelman, EJ Gaither, J Gordon, AJ Goulet, J Kerns, RD Moore, BA Tate, J Justice, AC Fiellin, DA AF Weisberg, Daniel F. Gordon, Kirsha S. Barry, Declan T. Becker, William C. Crystal, Stephen Edelman, Eva J. Gaither, Julie Gordon, Adam J. Goulet, Joseph Kerns, Robert D. Moore, Brent A. Tate, Janet Justice, Amy C. Fiellin, David A. TI Long-term Prescription of Opioids and/or Benzodiazepines and Mortality Among HIV-Infected and Uninfected Patients SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE opioid analgesics; benzodiazepines; HIV; pharmacoepidemiology; polypharmacy ID HUMAN-IMMUNODEFICIENCY-VIRUS; CORONARY-HEART-DISEASE; VETERANS AGING COHORT; PROBLEM DRUG-USE; NONCANCER PAIN; NONMALIGNANT PAIN; PROPENSITY SCORES; OLDER-ADULTS; PRIMARY-CARE; ADMINISTRATIVE DATA AB Background: Increased long-term prescription of opioids and/or benzodiazepines necessitates evaluating risks associated with their receipt. We sought to evaluate the association between long-term opioids and/or benzodiazepines and mortality in HIV-infected patients receiving antiretroviral therapy and uninfected patients. Methods: Prospective analysis of all-cause mortality using multivariable methods and propensity score matching among HIV-infected patients receiving antiretroviral therapy and uninfected patients. Results: Of 64,602 available patients (16,989 HIV-infected and 47,613 uninfected), 27,128 (exposed and unexposed to long-term opioids and/or benzodiazepines) were 1: 1 matched by propensity score. The hazard ratio for death was 1.40 [95% confidence interval (CI): 1.22 to 1.61] for long-term opioid receipt, 1.26 (95% CI: 1.08 to 1.48) for long-term benzodiazepine receipt, and 1.56 (95% CI: 1.26 to 1.92) for long-term opioid and benzodiazepine receipt. There was an interaction (P = 0.01) between long-term opioid receipt and HIV status with mortality. For long-term opioid receipt, the hazard ratio was 1.46 (95% CI: 1.15 to 1.87) among HIV-infected patients, and 1.25 (95% CI: 1.05 to 1.49) among uninfected patients. Mortality risk was increased for patients receiving both long-term opioids and benzodiazepines when opioid doses were >= 20 mg morphine-equivalent daily dose and for patients receiving long-term opioids alone when doses were >= 50 mg morphine-equivalent daily dose. Conclusions: Long-term opioid receipt was associated with an increased risk of death; especially with long-term benzodiazepine receipt, higher opioid doses, and among HIV-infected patients. Long-term benzodiazepine receipt was associated with an increased risk of death regardless of opioid receipt. Strategies to mitigate risks associated with these medications, and caution when they are coprescribed, are needed particularly in HIV-infected populations. C1 [Weisberg, Daniel F.] Yale Univ, Sch Med, New Haven, CT 06510 USA. [Gordon, Kirsha S.; Goulet, Joseph; Kerns, Robert D.; Moore, Brent A.; Tate, Janet; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Barry, Declan T.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. [Becker, William C.; Edelman, Eva J.; Tate, Janet; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, Dept Internal Med, ES Harkness Bldg A,367 Cedar St,Suite 406A, New Haven, CT 06510 USA. [Crystal, Stephen] Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, New Brunswick, NJ 08903 USA. [Edelman, Eva J.; Moore, Brent A.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT 06510 USA. [Gaither, Julie] Yale Univ, Sch Publ Hlth, New Haven, CT 06510 USA. [Gordon, Adam J.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Goulet, Joseph; Kerns, Robert D.; Moore, Brent A.] VA Connecticut Healthcare Syst, Pain Res Informat Multimorbid & Educ PRIME Ctr, West Haven, CT USA. RP Fiellin, DA (reprint author), Yale Univ, Sch Med, Dept Internal Med, ES Harkness Bldg A,367 Cedar St,Suite 406A, New Haven, CT 06510 USA. EM david.fiellin@yale.edu RI Moore, Brent/O-4867-2015; OI Moore, Brent/0000-0003-0123-6616; Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502; Goulet, Joseph/0000-0002-0842-804X FU NIH [U01 AA020790, U24 AA020794, U10 AA 13566]; Office of Medical Student Research, Yale School of Medicine, New Haven, CT; Veterans Aging Cohort study - National Institute on Alcohol Abuse and Alcoholism [U10 AA 13566] FX Supported by NIH Grants U01 AA020790; U24 AA020794; U10 AA 13566. Funding for this study was provided by the Office of Medical Student Research, Yale School of Medicine, New Haven, CT, and the Veterans Aging Cohort study, funded by the National Institute on Alcohol Abuse and Alcoholism [U10 AA 13566]. NR 77 TC 8 Z9 9 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2015 VL 69 IS 2 BP 223 EP 233 DI 10.1097/QAI.0000000000000591 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC5GW UT WOS:000369250500020 PM 26009831 ER PT J AU Safren, SA Mayer, KH Ou, SS McCauley, M Grinsztejn, B Hosseinipour, MC Kumarasamy, N Gamble, T Hoffman, I Celentano, D Chen, YQ Cohen, MS AF Safren, Steven A. Mayer, Kenneth H. Ou, San-San McCauley, Marybeth Grinsztejn, Beatriz Hosseinipour, Mina C. Kumarasamy, Nagalingeswaran Gamble, Theresa Hoffman, Irving Celentano, David Chen, Ying Qing Cohen, Myron S. CA HPTN 052 Study Team TI Adherence to Early Antiretroviral Therapy: Results From HPTN 052, a Phase III, Multinational Randomized Trial of ART to Prevent HIV-1 Sexual Transmission in Serodiscordant Couples SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE ART for prevention; treatment as prevention; adherence ID SELF-REPORTED ADHERENCE; MEDICATION ADHERENCE; SUBSTANCE USE; VIRAL LOAD; INFECTION; QUESTIONNAIRE; NONADHERENCE; METAANALYSIS; INITIATION; OUTCOMES AB Background: Combination antiretroviral therapy (ART) for HIV-1-infected individuals prevents sexual transmission if viral load is suppressed. Methods: Participants were HIV-1-infected partners randomized to early ART (CD4 350-550) in HPTN052 (n = 886, median follow-up = 2.1 years), a clinical trial of early ART to prevent sexual transmission of HIV-1 in serodiscordant couples at 13 sites in 9 countries. Adherence was assessed through pill count (dichotomized at <95%) and through self-report items. Predictors of adherence were mental health and general health perceptions, substance use, binge drinking, social support, sexual behaviors, and demographics. Viral suppression was defined as HIV plasma viral load <400 copies per milliliter. Adherence counseling and couples' counseling about safer sex were provided. Logistic and linear regression models using generalized estimating equation for repeated measurements were used. Findings: Through pill count, 82% of participants were adherent at 1 month and 83.3% at 1 year. Mental health was the only psychosocial variable associated with adherence [pill count, odds ratios (OR) = 1.05, 95% confidence intervals (CIs): 1.00 to 1.11; self-report parameter estimate, OR = 0.02, 95% CI: 0.01 to 0.04], although regional differences emerged. Pill count (OR = 1.19, 95% CI: 1.10 to 1.30) and self-report (OR = 1.42, 95% CI: 1.14 to 1.77) adherence were associated with viral suppression. Interpretation: Although adherence was high among individuals in stable relationships taking ART for prevention, mental health and adherence covaried. Assessing and intervening on mental health inthe context of promoting adherence to ART as prevention should be explored. Adherence and couples' counseling, feedback about viral suppression, and/or altruism may also help explain the magnitude of adherence observed. C1 [Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Safren, Steven A.; Mayer, Kenneth H.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Safren, Steven A.; Mayer, Kenneth H.] Fenway Hlth, Dept Med, Boston, MA USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Ou, San-San; Chen, Ying Qing] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [McCauley, Marybeth] FHI 360, Sci Facilitat Dept, Washington, DC USA. [Grinsztejn, Beatriz] Inst Pesquisa Clin Evandro Chagas, HIV AIDS Clin Trials Unit, Rio De Janeiro, Brazil. [Hosseinipour, Mina C.] Univ North Carolina Chapel Hill, Div Infect Dis, Inst Global Hlth & Infect Dis, Lilongwe, Malawi. [Kumarasamy, Nagalingeswaran] VHS Chennai CRS, YRGCARE Med Ctr, CART CRS, Madras, Tamil Nadu, India. [Gamble, Theresa] FHI 360, Sci Facilitat Dept, Durham, NC USA. [Hoffman, Irving; Cohen, Myron S.] Univ N Carolina, Sch Med, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Celentano, David] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Safren, SA (reprint author), MGH Behav Med Serv, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ssafren@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068619, UM1AI068617, UM1AI068613]; NIH/NIAID [R01 AI089341]; NIH/NCI [R01 CA172415]; Gilead Science; [5K24MH094214]; [1P30AI094189] FX Overall support for the HIV Prevention Trials Network (HPTN) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 (HPTN Statistical and Data Management Center), and UM1AI068613 (HPTN Laboratory Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Additionally, S.A.S. was partially supported by 5K24MH094214, Y.Q.C. was partially supported by NIH/NIAID R01 AI089341 and NIH/NCI R01 CA172415, and D.C. was partially supported by 1P30AI094189. NIAID assumes all sponsor responsibilities through an investigational new drug application with the US Food and Drug Administration. The antiretroviral drugs used in this study were donated by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, and Merck. MMC, BG, MH, NK, TG, IH, DC, MC and YC have no relevant disclosures to report. SAS receives book royalties from Oxford University Press and Guilford Publications. KM receives a grant for clinical research from Gilead Science. NR 34 TC 8 Z9 8 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2015 VL 69 IS 2 BP 234 EP 240 DI 10.1097/QAI.0000000000000593 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC5GW UT WOS:000369250500021 PM 26009832 ER PT J AU Trevelyan, AJ Muldoon, SF Merricks, EM Racca, C Staley, KJ AF Trevelyan, Andrew J. Muldoon, Sarah F. Merricks, Edward M. Racca, Claudia Staley, Kevin J. TI The Role of Inhibition in Epileptic Networks SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Review DE epilepsy; seizure; GABA; interneuron; chloride ID TEMPORAL-LOBE EPILEPSY; GAP-JUNCTION BLOCKERS; HILAR SOMATOSTATIN INTERNEURONS; HIPPOCAMPAL PYRAMIDAL CELLS; MOSSY FIBER REORGANIZATION; DENTATE GRANULE CELLS; GABAERGIC NEURONS; PILOCARPINE MODEL; VISUAL-CORTEX; MOUSE MODEL AB Inhibition plays many roles in cortical circuits, including coordination of network activity in different brain rhythms and neuronal clusters, gating of activity, gain control, and dictating the manner in which activity flows through the network. This latter is particularly relevant to epileptic states, when extreme hypersynchronous discharges can spread across cortical territories. We review these different physiological and pathological roles and discuss how inhibition can be compromised and why this predisposes the network to seizures. C1 [Trevelyan, Andrew J.; Merricks, Edward M.; Racca, Claudia] Newcastle Univ, Sch Med, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 2PP, Tyne & Wear, England. [Muldoon, Sarah F.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Muldoon, Sarah F.] US Army, Res Lab, Bethesda, MD USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Neurol Res, Boston, MA 02114 USA. RP Trevelyan, AJ (reprint author), Newcastle Univ, Sch Med, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 2PP, Tyne & Wear, England. EM andytrev@gmail.com FU Medical Research Council [MR/J013250/1] NR 100 TC 3 Z9 4 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0736-0258 EI 1537-1603 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD JUN PY 2015 VL 32 IS 3 BP 227 EP 234 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DD0DB UT WOS:000369589400007 PM 26035675 ER PT J AU Bebell, LM Riley, LE AF Bebell, Lisa M. Riley, Laura E. TI Ebola Virus Disease and Marburg Disease in Pregnancy A Review and Management Considerations for Filovirus Infection SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID HEMORRHAGIC-FEVER; WEST-AFRICA; CONGO; OUTBREAK; KIKWIT; LASSA AB The largest-ever recorded outbreak of viral hemorrhagic fever is ongoing. As a result of the epidemic and rural nature of outbreaks, little is published about the Filovirus infections Ebola virus disease and Marburg disease in pregnancy. This review of viral hemorrhagic fever focusing on Marburg and Ebola uses knowledge of disease in nonpregnant individuals and pregnancy-specific data to inform management for pregnant women. Filovirus infection presentation is similar between pregnant and nonpregnant patients, although infections may be more severe in pregnancy. Although labeled as hemorrhagic fevers, Marburg and Ebola do not commonly cause gross bleeding and should be conceptualized as diseases of high gastrointestinal losses. Early, aggressive supportive care is the mainstay of Filovirus infection management with massive fluid resuscitation as the key management principle. Patients often require 5-10 L or more per day of intravenous or oral fluid to maintain circulating blood volume in the setting of ongoing gastrointestinal loss. Fluid shifts warrant aggressive monitoring and correction of potassium levels and acid-base disturbances to prevent life-threatening arrhythmias and metabolic complications. Regardless of maternal survival, fetal loss rates are nearly 100% in Filovirus infection, likely resulting from unchecked transplacental and hematogenous viral spread. High fetal loss rates support the placenta as a difficult-to-eradicate Filovirus infection reservoir. In conclusion, the management of Filovirus infection in pregnancy should focus on stabilizing the mother with intensive monitoring and aggressive fluid and electrolyte repletion as well as maintaining strict infection control to minimize transmission to others. C1 [Bebell, Lisa M.] Massachusetts Gen Hosp, Dept Infect Dis, 55 Fruit St,GRJ-504, Boston, MA 02115 USA. [Bebell, Lisa M.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Riley, Laura E.] Massachusetts Gen Hosp, Global Hlth Collaborat, Boston, MA 02115 USA. RP Bebell, LM (reprint author), Massachusetts Gen Hosp, Dept Infect Dis, 55 Fruit St,GRJ-504, Boston, MA 02115 USA. EM lbebell@mgh.harvard.edu FU FIC NIH HHS [R25 TW009337]; NIAID NIH HHS [T32 AI007433] NR 33 TC 2 Z9 2 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2015 VL 125 IS 6 BP 1293 EP 1298 DI 10.1097/AOG.0000000000000853 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DD0VA UT WOS:000369637100005 PM 26000499 ER PT J AU Bryant, AS Norton, ME Nakagawa, S Bishop, JT Pena, S Gregorich, SE Kuppermann, M AF Bryant, Allison S. Norton, Mary E. Nakagawa, Sanae Bishop, Judith T. Pena, Sherri Gregorich, Steven E. Kuppermann, Miriam TI Variation in Women's Understanding of Prenatal Testing SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID HEALTH LITERACY; INFORMATION; DIAGNOSIS; BARRIERS; RISK AB OBJECTIVE: To investigate women's understanding of prenatal testing options and of their own experience with screening, diagnostic genetic testing, or both. METHODS: This was a secondary analysis of data from a randomized controlled trial of enhanced information and values clarification regarding prenatal genetic testing in the absence of financial barriers to testing. Women in the third trimester of pregnancy were asked whether they had discussed prenatal genetic testing with their health care providers, whether they understood this testing was optional, and whether they had undergone testing during their pregnancy. Multivariable logistic regression models were fit to determine independent predictors of these outcomes. RESULTS: Data were available from 710 study participants. Discussions about screening tests were reported by 654 participants (92%); only 412 (58%) reported discussing diagnostic testing. That screening and diagnostic testing were optional was evident to approximately two thirds of women (n=470 and 455, respectively). Recall of actual tests undergone was correct for 626 (88%) for screening and for 700 (99%) for diagnostic testing. Racial, ethnic and socioeconomic variation existed in the understanding of whether screening and diagnostic tests were optional and in the correct recall of whether screening had been undertaken in the current pregnancy. In the usual care group, women receiving care in low-income settings were less likely to recall being offered diagnostic testing (adjusted odds ratio 0.23 [0.14-0.39]). CONCLUSION: Disparities exist in women's recall of prenatal genetic testing discussions and their understanding of their own experience. Interventions that explain testing options to women and help clarify their preferences may help to eliminate these differences. C1 Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Med Effectiveness Ctr Div Populat, San Francisco, CA 94143 USA. RP Bryant, AS (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM abryant@partners.org FU Ariosa Diagnostics; Verinata Health and Natera FX Dr. Norton is a co-Principal Investigator on clinical trial NCT0145167, sponsored by Ariosa Diagnostics. Her institution has received unrestricted research funding for her research program from Verinata Health and Natera. Dr. Kuppermann was the University of California, San Francisco site Principal Investigator for clinical trial NCT0145167, and her institution has received unrestricted research funding for her research program from Verinata Health and Natera. The other authors did not report any potential conflicts of interest. NR 19 TC 4 Z9 4 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2015 VL 125 IS 6 BP 1306 EP 1312 DI 10.1097/AOG.0000000000000843 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DD0VA UT WOS:000369637100007 PM 26000501 ER PT J AU Ghezelayagh, T Rauh-Hain, JA Growdon, WB AF Ghezelayagh, Talayeh Rauh-Hain, Jose Alejandro Growdon, Whitfield B. TI Comparing Mortality of Vaginal Sarcoma, Squamous Cell Carcinoma, and Adenocarcinoma in the Surveillance, Epidemiology, and End Results Database SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PRIMARY INVASIVE-CARCINOMA; FEMALE GENITAL-TRACT; RADIATION-THERAPY; CANCER; RHABDOMYOSARCOMA AB OBJECTIVE: To evaluate the mortality outcomes of vaginal sarcomas in a large cohort compared with vaginal squamous cell and adenocarcinomas. METHODS: Women with primary invasive vaginal sarcomas, squamous cell carcinomas, and adenocarcinomas diagnosed between 1988 and 2010 were identified within the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Parametric and nonparametric methods were used to compare the demographic and clinical characteristics of women among the three tumor types as well as between sarcoma histologic subtypes. Overall and cancer-specific mortality outcomes were examined using Kaplan-Meier and multivariable Cox proportional hazards models. RESULTS: The final cohort consisted of 3,121 patients with vaginal squamous cell carcinoma, 720 patients with adenocarcinoma, and 221 patients with sarcoma. Compared with women with squamous cell carcinoma and adenocarcinoma, patients diagnosed with vaginal sarcomas tended to be younger, have larger tumors with less regional extension and lymph node positivity, and be treated primarily with surgery without radiation. In unadjusted analysis, 5-year mortality rates border 30% for all three histologies. After adjusting for other prognostic factors including use of radiation and surgery, patients with vaginal sarcomas had a 69% greater risk of cancer-related mortality compared with patients with squamous cell carcinoma (hazard ratio 1.69, 95% confidence interval 1.26-2.26). Although sarcoma histology failed to associate with mortality risk, age, tumor extension and metastasis, and surgery were poor prognostic factors. CONCLUSION: Primary vaginal sarcomas are aggressive neoplasms with different presenting characteristics and increased adjusted risk of mortality compared with squamous cell and adenocarcinoma subtypes. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, TH Chan Sch Publ Hlth, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Growdon, WB (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9 E, Boston, MA 02114 USA. EM wgrowdon@MGH.Harvard.edu NR 27 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2015 VL 125 IS 6 BP 1353 EP 1361 DI 10.1097/AOG.0000000000000861 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DD0VA UT WOS:000369637100014 PM 26000506 ER PT J AU Rauh-Hain, JA Hariton, E Clemmer, J Clark, RM Hall, T Boruta, DM Schorge, JO del Carmen, MG AF Rauh-Hain, J. Alejandro Hariton, Eduardo Clemmer, Joel Clark, Rachel M. Hall, Tracilyn Boruta, David M. Schorge, John O. del Carmen, Marcela G. TI Incidence and Effects on Mortality of Venous Thromboembolism in Elderly Women With Endometrial Cancer SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RISK-FACTORS; VALIDATION; CLAIMS AB OBJECTIVE: To describe the incidence of thromboembolic events (venous thromboembolism) before and after the diagnosis of epithelial endometrial cancer and to evaluate the effects of these events on survival. METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claim files to identify patients with epithelial endometrial cancer diagnosed between 1992 and 2009. To identify venous thromboembolism events 3 months before diagnosis and up to 24 months after diagnosis, we used International Classification of Diseases, 9th Revision, and Healthcare Common Procedure Coding System codes. RESULTS: A total of 23,122 patients were included; of them 1,873 (8.1%) developed a venous thromboembolism. Patients with low-grade (grades 1 and 2) endometrioid adenocarcinoma had a significantly lower rate of venous thromboembolism 3 months before and 6 months after the diagnosis of cancer (3.6%; 95% confidence interval [CI] 3.3-3.9%) compared with carcinosarcoma (9.2%; 95% CI 7.8-10.8%), clear cell (6.9%; 95% CI 4.8-9.7%), uterine serous cancer (8.1%; 95% CI 7.01-9.3%), and grade 3 endometrioid adenocarcinoma (6.1%; 95% CI 5.4-6.9%) (P<.001). On multivariate analysis during the same time period, most recent time periods of diagnosis, carcinosarcoma histology compared with lower grade endometrial cancer, higher stage, African American race, marital status, chemotherapy delivery, and lymph node dissection were associated with increased risk of venous thromboembolism. The median overall survival for women who experienced a venous thromboembolism 3 months before the diagnosis of endometrial cancer was 31 months (95% CI 20-48 months); in women diagnosed with venous thromboembolism 6 months after the cancer diagnosis was 37 months (95% CI 31-44), and in women who did not experienced a venous thromboembolism was 111 months (95% CI 109-114). After adjusting for prognostic factors, there was an association between venous thromboembolism diagnosed 3 months before endometrial cancer (hazard ratio 1.69, 95% CI 1.34-2.13) or 6 months after the diagnosis (hazard ratio 1.57, 95% CI 1.44-1.71) and lower survival. CONCLUSION: Patients with uterine serous cancer, carcinosarcoma, clear cell carcinoma, and grade 3 endometrioid adenocarcinoma had a higher rate of venous thromboembolism than patients with low-grade endometrioid adenocarcinoma. A diagnosis of venous thromboembolism was associated with decreased survival in elderly patients with endometrial cancer. C1 [Rauh-Hain, J. Alejandro; Hariton, Eduardo; Clemmer, Joel; Clark, Rachel M.; Hall, Tracilyn; Boruta, David M.; Schorge, John O.; del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9 E, Boston, MA 02114 USA. EM mdelcarmen@partners.org FU Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital FX Supported by The Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital. NR 17 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2015 VL 125 IS 6 BP 1362 EP 1370 DI 10.1097/AOG.0000000000000866 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DD0VA UT WOS:000369637100015 PM 26000507 ER PT J AU Althabe, F Belizan, JM McClure, EM Hemingway-Foday, J Berrueta, M Mazzoni, A Ciganda, A Goudar, SS Kodkany, BS Mahantshetti, NS Dhaded, SM Katageri, GM Metgud, MC Joshi, AM Bellad, MB Honnungar, NV Derman, RJ Saleem, S Pasha, O Ali, S Hasnain, F Goldenberg, RL Esamai, F Nyongesa, P Ayunga, S Liechty, EA Garces, AL Figueroa, L Hambidge, KM Krebs, NF Patel, A Bhandarkar, A Waikar, M Hibberd, PL Chomba, E Carlo, WA Mwiche, A Chiwila, M Manasyan, A Pineda, S Meleth, S Thorsten, V Stolka, K Wallace, DD Koso-Thomas, M Jobe, AH Buekens, PM AF Althabe, Fernando Belizan, Jose M. McClure, Elizabeth M. Hemingway-Foday, Jennifer Berrueta, Mabel Mazzoni, Agustina Ciganda, Alvaro Goudar, Shivaprasad S. Kodkany, Bhalachandra S. Mahantshetti, Niranjana S. Dhaded, Sangappa M. Katageri, Geetanjali M. Metgud, Mrityunjay C. Joshi, Anjali M. Bellad, Mrutyunjaya B. Honnungar, Narayan, V Derman, Richard J. Saleem, Sarah Pasha, Omrana Ali, Sumera Hasnain, Farid Goldenberg, Robert L. Esamai, Fabian Nyongesa, Paul Ayunga, Silas Liechty, Edward A. Garces, Ana L. Figueroa, Lester Hambidge, K. Michael Krebs, Nancy F. Patel, Archana Bhandarkar, Anjali Waikar, Manjushri Hibberd, Patricia L. Chomba, Elwyn Carlo, Waldemar A. Mwiche, Angel Chiwila, Melody Manasyan, Albert Pineda, Sayury Meleth, Sreelatha Thorsten, Vanessa Stolka, Kristen Wallace, Dennis D. Koso-Thomas, Marion Jobe, Alan H. Buekens, Pierre M. TI A Population-Based, Multifaceted Strategy to Implement Antenatal Corticosteroid Treatment Versus Standard Care for the Reduction of Neonatal Mortality Due to Preterm Birth in Low-Income and Middle-Income Countries: The ACT Cluster Randomized Trial SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Antenatal corticosteroids are 1 of the most effective hospital-based treatments to reduce neonatal mortality for pregnant women at risk of preterm birth. While studies have shown reductions in neonatal mortality in high-and middle-income countries, and the treatment has been recommended by national and international health organizations, less than 10% of women in low-income countries at risk of preterm birth receive antenatal corticosteroids. This cluster-randomized trial aimed to assess the feasibility, safety, and effectiveness of a multifaceted intervention to increase the use of these treatments in middle-and low-income countries. Between October 2011 and March 2014, this trial randomly assigned (1: 1) clusters in rural and semiurban areas in Guatemala, Argentina, India, Kenya, Pakistan, and Zambia to this intervention or to standard care. To be eligible, clusters had to have at least 300 births annually in the defined area, either at homes or in facilities. Part of the intervention included better identification of women at risk of preterm birth. In intervention clusters, all health care providers were trained to identify women at risk of preterm birth and to administer dexamethasone in 1 course of four 6-mg doses every 12 hours to at risk women at less than 36 weeks' gestational age. In the intervention arm, women identified as high risk of preterm birth were also referred, but transportation was not provided. All clusters were training in newborn care. There were 51 intervention clusters with 2520 live births less than the fifth percentile for birth weight and 50 control clusters with 2258 in that percentile. In the intervention cluster, 45% of women received antenatal corticosteroids, whereas 10% of the control group received them (P < 0.0001). Of the less-than-fifth-percentile infants in the intervention group, 28-day neonatal mortality was 225 per 1000 live births, compared with a 323-per-1000-live-births neonatal mortality rate in that percentile in the control group (relative risk (RR), 0.96; 95% confidence interval [CI], 0.87-1.06; P = 0.65). Stillbirths occurred in 229 per 1000 births in the intervention group and 247 per 1000 births in the control group (RR, 0.99; 95% CI, 0.90-1.09; P = 0.81). Including all pregnancies, the neonatal mortality rate for the intervention group was 27.4 per 1000 and 23.9 per 1000 for the control group (RR, 1.12; 95% CI, 1.02-1.22; P = 0.0127), and the stillbirth rate in the intervention group was 26.8 per 1000, and that rate was 24.3 per 1000 in the control group (RR, 1.11; 95% CI, 1.02-1.22; P = 0.0181). Researchers found that the intervention group was overtreated with antenatal corticosteroids, and even though nearly half of women delivering less-than-fifth-percentile infants received steroids, neonatal mortality did not decrease. Neonatal deaths were significantly increased in the intervention group (3.5 per 1000 live births), as were perinatal deaths (5.1 per 1000 live births) and maternal infection (3%-6% increase). The authors of the study advise caution in implementing interventions such as this one. The findings do not support this strategy, and whether the antenatal corticosteroids directly caused the unfavorable results in the intervention group should be further explored. C1 [Althabe, Fernando; Belizan, Jose M.; Berrueta, Mabel; Mazzoni, Agustina; Ciganda, Alvaro] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [Ciganda, Alvaro] UNICEM, Montevideo, Uruguay. [McClure, Elizabeth M.; Hemingway-Foday, Jennifer; Meleth, Sreelatha; Thorsten, Vanessa; Stolka, Kristen; Wallace, Dennis D.] RTI Int, Durham, NC USA. [Goudar, Shivaprasad S.; Kodkany, Bhalachandra S.; Mahantshetti, Niranjana S.; Dhaded, Sangappa M.; Metgud, Mrityunjay C.; Joshi, Anjali M.; Bellad, Mrutyunjaya B.; Honnungar, Narayan, V] KLE Univ, Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. [Katageri, Geetanjali M.] S Nijalingappa Med Coll, Bagalkot, Karnataka, India. [Derman, Richard J.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Saleem, Sarah; Pasha, Omrana; Ali, Sumera; Hasnain, Farid] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Esamai, Fabian; Nyongesa, Paul; Ayunga, Silas] Moi Univ, Sch Med, Eldoret, Kenya. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Garces, Ana L.; Figueroa, Lester; Pineda, Sayury] Ctr Amer & Panama, Fdn Alimentac & Nutr, Guatemala City, Guatemala. [Garces, Ana L.] Francisco Marroquin Univ, Guatemala City, Guatemala. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Patel, Archana; Bhandarkar, Anjali; Waikar, Manjushri] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chomba, Elwyn; Mwiche, Angel] Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar A.; Mwiche, Angel] Univ Alabama Birmingham, Birmingham, AL USA. [Chiwila, Melody] Ctr Infect Dis Zambia, Lusaka, Zambia. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Althabe, F (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. NR 0 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUN PY 2015 VL 70 IS 6 BP 379 EP U90 DI 10.1097/01.ogx.0000467226.29492.11 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC2UT UT WOS:000369073600006 ER PT J AU Moore, HCF Unger, JM Phillips, KA Boyle, F Hitre, E Porter, D Francis, PA Goldstein, LJ Gomez, HL Vallejos, CS Partridge, AH Dakhil, SR Garcia, AA Gralow, J Lombard, JM Forbe, JF Martino, S Barlow, WE Fabian, CJ Minasian, L Meyskens, FL Gelber, RD Hortobagyi, GN Albain, KS AF Moore, Halle C. F. Unger, Joseph M. Phillips, Kelly-Anne Boyle, Frances Hitre, Erika Porter, David Francis, Prudence A. Goldstein, Lori J. Gomez, Henry L. Vallejos, Carlos S. Partridge, Ann H. Dakhil, Shaker R. Garcia, Agustin A. Gralow, Julie Lombard, Janine M. Forbe, John F. Martino, Silvana Barlow, William E. Fabian, Carol J. Minasian, Lori Meyskens, Frank L., Jr. Gelber, Richard D. Hortobagyi, Gabriel N. Albain, Kathy S. CA POEMS S0230 Investigators TI Goserelin for Ovarian Protection During Breast-Cancer Adjuvant Chemotherapy SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Premature ovarian failure is a devastating long-term toxic effect of chemotherapy for premenopausal women. The survival benefit of adjuvant chemotherapy in young women with operable hormone receptor-negative breast cancer is well known, but concern over becoming infertile may influence the choice of treatment for many women. A number of trials have investigated the combined use of a gonadotropin-releasing hormone (GnRH) agonist and adjuvant chemotherapy in an attempt to protect ovarian function in premenopausal women. Results of such studies were mixed, and there were few data on pregnancy outcomes. The aim of this randomized trial was to determine whether administration of the GnRH agonist goserelin with chemotherapy would reduce the rate of ovarian failure after adjuvant or neoadjuvant treatment of hormone-receptor-negative early-stage breast cancer. A total of 257 premenopausal women with operable hormone receptor-negative breast cancer were randomized to receive standard chemotherapy with goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The rate of ovarian failure at 2 years was the primary study end point. Ovarian failure was defined as the absence of menses for the preceding 6 months and follicle-stimulating hormone levels in the postmenopausal range at 2 years. Conditional logistic regression was used to compare rates. Secondary end points evaluated included pregnancy outcomes and disease-free and overall survival. Of the 257 patients, 218 were eligible and could be evaluated: 113 in the chemotherapy-alone group and 105 in the goserelin group. Complete primary end-point data were available for 135 of the 218 patients who could be evaluated. Among these, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group; the odds ratio was 0.30, with a 95% confidence interval of 0.09 to 0.97; 2-sided P = 0.04. To determine the effect of the missing primary end-point data on the main study findings, sensitivity analyses were performed. The results of these analyses showed that the missing data had no significant effect on the association between treatment and stratification variables (age and planned chemotherapy regimen). Among the 218 patients who could be evaluated, more women became pregnant in the goserelin group than in the chemotherapy-alone group (21% vs 11%, P = 0.03). Kaplan-Meier curves showed that more women in the goserelin group had improved disease-free survival (P = 0.04) and overall survival (P = 0.05). Consistent with the findings of previous randomized trials, these data suggest that administration of a GnRH agonist with chemotherapy protects ovarian function, reducing the risk of early menopause and improving prospects for fertility. Although missing primary-end-point data weaken interpretation of the findings, there is no evidence that the missing data influenced the relative comparison between randomized groups. C1 [Moore, Halle C. F.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Unger, Joseph M.; Barlow, William E.] Fred Hutchinson Canc Res Ctr, SWOG Canc Res Grp Stat Ctr, Seattle, WA 98104 USA. [Gralow, Julie] Seattle Canc Care Alliance, Seattle, WA USA. [Gralow, Julie] Univ Washington, Seattle, WA 98195 USA. [Phillips, Kelly-Anne; Francis, Prudence A.] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.; Forbe, John F.] Australia & New Zealand Breast Canc Trials Grp, Newcastle, NSW, Australia. [Boyle, Frances; Lombard, Janine M.; Forbe, John F.] Calvary Mater Hosp, Newcastle, NSW, Australia. [Boyle, Frances] Univ Sydney, Sydney, NSW 2006, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.] Int Breast Canc Study Grp, Bern, Switzerland. [Hitre, Erika] Natl Inst Oncol, Budapest, Hungary. [Porter, David] Auckland Reg Canc & Blood Serv, Auckland, New Zealand. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Gomez, Henry L.] Inst Enfermedades Neoplas, Lima, Peru. [Vallejos, Carlos S.] Oncosalud SAC, Lima, Peru. [Partridge, Ann H.; Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.] IBCSG Stat Ctr, Boston, MA USA. [Dakhil, Shaker R.] Wichita Community Clin Oncol Program, Wichita, KS USA. [Fabian, Carol J.] Univ Kansas, Westwood, KS USA. [Garcia, Agustin A.] Univ So Calif, Norris Canc Ctr, Los Angeles, CA USA. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. [Minasian, Lori] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Albain, Kathy S.] Loyola Univ, Med Ctr, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. RP Moore, HCF (reprint author), Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. OI Gomez, Henry/0000-0003-2660-1843 NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUN PY 2015 VL 70 IS 6 BP 392 EP 393 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC2UT UT WOS:000369073600013 ER PT J AU Marcus, EA Li, N Cheng, EY Wozniak, LJ Venick, RS Farmer, DG AF Marcus, Elizabeth A. Li, Ning Cheng, Elaine Y. Wozniak, Laura J. Venick, Robert S. Farmer, Douglas G. TI A Single Center Analysis of Reoperative Frequency Following Intestinal Transplantation. SO TRANSPLANTATION LA English DT Meeting Abstract CT 14th International Small Bowel Transplant Symposium (ISBTS) CY JUN 10-13, 2015 CL Univ Catolica Argentina, Buenos Aires, ARGENTINA HO Univ Catolica Argentina C1 [Marcus, Elizabeth A.; Wozniak, Laura J.; Venick, Robert S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Marcus, Elizabeth A.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Li, Ning] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA USA. [Cheng, Elaine Y.; Venick, Robert S.; Farmer, Douglas G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. NR 0 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN PY 2015 VL 99 SU 1 MA 232 BP S43 EP S43 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6EC UT WOS:000368605200076 ER PT J AU Merlin, JS Westfall, AO Chamot, E Saag, M Walcott, M Ritchie, C Kertesz, S AF Merlin, Jessica S. Westfall, Andrew O. Chamot, Eric Saag, Michael Walcott, Melonie Ritchie, Christine Kertesz, Stefan TI Quantitative Evaluation of an Instrument to Identify Chronic Pain in HIV-Infected Individuals SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID PATIENT-REPORTED OUTCOMES; SCREENING-TEST; CARE; VALIDATION; RECOMMENDATIONS; POPULATION; ADHERENCE; SCALE; SF-36 AB A method to rapidly identify the presence of chronic pain would enhance the care of HIV-infected individuals, but such an instrument has not been assessed in this population to date. We assessed the construct validity of the two-question Brief Chronic Pain Questionnaire (BCPQ) in HIV-infected patients by assessing the association between BCPQ responses and known correlates of chronic pain. Participants in the University of Alabama Center for AIDS Research Network of Integrated Clinical Systems cohort completed the BCPQ, along with the EuroQOL to assess physical function, the PHQ-9 to assess depression, and the PHQ-anxiety module to assess anxiety. Among 100 participants, 25% were female, the mean age was 45 (SD 12), 63% were African American, 27% were publicly insured, the median CD4(+) T cell count was 572 cells/mm(3) (IQR 307-788), and 82% had an undetectable viral load. Participants with chronic pain were more likely to have impaired mobility (43% vs. 12%, p=0.001), difficulty with usual activities (47% vs. 12%, p<0.001), lower overall health state (70 vs. 84, p=0.002), pain today (80% vs. 27%, p<0.001), depression (30% vs. 15%, p=0.10), and anxiety (43% vs. 10%, p<0.001) than those without chronic pain. This study provides preliminary evidence for the BCPQ as a brief questionnaire to identify the presence of chronic pain in HIV care settings. C1 [Merlin, Jessica S.; Westfall, Andrew O.; Saag, Michael; Walcott, Melonie] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Merlin, Jessica S.] Univ Alabama Birmingham, Div Gerontol Geriatr & Palliat Care, Birmingham, AL USA. [Chamot, Eric] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Ritchie, Christine] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Ritchie, Christine] San Francisco VA Med Ctr, San Francisco, CA USA. [Kertesz, Stefan] Birmingham VA Med Ctr, Birmingham, AL USA. [Kertesz, Stefan] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. RP Merlin, JS (reprint author), BBRB 222,1530 3rd Ave S, Birmingham, AL 35294 USA. EM jmerlin@uab.edu FU University of Alabama at Birmingham (UAB) Center for AIDS Research CFAR; NIH funded program [P30 A1027767]; AHRQ [1K12HS02169401]; NIA [7K07AG031779]; Mary Fisher CARE Fund at UAB FX This research was supported by the University of Alabama at Birmingham (UAB) Center for AIDS Research CFAR, an NIH funded program (P30 A1027767) that was made possible by the following institutes: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR. J.S.M. is supported by 1K12HS02169401 (AHRQ). C.S.R. is supported by 7K07AG031779 (NIA). Funding was also provided by the Mary Fisher CARE Fund at UAB. NR 34 TC 0 Z9 0 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 1 PY 2015 VL 31 IS 6 BP 623 EP 627 DI 10.1089/aid.2014.0362 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB7LD UT WOS:000368695700009 PM 25693683 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI Is there recent evidence supporting NOT using paralytics during hypothermia induction and re-warming OR continuous dosing? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter ID CARDIAC-ARREST; SURVIVORS C1 [Guanci, Mary McKenna] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD JUN 1 PY 2015 VL 5 IS 2 BP 112 EP 112 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA DB4YO UT WOS:000368519800013 ER PT J AU Leonard, D Powell, H Eberlin, KR Winograd, J Kurtz, JM Cetrulo, CL AF Leonard, David Powell, Harrison Eberlin, Kyle R. Winograd, Jonathan Kurtz, Josef M. Cetrulo, Curtis L., Jr. TI Upper Extremity Transplantation: Functional and Immunological Status Two Years Post-Transplant SO TRANSPLANTATION LA English DT Meeting Abstract CT 12th Congress of the International-Hand-and-Composite-Tissue-Allotransplantation-Society (IHCTAS) CY APR 15-18, 2015 CL Univ Penn, Philadelphia, PA SP Int Hand & Composite Tissue Allotransplantat Soc HO Univ Penn C1 [Leonard, David; Powell, Harrison; Kurtz, Josef M.; Cetrulo, Curtis L., Jr.] Massachusetts Gen Hosp, Ctr Transplantat Sci, Vascularized Composite Allotransplantat Lab, Boston, MA 02114 USA. [Leonard, David; Eberlin, Kyle R.; Winograd, Jonathan; Cetrulo, Curtis L., Jr.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Kurtz, Josef M.] Emmanual Coll, Dept Biol, Boston, MA USA. NR 1 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN PY 2015 VL 99 SU 2 MA MO-13 BP S20 EP S20 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6EH UT WOS:000368605700037 ER PT J AU Leonard, D Shanmugarajah, K Powell, H Albritton, A Mallard, C Sachs, DH Cetrulo, CL Kurtz, JM AF Leonard, David Shanmugarajah, Kumaran Powell, Harrison Albritton, Alexander Mallard, Christopher Sachs, David H. Cetrulo, Curtis L., Jr. Kurtz, Josef M. TI The Role of Skin-Specific Immunobiology and Major Histocompatibility Complex Sharing in Vascularized Composite Allograft Tolerance SO TRANSPLANTATION LA English DT Meeting Abstract CT 12th Congress of the International-Hand-and-Composite-Tissue-Allotransplantation-Society (IHCTAS) CY APR 15-18, 2015 CL Univ Penn, Philadelphia, PA SP Int Hand & Composite Tissue Allotransplantat Soc HO Univ Penn C1 [Leonard, David] Massachusetts Gen Hosp, Ctr Transplantat Sci, Vasc Composite Allotransplantat Lab, Boston, MA 02114 USA. [Leonard, David; Shanmugarajah, Kumaran; Powell, Harrison; Albritton, Alexander; Mallard, Christopher; Sachs, David H.; Cetrulo, Curtis L., Jr.; Kurtz, Josef M.] Univ Manchester, Dept Plast & Reconstruct Surg Res, Manchester, Lancs, England. [Kurtz, Josef M.] Emmanual Coll, Dept Biol, Boston, MA USA. NR 0 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN PY 2015 VL 99 SU 2 MA O.08 BP S4 EP S4 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6EH UT WOS:000368605700009 ER PT J AU Robinson, ES Werth, VP AF Robinson, E. S. Werth, V. P. TI The role of cytokines in the pathogenesis of cutaneous lupus erythematosus SO CYTOKINE LA English DT Article DE Cutaneous lupus erythematous; Ultraviolet light; Interferon; Interleukin; Tumor necrosis factor-alpha ID NECROSIS-FACTOR-ALPHA; PLASMACYTOID DENDRITIC CELLS; QUALITY-OF-LIFE; HUMAN KERATINOCYTES; TNF-ALPHA; ULTRAVIOLET-LIGHT; DISEASE-ACTIVITY; MONOCLONAL-ANTIBODY; CLINICAL ACTIVITY; APOPTOTIC CELLS AB Cutaneous lupus erythematosus (CLE) is an inflammatory disease with a broad range of cutaneous manifestations that may be accompanied by systemic symptoms. The pathogenesis of CLE is complex, multifactorial and incompletely defined. Below we review the current understanding of the cytokines involved in these processes. Ultraviolet (UV) light plays a central role in the pathogenesis of CLE, triggering keratinocyte apoptosis, transport of nucleoprotein autoantigens to the keratinocyte cell surface and the release of inflammatory cytokines (including interferons (IFNs), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-8, IL-10 and IL-17). Increased IFN, particularly type I IFN, is central to the development of CLE lesions. In CLE, type I IFN is produced in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines, and adhesion molecules, thereby inducing a cycle of cutaneous inflammation. Increased TNF alpha in CLE may also cause inflammation. However, decreasing TNF alpha with an anti-TNF alpha agent can induce CLE-like lesions. TNF alpha regulates B cells, increases the production of inflammatory molecules and inhibits the production of IFN-alpha. An increase in the inflammatory cytokines IL-1, IL-6, IL-10, 1L-17 and IL-18 and a decrease in the anti-inflammatory cytokine IL-12 also act to amplify inflammation in CLE. Specific gene mutations may increase the levels of these inflammatory cytokines in some CLE patients. New drugs targeting various aspects of these cytokine pathways are being developed to treat CLE and systemic lupus erythematosus (SLE). Published by Elsevier Ltd. C1 Vet Affairs Med Ctr, Philadelphia, PA USA. Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. RP Werth, VP (reprint author), Univ Penn, Dept Dermatol, Perelman Ctr Adv Med, Suite 1-330A,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM werth@mail.med.upenn.edu FU Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; VA Merit Review grant FX This material is supported by the Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development and a VA Merit Review grant to VPW. NR 91 TC 7 Z9 9 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD JUN PY 2015 VL 73 IS 2 BP 326 EP 334 DI 10.1016/j.cyto.2015.01.031 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DB2AB UT WOS:000368309600022 PM 25767072 ER PT J AU Elsheikh, S Kuusikko-Gauffin, S Mattila, ML Jussila, K Ebeling, H Loukus, S Omar, M Ria, G Pauls, D Moilanen, I AF Elsheikh, Sherin Kuusikko-Gauffin, Sanna Mattila, Marja-Leena Jussila, Katja Ebeling, Hanna Loukus, Soile Omar, Manal Ria, Geylan Pauls, David Moilanen, Irma TI Neuropsychological performance of finnish and egyptian children with and without autism spectrum disorder SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Meeting Abstract DE Autism spectrum disorder; NEPSY; Neuropsychology; Neuropsychological abilities; Culture C1 [Elsheikh, Sherin; Kuusikko-Gauffin, Sanna; Mattila, Marja-Leena; Jussila, Katja; Ebeling, Hanna; Loukus, Soile; Moilanen, Irma] Univ Oulu, Dept Child Psychiat, Inst Clin Med, Fac Med, SF-90100 Oulu, Finland. [Elsheikh, Sherin; Kuusikko-Gauffin, Sanna; Mattila, Marja-Leena; Jussila, Katja; Ebeling, Hanna; Loukus, Soile; Moilanen, Irma] Univ Hosp Oulu, Oulu, Finland. [Elsheikh, Sherin] Abbassia Mental Hosp, Child Psychiat Unit, Cairo, Egypt. [Elsheikh, Sherin] Univ Oulu, Thule Inst, SF-90100 Oulu, Finland. [Loukus, Soile; Ria, Geylan] Univ Oulu, Child Language Res Ctr, Fac Humanities, Logoped, SF-90100 Oulu, Finland. [Omar, Manal] Ain Shams Univ, Inst Postgrad Childhood Studies, Cairo, Egypt. [Ria, Geylan] Helwan Univ, Fac Arts, Dept Psychol, Cairo, Egypt. [Pauls, David] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD JUN PY 2015 VL 24 SU 1 MA S2-03-04 BP S30 EP S31 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DA5DY UT WOS:000367823900064 ER PT J AU Jussila, K Junttila, M Mattila, ML Kuusikko-Gauffin, S Pollock-Wurman, R Joskitt, L Ebeling, H Moilanen, I Pauls, D AF Jussila, Katja Junttila, Maria Mattila, Marja-Leena Kuusikko-Gauffin, Sanna Pollock-Wurman, Rachel Joskitt, Leena Ebeling, Hanna Moilanen, Irma Pauls, David TI Sensory processing patterns and the core features of autism spectrum disorder SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Meeting Abstract C1 [Jussila, Katja; Mattila, Marja-Leena; Kuusikko-Gauffin, Sanna; Joskitt, Leena; Ebeling, Hanna; Moilanen, Irma] Univ Oulu, Dept Child Psychiat, Oulu, Finland. [Junttila, Maria] Univ Hosp Oulu, Oulu, Finland. [Junttila, Maria] Univ Oulu, Fac Educ, Oulu, Finland. [Pollock-Wurman, Rachel; Pauls, David] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pollock-Wurman, Rachel] Obsess Compuls Disorder Resource Ctr Florida, Ft Lauderdale, FL USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD JUN PY 2015 VL 24 SU 1 MA S2-03-05 BP S31 EP S31 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DA5DY UT WOS:000367823900065 ER PT J AU Pollock-Wurman, R Kuusikko-Gauffin, S Haapsamo, H Hurtig, T Mattila, ML Jussila, K Ebeling, H Moilanen, I Pauls, D AF Pollock-Wurman, Rachel Kuusikko-Gauffin, Sanna Haapsamo, Helena Hurtig, Tuula Mattila, Marja-Leena Jussila, Katja Ebeling, Hanna Moilanen, Irma Pauls, David TI Obsessive-compulsive disorder and anxiety disorders in children with autism spectrum disorder SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Meeting Abstract C1 [Pollock-Wurman, Rachel; Pauls, David] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pollock-Wurman, Rachel] Obsess Compuls Disorder Resource Ctr Florida, Ft Lauderdale, FL USA. [Kuusikko-Gauffin, Sanna; Haapsamo, Helena; Hurtig, Tuula; Mattila, Marja-Leena; Jussila, Katja; Ebeling, Hanna; Moilanen, Irma] Univ Oulu, Dept Child Psychiat, Oulu, Finland. [Kuusikko-Gauffin, Sanna; Haapsamo, Helena; Hurtig, Tuula; Mattila, Marja-Leena; Jussila, Katja; Ebeling, Hanna; Moilanen, Irma] Univ Hosp Oulu, Oulu, Finland. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD JUN PY 2015 VL 24 SU 1 MA S2-03-01 BP S29 EP S29 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DA5DY UT WOS:000367823900061 ER PT J AU Zhuang, YH Heather, MB Leser, JS Clarke, P Tyler, KL AF Zhuang, Yonghua Heather, M. Berens Leser, J. Smith Clarke, Penny Tyler, Kenneth L. TI Mitochondrial apoptotic activity of P53 contributes to neuronal apoptosis and pathogenesis during reovirus encephalitis SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 13th International Symposium on NeuroVirology CY JUN 02-06, 2015 CL San Diego, CA C1 [Zhuang, Yonghua; Heather, M. Berens; Leser, J. Smith; Clarke, Penny; Tyler, Kenneth L.] Univ Colorado Denver, Dept Neurol, Denver, CO USA. [Tyler, Kenneth L.] Denver Vet Affairs Med Ctr, Denver, CO USA. EM Yonghua.Zhuang@UCDenver.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2015 VL 21 SU 1 MA P174 BP S81 EP S81 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA DA5ET UT WOS:000367826400175 ER PT J AU Hayes, SM Salat, DH Forman, DE Sperling, RA Verfaellie, M AF Hayes, Scott M. Salat, David H. Forman, Daniel E. Sperling, Reisa A. Verfaellie, Mieke TI Cardiorespiratory fitness is associated with white matter integrity in aging SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID OLDER-ADULTS; AEROBIC FITNESS; COGNITIVE DECLINE; PHYSICAL-ACTIVITY; EXERCISE; BRAIN; AGE; DISEASE; NEUROPLASTICITY; ALZHEIMERS AB Objective: Aging is associated with reduced neural integrity, yet there are remarkable individual differences in brain health among older adults (OA). One factor that may attenuate age-related neural decline is cardiorespiratory fitness (CRF). The primary aim of this study was to link CRF to neural white matter microstructure using diffusion tensor imaging in OA. Methods: Young adults (YA; n = 32) and OA (n = 27) completed a graded maximal exercise test to evaluate CRF and diffusion tensor magnetic resonance imaging to examine neural white matter integrity. Results: As expected, pervasive age-related declines in white matter integrity were observed when OA were compared to YA. Further, peak VO2 was positively associated with fractional anisotropy (FA), an indicator of white matter integrity, in multiple brain regions in OA, but not YA. In multiple posterior regions such as the splenium, sagittal stratum, posterior corona radiata, and superior parietal white matter, FA values were similar in YA and OA classified as higher fit, with both groups having greater FA than lower fit OA. However, age-related differences in FA values remained in other regions, including the body and genu of the corpus callosum, precuneus, and superior frontal gyrus. Interpretation: CRF is positively associated with neural white matter microstructure in aging. The relationship between peak VO2 and FA appears to be tract-specific, as equivalent FA values were observed in higher fit OA and YA in some white matter tracts, but not others. Further, the association between peak VO2 and FA appears to be age-dependent. C1 [Hayes, Scott M.; Verfaellie, Mieke] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02130 USA. [Hayes, Scott M.; Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hayes, Scott M.; Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA 02130 USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Geriatr Cardiol Sect, Pittsburgh, PA USA. [Salat, David H.; Sperling, Reisa A.] MGH Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sperling, Reisa A.] Harvard Univ, Sch Med, Boston, MA USA. [Sperling, Reisa A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimers Res & Treatment, Boston, MA 02115 USA. RP Hayes, SM (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr 151A, 150 South Huntington Ave, Boston, MA 02130 USA. EM smhayes@bu.edu RI Meijer, Anna/K-5118-2016 FU NIA NIH HHS [K24 AG035007, P30 AG013846, P50 AG005134] NR 43 TC 7 Z9 7 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD JUN PY 2015 VL 2 IS 6 BP 688 EP 698 DI 10.1002/acn3.204 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CZ3CV UT WOS:000366982700008 PM 26125043 ER PT J AU Moses, JF Hughes, CD Patel, PB Chao, TE Konneh, SA Jallabah, TY Kikubaire, MK Meara, JG Hagander, LE AF Moses, J. Fallah Hughes, Christopher D. Patel, Pratik B. Chao, Tiffany E. Konneh, Solomane A. Jallabah, Torsou Y. Kikubaire, Michael Kiiza Meara, John G. Hagander, Lars E. TI Surgical outcomes for perforated peptic ulcer: A prospective case series at an academic hospital in Monrovia, Liberia SO AFRICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; CARE; PREVALENCE; MORTALITY AB Introduction: The incidence of perforated peptic ulcer remains high in low and middle-income countries. Mortality can be significant, and early surgical management with careful evaluation of pre-operative risk factors is essential. The purpose of this study was to describe the clinical outcomes of surgical treatment for perforated peptic ulcer disease in Liberia and to explore risk factors for adverse outcomes. Methods: This study prospectively examined 20 consecutive patients undergoing primary closure with omental patch for perforated pre-pyloric or duodenal peptic ulcer at the John F. Kennedy Medical Centre (JFKMC) in Monrovia, Liberia from May 2009 to March 2010. Pre-operative information was captured in a questionnaire. Risk factors were assessed for univariate and multivariate associations with in-hospital mortality. Results: Median age was 33 years and 85% were males. A majority of the patients (70%) had a history of gastritis and antacid use. Median time from beginning of symptoms to surgery was 4.5 days. Over-all in-hospital mortality following surgical therapy for perforated peptic ulcer disease was 35%. Median length of stay among survivors was 16 days, and death occurred at median 1 day after admission. Long symptom duration and age >30 years of age were significantly associated with in-hospital mortality on univariate (beta = 2.60 [0.18-5.03], p = 0.035) and multivariate testing (beta = 2.95 [0.02-5.88], p = 0.049). Conclusion: Peptic ulcer disease and its treatment represent a potentially substantial source of morbidity and mortality in limited-resource settings. In this case series, surgical treatment for perforated peptic ulcer disease carried a high mortality, and the results highlight the potential for public health systems strengthening to prevent poor health outcomes. Peptic ulcer disease in low-and middle-income countries presents unique epidemiology and treatment challenges that may differ significantly from evidence-based guidelines in high-income countries. C1 [Moses, J. Fallah; Konneh, Solomane A.; Jallabah, Torsou Y.; Kikubaire, Michael Kiiza] John F Kennedy Med Ctr, Monrovia, Liberia. [Hughes, Christopher D.; Patel, Pratik B.; Chao, Tiffany E.; Meara, John G.; Hagander, Lars E.] Harvard Univ, Sch Med, Program Global Surg & Social Change, Boston, MA USA. [Hughes, Christopher D.; Patel, Pratik B.; Chao, Tiffany E.; Meara, John G.; Hagander, Lars E.] Childrens Hosp Boston, Dept Plast & Oral Surg, Boston, MA USA. [Hughes, Christopher D.] Univ Connecticut, Sch Med, Dept Surg, Farmington, CT USA. [Chao, Tiffany E.; Hagander, Lars E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hagander, Lars E.] Lund Univ, Fac Med, Dept Clin Sci Lund, Pediat Surg & Int Pediat, Lund, Sweden. RP Moses, JF (reprint author), John F Kennedy Med Ctr, Monrovia, Liberia. EM fallahmoses@yahoo.com NR 17 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-419X EI 2211-4203 J9 AFR J EMERG MED JI Afr. J. Emerg. Med. PD JUN PY 2015 VL 5 IS 2 BP 60 EP 65 DI 10.1016/j.afjem.2014.11.002 PG 6 WC Emergency Medicine SC Emergency Medicine GA CY8CK UT WOS:000366636000006 ER PT J AU Ogawa, M LaRue, AC Mehrotra, M AF Ogawa, Makio LaRue, Amanda C. Mehrotra, Meenal TI Plasticity of hematopoietic stem cells SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE Hematopoietic stem cells (HSCs); Plasticity; Stem cells; Tissue regeneration; Transplantation ID BONE-MARROW-CELLS; OSTEOGENESIS IMPERFECTA; IN-VIVO; MESENCHYMAL CELLS; ORIGIN; TRANSPLANTATION; MUSCLE; MICE; MYOFIBROBLASTS; CHILDREN AB Almost two decades ago, a number of cell culture and preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired by controversy and remained dormant This chapter provides a brief review of evidence for HSC plasticity including our findings based on single HSC transplantation in mouse. These studies strongly support the concept that HSCs are pluripotent and may be the source for the majority, if not all, of the cell types in our body. (C) 2015 Published by Elsevier Ltd. C1 [Ogawa, Makio; LaRue, Amanda C.; Mehrotra, Meenal] Med Univ S Carolina, Charleston, SC 29425 USA. [LaRue, Amanda C.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29425 USA. [LaRue, Amanda C.; Mehrotra, Meenal] Hollings Canc Ctr, Charleston, SC 29425 USA. RP Ogawa, M (reprint author), Med Univ S Carolina, 165 Ashley Ave,MSC 908, Charleston, SC 29425 USA. EM ogawam@musc.edu FU BLRD VA [I01 BX000333] NR 44 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 EI 1532-1924 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN-SEP PY 2015 VL 28 IS 2-3 BP 73 EP 80 DI 10.1016/j.beha.2015.10.003 PG 8 WC Hematology SC Hematology GA CY0CQ UT WOS:000366074300002 PM 26590762 ER PT J AU Stone, RM AF Stone, Richard M. TI Should older adults with AML receive post-remission therapy? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE AML; Chemotherapy; Post-remission ID ACUTE MYELOID-LEUKEMIA; 1ST COMPLETE REMISSION; LOW-DOSE CYTARABINE; ACUTE NONLYMPHOCYTIC LEUKEMIA; RANDOMIZED PHASE-III; INDUCTION CHEMOTHERAPY; MYELODYSPLASTIC SYNDROME; EUROPEAN ORGANIZATION; CELL TRANSPLANTATION; ELDERLY-PATIENTS AB The evolution of post-remission therapy in older adults has for the most part mirrored that for younger adults. However, the suitability of those regimens for an older population is less clear-cut, mainly due to poorer tolerance of therapy and a relatively higher level of disease resistance. Not only is intensive post-remission therapy not appropriate for the majority of older adults, but the role of intensive induction therapy is also unclear. Treatment goals in patients over 55-65 years differ from those in younger patients and may not necessarily be curative but life-prolonging or purely palliative. This paper reviews treatments for older AML patients in an effort to shed some light on choosing appropriate therapy. (C) 2015 Published by Elsevier Ltd. C1 [Stone, Richard M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Stone, RM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,D-2053, Boston, MA 02215 USA. EM rstone@partners.org NR 26 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 EI 1532-1924 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN-SEP PY 2015 VL 28 IS 2-3 BP 106 EP 111 DI 10.1016/j.beha.2015.10.007 PG 6 WC Hematology SC Hematology GA CY0CQ UT WOS:000366074300006 PM 26590766 ER PT J AU Ballen, KK AF Ballen, Karen K. TI Is there a best graft source of transplantation in acute myeloid leukemia? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE Acute myeloid leukemia; AML; Haploidentical transplant; Umbilical cord blood transplantation; Unrelated donor transplantation ID UMBILICAL-CORD BLOOD; HEMATOPOIETIC-CELL TRANSPLANTATION; ALTERNATIVE DONOR TRANSPLANTATION; MISMATCHED UNRELATED DONOR; ACUTE MYELOGENOUS LEUKEMIA; HOST-DISEASE PROPHYLAXIS; REDUCED-INTENSITY; HEMATOLOGIC MALIGNANCIES; MARROW-TRANSPLANTATION; OLDER PATIENTS AB Only 30% of patients in the US who require an allogeneic hematopoietic cell transplant will have a fully HLA matched sibling donor. The National Marrow Donor Program/Be the Match has grown to over 25 million unrelated donors. However, a fully matched unrelated donor may not be available for many patients, particularly for patients of diverse racial and ethnic backgrounds. Over the last 10 years, considerable progress has been made in alternative donor transplant with improvements in outcomes for umbilical cord blood (UCB), haploidentical (haplo) related donor, and mismatched unrelated donor (MMUD) for patients with acute myeloid leukemia. Retrospective studies indicate comparable survival for these three graft sources. In this chapter, we review the latest results for patients receiving alternative donor transplants, and discuss strategies for choosing the optimal donor for each individual patient. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ballen, Karen K.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Ballen, Karen K.] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Zero Emerson,Suite 118, Boston, MA 02114 USA. EM kballen@partners.org NR 50 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 EI 1532-1924 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN-SEP PY 2015 VL 28 IS 2-3 BP 147 EP 154 DI 10.1016/j.beha.2015.10.012 PG 8 WC Hematology SC Hematology GA CY0CQ UT WOS:000366074300012 PM 26590772 ER PT J AU Hou, LF Joyce, BT Gao, T Liu, L Zheng, YN Penedo, FJ Liu, SR Zhang, W Bergan, R Dai, Q Vokonas, P Hoxha, M Schwartz, J Baccarelli, A AF Hou, Lifang Joyce, Brian Thomas Gao, Tao Liu, Lei Zheng, Yinan Penedo, Frank J. Liu, Siran Zhang, Wei Bergan, Raymond Dai, Qi Vokonas, Pantel Hoxha, Mirjam Schwartz, Joel Baccarelli, Andrea TI Blood Telomere Length Attrition and Cancer Development in the Normative Aging Study Cohort SO EBIOMEDICINE LA English DT Article DE Telomere; Longitudinal study; Cancer incidence ID PROSTATE-CANCER; RISK; INSTABILITY; TUMORIGENESIS; DYSFUNCTION; ELONGATION; SENESCENCE; LONGER; CELL; DNA AB Background: Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence. Methods: We included 792 Normative Aging Study participants with 1-4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis. Findings: Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (p(difference)=0.017); all participants had similar age-adjusted BTL 8-14 years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p=0.003) and four (p=0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR = 1.79, p = 0.03), and longer BTL measured <= 4 years pre-diagnosis with any (OR = 3.27, p < 0.001) and prostate cancers (OR = 6.87, p < 0.001). Interpretation: Age-related BTL attrition was faster in cancer cases but their age-adjusted BTL attrition began decelerating as diagnosis approached. This may explain prior inconsistencies and help develop BTL as a cancer detection biomarker. (C) 2015 The Authors. Published by Elsevier B.V. C1 [Hou, Lifang; Joyce, Brian Thomas; Gao, Tao; Liu, Lei; Zhang, Wei] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang; Liu, Lei; Penedo, Frank J.; Bergan, Raymond] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Joyce, Brian Thomas] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL 60613 USA. [Zheng, Yinan] Northwestern Univ, Feinberg Sch Med, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Penedo, Frank J.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Liu, Siran] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA. [Bergan, Raymond] Northwestern Univ, Feinberg Sch Med, Div Hematol & Oncol, Dept Med, Chicago, IL 60611 USA. [Dai, Qi] Vanderbilt Univ, Med Ctr, Nashville, TN 37203 USA. [Vokonas, Pantel] VA Boston Healthcare Syst, VA Normat Aging Study, Boston, MA 02130 USA. [Vokonas, Pantel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Hoxha, Mirjam] Univ Milan, Dept Clin Sci & Community Hlth, Mol Epidemiol & Environm Epigenet Lab, I-20122 Milan, Italy. [Schwartz, Joel; Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Hou, LF (reprint author), Northwestern Univ, Dept Prevent Med, 680 N Lake Shore Dr,Ste 1400, Evanston, IL 60208 USA. EM l-hou@northwestern.edu RI Liu, Lei/B-4968-2009; Zheng, Yinan/E-5775-2017; OI Liu, Lei/0000-0003-1844-338X; Baccarelli, Andrea/0000-0002-3436-0640 FU NCI NIH HHS [P30 CA060553]; NIEHS NIH HHS [P30ES00002, R01ES015172, R01ES021733] NR 34 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD JUN PY 2015 VL 2 IS 6 BP 591 EP 596 DI 10.1016/j.ebiom.2015.04.008 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CX8KT UT WOS:000365953000022 PM 26288820 ER PT J AU Carson, PE Anand, IS Win, S Rector, T Haass, M Lopez-Sendon, J Miller, A Teerlink, JR White, M McKelvie, RS Komajda, M Zile, MR McMurray, JJ Massie, B AF Carson, Peter E. Anand, Inder S. Win, Sithu Rector, Thomas Haass, Markus Lopez-Sendon, Jose Miller, Alan Teerlink, John R. White, Michel McKelvie, Robert S. Komajda, Michel Zile, Michael R. McMurray, John J. Massie, Barry TI The Hospitalization Burden and Post-Hospitalization Mortality Risk in Heart Failure With Preserved Ejection Fraction Results From the I-PRESERVE Trial (Irbesartan in Heart Failure and Preserved Ejection Fraction) SO JACC-HEART FAILURE LA English DT Article DE heart failure; hospitalizations; preserved ejection fraction; prognosis ID VENTRICULAR SYSTOLIC FUNCTION; CLINICAL CHARACTERISTICS; SURVIVAL; POPULATION; MORBIDITY; OUTCOMES; PREVALENCE; MANAGEMENT; REGISTRY; DEATH AB OBJECTIVES The aim of this study was to investigate prognosis in patients with heart failure (HF) with preserved ejection fraction and the causes of hospitalization and post-hospitalization mortality. BACKGROUND Although hospitalizations in patients with HF with preserved ejection fraction are common, there are limited data from clinical trials on the causes of admission and the influence of hospitalizations on subsequent mortality risk. METHODS Patients (n = 4,128) with New York Heart Association functional class II to IV HF and left ventricular ejection fractions >45% were enrolled in I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction). A blinded events committee adjudicated cardiovascular hospitalizations and all deaths using predefined and standardized definitions. The risk for death after HF, any-cause, or non-HF hospitalization was assessed using time-dependent Cox proportional hazard models. RESULTS A total of 2,278 patients had 5,863 hospitalizations during the 49 months of follow-up, of which 3,585 (61%) were recurrent hospitalizations. For any-cause hospitalizations, 26.5% of patients died during follow-up, with an incident mortality rate of 11.1 deaths per 100 patient-years (PYs) and an adjusted hazard ratio of 5.32 (95% confidence interval: 4.21 to 6.23). Overall, 53.6% of hospitalizations were classified as cardiovascular and 43.7% as noncardiovascular, with 2.7% not classifiable. HF was the largest single cause of initial (17.6%) and overall (21.1%) hospitalizations, although, after HF hospitalization, a substantially higher proportion of readmissions were due to primary HF causes (40%). HF hospitalization occurred in 685 patients, with 41% deaths during follow-up, an incident mortality rate of 19.3 deaths per 100 PYs. The adjusted hazard ratio was 2.93 (95% confidence interval: 2.40 to 3.57) relative to patients who were not hospitalized for HF and was greater in those with longer durations of hospitalization. There were 1,593 patients with only non-HF hospitalizations, 21% of whom died during follow-up, with an incident mortality rate of 8.7 deaths per 100 PYs and an adjusted hazard ratio of 4.25 (95% confidence interval: 3.27 to 5.32). The risk for death was highest in the first 30 days and declined over time for all hospitalization categories. Patients not hospitalized for HF or for any cause had observed incident mortality rates of 3.8 and 1.3 deaths per 100 PYs, respectively. CONCLUSIONS In I-PRESERVE, HFpEF patients hospitalized for any reason, and especially for HF, were at high risk for subsequent death, particularly early. The findings support the need for careful attention in the post-discharge time period including attention to comorbid conditions. Among those hospitalized for HF, the high mortality rate and increased proportion of readmissions due to HF (highest during the first 30 days), suggest that this group would be an appropriate target for investigation of new interventions. (C) 2015 by the American College of Cardiology Foundation. C1 [Carson, Peter E.] Washington Vet Affairs Med Ctr, Washington, DC 20422 USA. [Carson, Peter E.] Georgetown Univ, Washington, DC USA. [Anand, Inder S.; Win, Sithu; Rector, Thomas; Haass, Markus] Vet Affairs Hlth Care Syst, Minneapolis, MN USA. [Anand, Inder S.; Win, Sithu; Rector, Thomas] Univ Minnesota, Minneapolis, MN USA. [Haass, Markus] Theresienkrankenhaus, Mannheim, Germany. [Lopez-Sendon, Jose] Hosp Gregorio Maranon, Madrid, Spain. [Miller, Alan] Univ Florida, Jacksonville, FL USA. [Teerlink, John R.; Massie, Barry] San Francisco VA Med Ctr, San Francisco, CA USA. [Teerlink, John R.; Massie, Barry] Univ Calif San Francisco, San Francisco, CA 94143 USA. [White, Michel] Montreal Heart Inst Res Ctr, Montreal, PQ, Canada. [McKelvie, Robert S.] Populat Hlth Res Inst, Hamilton, ON, Canada. [McKelvie, Robert S.] McMaster Univ, Hamilton, ON, Canada. [Komajda, Michel] Univ Paris, Pitie Salpetriere Hosp, F-75252 Paris, France. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [McMurray, John J.] British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. RP Carson, PE (reprint author), Washington Vet Affairs Med Ctr, Dept Cardiol, 151D,50 Irving St NW, Washington, DC 20422 USA. EM peter.carson@med.va.gov OI mcmurray, john/0000-0002-6317-3975 FU I-PRESERVE trial; Minneapolis Veterans Affairs Health Care System FX Bristol-Myers Squibb sponsored the I-PRESERVE trial. The views expressed herein do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government. Dr. Rector was supported by resources and facilities of the Minneapolis Veterans Affairs Health Care System. Drs. Carson, Anand, Haass, Lopez-Sendon, Miller, Teerlink, White, McKelvie, Komajda, Zile, McMurray, and Massie were consultants to Bristol-Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 31 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD JUN PY 2015 VL 3 IS 6 BP 429 EP 441 DI 10.1016/j.jchf.2014.12.017 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4ER UT WOS:000365652200001 PM 25982110 ER PT J AU Abraham, WT Zile, MR Weaver, FA Butter, C Ducharme, A Halbach, M Klug, D Lovett, EG Muller-Ehmsen, J Schafer, JE Senni, M Swarup, V Wachter, R Little, WC AF Abraham, William T. Zile, Michael R. Weaver, Fred A. Butter, Christian Ducharme, Anique Halbach, Marcel Klug, Didier Lovett, Eric G. Mueller-Ehmsen, Jochen Schafer, Jill E. Senni, Michele Swarup, Vijay Wachter, Rolf Little, William C. TI Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction SO JACC-HEART FAILURE LA English DT Article DE autonomic nervous system; baroreflex; device; heart failure; randomized controlled trial ID INHIBITION; METOPROLOL; SYSTEM; TRIAL; HF AB OBJECTIVES The objective of this clinical trial was to assess the safety and efficacy of carotid BAT in advanced HF. BACKGROUND Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Baroreflex activation therapy (BAT) results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity. METHODS Patients with New York Heart Association (NYHA) functional class III HF and ejection fractions <= 35% on chronic stable guideline-directed medical therapy (GDMT) were enrolled at 45 centers in the United States, Canada, and Europe. They were randomly assigned to receive ongoing GDMT alone (control group) or ongoing GDMT plus BAT (treatment group) for 6 months. The primary safety end point was system-and procedure-related major adverse neurological and cardiovascular events. The primary efficacy end points were changes in NYHA functional class, quality-of-life score, and 6-minute hall walk distance. RESULTS One hundred forty-six patients were randomized, 70 to control and 76 to treatment. The major adverse neurological and cardiovascular event-free rate was 97.2% (lower 95% confidence bound 91.4%). Patients assigned to BAT, compared with control group patients, experienced improvements in the distance walked in 6 min (59.6 +/- 14 m vs. 1.5 +/- 13.2 m; p = 0.004), quality-of-life score (-17.4 +/- 2.8 points vs. 2.1 +/- 3.1 points; p < 0.001), and NYHA functional class ranking (p = 0.002 for change in distribution). BAT significantly reduced N-terminal pro-brain natriuretic peptide (p = 0.02) and was associated with a trend toward fewer days hospitalized for HF (p = 0.08). CONCLUSIONS BAT is safe and improves functional status, quality of life, exercise capacity, N-terminal pro-brain natriuretic peptide, and possibly the burden of heart failure hospitalizations in patients with GDMT-treated NYHA functional class III HF. (C) 2015 by the American College of Cardiology Foundation. C1 [Abraham, William T.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Zile, Michael R.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. [Weaver, Fred A.] Univ So Calif, Keck Sch Med, Div Vasc Surg & Endovasc Therapy, Los Angeles, CA 90033 USA. [Butter, Christian] Med Sch Brandenburg, Immanuel Heart Ctr Bernau, Dept Cardiol, Bernau, Germany. [Ducharme, Anique] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Halbach, Marcel] Univ Hosp Cologne, Dept Internal Med 3, Cologne, Germany. [Klug, Didier] Univ Hosp, Dept Cardiol A, Lille, France. [Lovett, Eric G.] CVRx Inc, Dept Res, Minneapolis, MN USA. [Mueller-Ehmsen, Jochen] Asklepios Klin Altona, Dept Med, Hamburg, Germany. [Schafer, Jill E.] NAMSA Inc, Dept Stat, Minneapolis, MN USA. [Senni, Michele] Osped Papa Giovanni XXIII, Cardiovasc Dept, Bergamo, Italy. [Swarup, Vijay] Arizona Heart Hosp, Dept Electrophysiol, Phoenix, AZ USA. [Wachter, Rolf] Univ Med Gottingen, Clin Cardiol & Pneumol, Gottingen, Germany. [Wachter, Rolf] German Cardiovasc Res Ctr, Gottingen, Germany. [Little, William C.] Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS 39216 USA. RP Abraham, WT (reprint author), Davis Heart & Lung Res Inst, Div Cardiovasc Med, 473 West 12th Ave,Room 110P, Columbus, OH 43210 USA. EM william.abraham@osumc.edu OI Wachter, Rolf/0000-0003-2231-2200 FU CVRx, Inc. (Minneapolis, Minnesota); CVRx FX This study was funded by CVRx, Inc. (Minneapolis, Minnesota). Drs. Abraham, Little, Weaver, and Zile have received consulting fees and speaking honoraria from CVRx and are members of the CVRx Heart Failure Executive Steering Committee. Dr. Butter has received research fees from CVRx. Dr. Ducharme has received research fees and consulting fees from CVRx. Dr. Halbach has received research fees and speaking honoraria from CVRx. Dr. Klug has received research fees from CVRx. Dr. Muller-Ehmsen has received research fees and speaking honoraria from CVRx. Dr. Senni has received research fees from CVRx. Dr. Swarup has received research fees from CVRx. Dr. Wachter has received research fees and consultant fees from CVRx. Ms. Schafer is a statistical consultant for CVRx. Dr. Lovett is an employee of CVRx. NR 19 TC 33 Z9 34 U1 2 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD JUN PY 2015 VL 3 IS 6 BP 487 EP 496 DI 10.1016/j.jchf.2015.02.006 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4ER UT WOS:000365652200009 PM 25982108 ER PT J AU Lo Re, V Kallan, MJ Tate, JP Lim, JK Goetz, MB Klein, MB Rimland, D Rodriguez-Barradas, MC Butt, AA Gibert, CL Brown, ST Park, LS Dubrow, R Reddy, KR Kostman, JR Justice, AC Localio, AR AF Lo Re, Vincent, III Kallan, Michael J. Tate, Janet P. Lim, Joseph K. Goetz, Matthew Bidwell Klein, Marina B. Rimland, David Rodriguez-Barradas, Maria C. Butt, Adeel A. Gibert, Cynthia L. Brown, Sheldon T. Park, Lesley S. Dubrow, Robert Reddy, K. Rajender Kostman, Jay R. Justice, Amy C. Localio, A. Russell TI Predicting Risk of End-Stage Liver Disease in Antiretroviral-Treated Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE end-stage liver disease; hepatic decompensation; HIV; hepatitis C; HIV/HCV coinfection ID SIMPLE NONINVASIVE INDEX; VETERANS AGING COHORT; NATIONAL DEATH INDEX; HEPATITIS-C; INFECTED VETERANS; HEPATOCELLULAR-CARCINOMA; SIGNIFICANT FIBROSIS; ANTIVIRAL THERAPY; PHARMACY RECORDS; HIV AB Background. End-stage liver disease (ESLD) is an important cause of morbidity among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. Quantifying the risk of this outcome over time could help determine which coinfected patients should be targeted for risk factor modification and HCV treatment. We evaluated demographic, clinical, and laboratory variables to predict risk of ESLD in HIV/HCV-coinfected patients receiving antiretroviral therapy (ART). Methods. We conducted a retrospective cohort study among 6016 HIV/HCV-coinfected patients who received ART within the Veterans Health Administration between 1997 and 2010. The main outcome was incident ESLD, defined by hepatic decompensation, hepatocellular carcinoma, or liver-related death. Cox regression was used to develop prognostic models based on baseline demographic, clinical, and laboratory variables, including FIB-4 and aspartate aminotransferase-to-platelet ratio index, previously validated markers of hepatic fibrosis. Model performance was assessed by discrimination and decision curve analysis. Results. Among 6016 HIV/HCV patients, 532 (8.8%) developed ESLD over a median of 6.6 years. A model comprising FIB-4 and race had modest discrimination for ESLD (c-statistic, 0.73) and higher net benefit than alternative strategies of treating no or all coinfected patients at relevant risk thresholds. For FIB-4 > 3.25, ESLD risk ranged from 7.9% at 1 year to 26.0% at 5 years among non-blacks and from 2.4% at 1 year to 14.0% at 5 years among blacks. Conclusions. Race and FIB-4 provided important predictive information on ESLD risk among HIV/HCV patients. Estimating risk of ESLD using these variables could help direct HCV treatment decisions among HIV/HCV-coinfected patients. C1 [Lo Re, Vincent, III; Reddy, K. Rajender; Kostman, Jay R.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Lo Re, Vincent, III; Kallan, Michael J.; Localio, A. Russell] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Lo Re, Vincent, III; Kallan, Michael J.; Localio, A. Russell] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Lo Re, Vincent, III] Philadelphia VA Med Ctr, Med Serv, Philadelphia, PA USA. [Tate, Janet P.; Lim, Joseph K.; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Tate, Janet P.; Lim, Joseph K.; Park, Lesley S.; Dubrow, Robert; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Goetz, Matthew Bidwell] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Klein, Marina B.] McGill Univ, Ctr Hlth, Chron Viral Illness Serv, Montreal, PQ, Canada. [Rimland, David] Atlanta VA Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Butt, Adeel A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Gibert, Cynthia L.] George Washington Univ, Med Ctr, Washington DC VA Med Ctr, Washington, DC 20037 USA. [Brown, Sheldon T.] James J Peters VA Med Ctr, New York, NY USA. [Brown, Sheldon T.] Mt Sinai Sch Med, New York, NY USA. [Park, Lesley S.; Dubrow, Robert] Yale Univ, Sch Publ Hlth, New Haven, CT USA. RP Lo Re, V (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 836 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM vincentl@mail.med.upenn.edu OI Butt, Adeel/0000-0002-1118-1826; Justice, Amy/0000-0003-0139-5502 NR 41 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SUM PY 2015 VL 2 IS 3 DI 10.1093/ofid/ofv109 PG 9 WC Infectious Diseases SC Infectious Diseases GA CX6BP UT WOS:000365786500024 ER PT J AU Mwanga-Amumpaire, J Carroll, RW Baudin, E Kemigisha, E Nampijja, D Mworozi, K Santorino, D Nyehangane, D Nathan, DI De Beaudrap, P Etard, JF Feelisch, M Fernandez, BO Berssenbrugge, A Bangsberg, D Bloch, KD Boum, Y Zapol, WM AF Mwanga-Amumpaire, Juliet Carroll, Ryan W. Baudin, Elisabeth Kemigisha, Elisabeth Nampijja, Dorah Mworozi, Kenneth Santorino, Data Nyehangane, Dan Nathan, Daniel I. De Beaudrap, Pierre Etard, Jean-Franois Feelisch, Martin Fernandez, Bernadette O. Berssenbrugge, Annie Bangsberg, David Bloch, Kenneth D. Boum, Yap, II Zapol, Warren M. TI Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE cerebral malaria; methemoglobin; nitric oxide; Plasmodium falciparum ID TRAUMATIC BRAIN-INJURY; SEVERE FALCIPARUM-MALARIA; ENDOTHELIAL DYSFUNCTION; UNCOMPLICATED MALARIA; CEREBROSPINAL-FLUID; AFRICAN CHILDREN; KENYAN CHILDREN; INHALATION; MARKERS; HUMANS AB Background. Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods. This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N-2) as an adjunctive treatment for CM patients receiving intravenous artesunate. We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results. Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N-2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-alpha, interferon-., interleukin [IL]-1 beta, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels-blood methemoglobin and plasma nitrate-increased in patients treated with NO (both P<.05). Seven patients in the N-2 group and 4 patients in the NO group died. Five patients in the N-2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions. Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe, increased blood methemoglobin and plasma nitrate levels, but did not result in a greater increase of plasma Ang-1 levels at 48 hours. C1 [Mwanga-Amumpaire, Juliet; Kemigisha, Elisabeth; Mworozi, Kenneth; Nyehangane, Dan; Boum, Yap, II] Epictr Mbarara Res Ctr, Mbarara, Uganda. [Mwanga-Amumpaire, Juliet; Nampijja, Dorah; Santorino, Data; Boum, Yap, II] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Carroll, Ryan W.; Nathan, Daniel I.; Bloch, Kenneth D.; Zapol, Warren M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Carroll, Ryan W.; Bangsberg, David] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Carroll, Ryan W.] MassGen Hosp Children, Pediat Crit Care Med, Boston, MA USA. [Baudin, Elisabeth; Etard, Jean-Franois] Epictr, Paris, France. [De Beaudrap, Pierre; Etard, Jean-Franois] Univ Montpellier I, Inst Rech Dev, UMI 233, F-34006 Montpellier, France. [Feelisch, Martin; Fernandez, Bernadette O.] Univ Southampton, Southampton SO9 5NH, Hants, England. [Berssenbrugge, Annie] Ikaria, Clinton, NJ USA. [Carroll, Ryan W.; Bangsberg, David; Bloch, Kenneth D.; Zapol, Warren M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Carroll, RW (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Thier Bldg,Floor 5, Boston, MA 02114 USA. EM rcarroll4@mgh.harvard.edu OI Fernandez, Bernadette/0000-0001-6337-0381 NR 38 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SUM PY 2015 VL 2 IS 3 DI 10.1093/ofid/ofv111 PG 9 WC Infectious Diseases SC Infectious Diseases GA CX6BP UT WOS:000365786500027 ER PT J AU Rhee, C Klompas, M Tamburini, FB Fremin, BJ Chea, N Epstein, L Halpin, AL Guh, A Gallen, R Coulliette, A Gee, J Hsieh, C Desjardins, CA Pedamullu, CS DeAngelo, DJ Manzo, VE Folkerth, RD Milner, DA Pecora, N Osborne, M Chalifoux-Judge, D Bhatt, AS Yokoe, DS AF Rhee, Chanu Klompas, Michael Tamburini, Fiona B. Fremin, Brayon J. Chea, Nora Epstein, Lauren Halpin, Alison Laufer Guh, Alice Gallen, Rachel Coulliette, Angela Gee, Jay Hsieh, Candace Desjardins, Christopher A. Pedamullu, Chandra Sekhar DeAngelo, Daniel J. Manzo, Veronica E. Folkerth, Rebecca Dunn Milner, Danny A., Jr. Pecora, Nicole Osborne, Matthew Chalifoux-Judge, Diane Bhatt, Ami S. Yokoe, Deborah S. TI Epidemiologic Investigation of a Cluster of Neuroinvasive Bacillus cereus Infections in 5 Patients With Acute Myelogenous Leukemia SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE acute myelogenous leukemia; Bacillus cereus; central nervous system infection; infection control investigation ID MULTIPLE BRAIN ABSCESSES; INFLAMMATORY REACTION; MENINGITIS; BACTEREMIA; TRANSPLANTATION; MALIGNANCIES; CHILDREN AB Background. Five neuroinvasive Bacillus cereus infections (4 fatal) occurred in hospitalized patients with acute myelogenous leukemia (AML) during a 9-month period, prompting an investigation by infection control and public health officials. Methods. Medical records of case-patients were reviewed and a matched case-control study was performed. Infection control practices were observed. Multiple environmental, food, and medication samples common to AML patients were cultured. Multilocus sequence typing was performed for case and environmental B cereus isolates. Results. All 5 case-patients received chemotherapy and had early-onset neutropenic fevers that resolved with empiric antibiotics. Fever recurred at a median of 17 days (range, 9-20) with headaches and abrupt neurological deterioration. Case-patients had B cereus identified in central nervous system (CNS) samples by (1) polymerase chain reaction or culture or (2) bacilli seen on CNS pathology stains with high-grade B cereus bacteremia. Two case-patients also had colonic ulcers with abundant bacilli on autopsy. No infection control breaches were observed. On case-control analysis, bananas were the only significant exposure shared by all 5 case-patients (odds ratio, 9.3; P =.04). Five environmental or food isolates tested positive for B cereus, including a homogenized banana peel isolate and the shelf of a kitchen cart where bananas were stored. Multilocus sequence typing confirmed that all case and environmental strains were genetically distinct. Multilocus sequence typing-based phylogenetic analysis revealed that the organisms clustered in 2 separate clades. Conclusions. The investigation of this neuroinvasive B cereus cluster did not identify a single point source but was suggestive of a possible dietary exposure. Our experience underscores the potential virulence of B cereus in immunocompromised hosts. C1 [Rhee, Chanu; Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Rhee, Chanu; Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Rhee, Chanu; Klompas, Michael; Yokoe, Deborah S.] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Folkerth, Rebecca Dunn; Milner, Danny A., Jr.; Pecora, Nicole] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Tamburini, Fiona B.; Fremin, Brayon J.; Manzo, Veronica E.; Bhatt, Ami S.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Chea, Nora; Epstein, Lauren; Halpin, Alison Laufer; Guh, Alice; Coulliette, Angela] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA USA. [Gallen, Rachel] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Gee, Jay] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Chea, Nora; Epstein, Lauren; Coulliette, Angela] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Div Sci Educ & Profess Dev, Atlanta, GA USA. [Desjardins, Christopher A.; Pedamullu, Chandra Sekhar] Broad Inst, Cambridge, MA USA. [Pedamullu, Chandra Sekhar; DeAngelo, Daniel J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Osborne, Matthew] Massachusetts Dept Publ Hlth, Div Epidemiol & Immunizat, Jamaica Plain, MA USA. [Chalifoux-Judge, Diane] Boston Inspect Serv Dept, Boston, MA USA. RP Bhatt, AS (reprint author), Stanford Univ, Med & Genet, 269 Campus Dr,CCSR1155b, Stanford, CA 94305 USA. EM asbhatt@stanford.edu RI Laufer Halpin, Alison/E-5453-2015 OI Laufer Halpin, Alison/0000-0003-1643-1617 NR 27 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SUM PY 2015 VL 2 IS 3 DI 10.1093/ofid/ofv096 PG 7 WC Infectious Diseases SC Infectious Diseases GA CX6BP UT WOS:000365786500029 ER PT J AU Stempel, JM Hammond, SP Sutton, DA Weiser, LM Marty, FM AF Stempel, Jessica M. Hammond, Sarah P. Sutton, Deanna A. Weiser, Linda M. Marty, Francisco M. TI Invasive Fusariosis in the Voriconazole Era: Single-Center 13-Year Experience SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE fungal disease; fusarium; invasive fusariosis; terbinafine; voriconazole ID STEM-CELL TRANSPLANTATION; VITRO ANTIFUNGAL SUSCEPTIBILITY; LIPOSOMAL AMPHOTERICIN-B; MYCOSES STUDY-GROUP; FUNGAL-INFECTIONS; EUROPEAN-ORGANIZATION; SALVAGE TREATMENT; SPECIES COMPLEX; TERBINAFINE; COMBINATION AB Background. Invasive fusariosis remains an aggressive, albeit infrequent infection in immunocompromised patients. Methods. We identified all cases of invasive fusariosis between January 2002 and December 2014. We recorded patient characteristics including clinical presentation, treatment, and outcomes at 6 and 12 weeks after diagnosis, as well as species identification and antifungal drug susceptibilities. Results. Fifteen patients were diagnosed with proven (12, 80%) or probable (3, 20%) fusariosis. Median age was 60 years (range, 26-78), and 10 patients were male. Underlying conditions included hematological malignancies (13, 87%), juvenile idiopathic arthritis (1, 7%), and third-degree burns (1, 7%). Five patients underwent hematopoietic stem-cell transplantation before diagnosis. Six patients (40%) received systemic glucocorticoids, and 11 patients (73%) had prolonged neutropenia at the time of diagnosis. Clinical presentations included the following: skin/ soft tissue infection (8, 53%), febrile neutropenia (4, 27%), respiratory tract infection (2, 13%), and septic arthritis (1, 7%). Twelve patients were treated with voriconazole: 6 (40%) with voriconazole alone, 4 (27%) with voriconazole and terbinafine, and 2 (13%) with voriconazole, terbinafine, and amphotericin. One patient (7%) was treated with terbinafine alone, and another with micafungin alone. Four patients underwent surgical debridement (4, 27%). Susceptibility testing was performed on 9 isolates; 8 demonstrated voriconazole minimum inhibitory concentrations >= 4 mu g/mL. The cumulative probability of survival was 66.7% and 53.3% at 6 and 12 weeks after diagnosis. Conclusions. Mortality associated with invasive fusariosis remains high. Cumulative mortality at our center was lower than previous reports despite elevated voriconazole minimum inhibitory concentrations. Combination therapy should be studied systematically for fusariosis. C1 [Stempel, Jessica M.; Hammond, Sarah P.; Weiser, Linda M.; Marty, Francisco M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Stempel, Jessica M.; Hammond, Sarah P.; Marty, Francisco M.] Harvard Univ, Sch Med, Boston, MA USA. [Hammond, Sarah P.; Marty, Francisco M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sutton, Deanna A.] Univ Texas Hlth Sci Ctr San Antonio, Fungus Testing Lab, San Antonio, TX 78229 USA. RP Stempel, JM (reprint author), Brigham & Womens Hosp, 75 Francis St,PBB A4, Boston, MA 02115 USA. EM stempel.jessica@gmail.com NR 33 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SUM PY 2015 VL 2 IS 3 DI 10.1093/ofid/ofv099 PG 6 WC Infectious Diseases SC Infectious Diseases GA CX6BP UT WOS:000365786500034 ER PT J AU Ghezzi, A Karlsson, G Haering, D Gartner, J Chitnis, T Pohl, D Putzki, N AF Ghezzi, A. Karlsson, G. Haering, D. Gaertner, J. Chitnis, T. Pohl, D. Putzki, N. TI Safety and effect of fingolimod on no evidence of disease activity (NEDA-4) in young adult patients with relapsing-remitting multiple sclerosis SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 1st Congress of the European-Academy-of-Neurology CY JUN, 2015 CL Berlin, GERMANY SP European Acad Neurol C1 [Ghezzi, A.] Ctr Studi Sclerosi Multipla, Gallarate, Italy. [Karlsson, G.; Haering, D.; Putzki, N.] Novartis Pharma AG, Basel, Switzerland. [Gaertner, J.] Univ Med, Dept Pediat & Adolescent Med, Gottingen, Germany. [Chitnis, T.] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Pohl, D.] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. 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 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD JUN PY 2015 VL 22 SU 1 SI SI MA F4120 BP 825 EP 825 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CV4LR UT WOS:000364239000625 ER PT J AU Luks, AM Swenson, ER AF Luks, Andrew M. Swenson, Erik R. TI Evaluating the Risks of High Altitude Travel in Chronic Liver Disease Patients SO HIGH ALTITUDE MEDICINE & BIOLOGY LA English DT Article DE altitude illness; cirrhosis; clinical hepatology; hepatopulmonary syndrome; hypoxia; portopulmonary hypertension ID ACUTE MOUNTAIN-SICKNESS; RIGHT PULMONARY-ARTERY; FACTOR-DEPENDENT PRODUCTION; HEPATIC TISSUE OXYGENATION; CONGENITAL HEART-DISEASE; CHRONIC KIDNEY-DISEASE; HEPATOPULMONARY SYNDROME; AIR-TRAVEL; PORTOPULMONARY HYPERTENSION; PROFIBROTIC MEDIATORS AB Luks, Andrew M., and Erik R. Swenson. Clinician's Corner: Evaluating the risks of high altitude travel in chronic liver disease patients. High Alt Med Biol 16:80-88, 2015.With improvements in the quality of health care, people with chronic medical conditions are experiencing better quality of life and increasingly participating in a wider array of activities, including travel to high altitude. Whenever people with chronic diseases travel to this environment, it is important to consider whether the physiologic responses to hypobaric hypoxia will interact with the underlying medical condition such that the risk of acute altitude illness is increased or the medical condition itself may worsen. This review considers these questions as they pertain to patients with chronic liver disease. While the limited available evidence suggests there is no evidence of liver injury or dysfunction in normal individuals traveling as high as 5000m, there is reason to suspect that two groups of cirrhosis patients are at increased risk for problems, hepatopulmonary syndrome patients, who are at risk for severe hypoxemia following ascent, and portopulmonary hypertension patients who may be at risk for high altitude pulmonary edema and acute right ventricular dysfunction. While liver transplant patients may tolerate high altitude exposure without difficulty, no information is available regarding the risks of long-term residence at altitude with chronic liver disease. All travelers with cirrhosis require careful pre-travel evaluation to identify conditions that might predispose to problems at altitude and develop risk mitigation strategies for these issues. Patients also require detailed counseling about recognition, prevention, and treatment of acute altitude illness and may require different medication regimens to prevent or treat altitude illness than used in healthy individuals. C1 [Luks, Andrew M.] Univ Washington, Div Pulm & Crit Care Med, Dept Med, Seattle, WA 98104 USA. [Swenson, Erik R.] VA Puget Sound Hlth Care Syst, Div Pulm & Crit Care Med, Seattle, WA USA. RP Luks, AM (reprint author), Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care Med, 325 Ninth Ave,Box 359762, Seattle, WA 98103 USA. EM aluks@u.washington.edu NR 93 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1527-0297 EI 1557-8682 J9 HIGH ALT MED BIOL JI High Alt. Med. Biol. PD JUN 1 PY 2015 VL 16 IS 2 BP 80 EP 88 DI 10.1089/ham.2014.1122 PG 9 WC Biophysics; Public, Environmental & Occupational Health; Sport Sciences SC Biophysics; Public, Environmental & Occupational Health; Sport Sciences GA CU9YG UT WOS:000363902400003 PM 25844541 ER PT J AU Greenblatt, E Winkler, T Harris, RS Kelly, VJ Kone, M Katz, I Martin, AR Caillibotte, G Venegas, J AF Greenblatt, Elliot Winkler, Tilo Harris, Robert Scott Kelly, Vanessa Jane Kone, Mamary Katz, Ira Martin, Andrew R. Caillibotte, Georges Venegas, Jose TI FACTORS AFFECTING SPATIAL HETEROGENEITY IN AEROSOL DEPOSITION: A QUANTITATIVE IMAGING STUDY SO JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY LA English DT Meeting Abstract C1 [Greenblatt, Elliot; Winkler, Tilo; Harris, Robert Scott; Kelly, Vanessa Jane; Kone, Mamary; Venegas, Jose] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Greenblatt, Elliot; Winkler, Tilo; Harris, Robert Scott; Kelly, Vanessa Jane; Kone, Mamary; Venegas, Jose] Harvard Univ, Sch Med, Boston, MA USA. [Katz, Ira; Caillibotte, Georges] Air Liquide Sante Int, R&D Med, Les Loges En Josas, France. [Katz, Ira; Caillibotte, Georges] Lafayette Coll, Dept Mech Engn, Easton, PA 18042 USA. [Martin, Andrew R.] Univ Alberta, Edmonton, AB T6G 2M7, Canada. RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1941-2711 EI 1941-2703 J9 J AEROSOL MED PULM D JI J. Aerosol Med. Pulm. Drug Deliv. PD JUN 1 PY 2015 VL 28 IS 3 MA P-107 BP A34 EP A34 PG 1 WC Respiratory System SC Respiratory System GA CV0IR UT WOS:000363934900113 ER PT J AU Venegas, J Greenblatt, E Kelly, VJ Winkler, T Kone, M Katz, I Martin, AR Caillibotte, G Hess, D Harris, RS AF Venegas, Jose Greenblatt, Elliot Kelly, Vanessa Jane Winkler, Tilo Kone, Mamary Katz, Ira Martin, Andrew R. Caillibotte, Georges Hess, Dean Harris, Robert Scott TI REGIONAL VENTILATION AND AEROSOL DEPOSITION IN THE LUNG UNDER HELIUM-OXYGEN BREATHING SO JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY LA English DT Meeting Abstract C1 [Venegas, Jose; Greenblatt, Elliot; Kelly, Vanessa Jane; Winkler, Tilo; Kone, Mamary; Hess, Dean; Harris, Robert Scott] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Venegas, Jose; Greenblatt, Elliot; Kelly, Vanessa Jane; Winkler, Tilo; Kone, Mamary; Hess, Dean; Harris, Robert Scott] Harvard Univ, Sch Med, Boston, MA USA. [Greenblatt, Elliot] MIT, Boston, MA USA. [Katz, Ira; Caillibotte, Georges] Air Liquide Sante Int, R&D Med, Les Loges En Josas, France. [Katz, Ira] Lafayette Coll, Dept Mech Engn, Easton, PA 18042 USA. [Martin, Andrew R.] Univ Alberta, Edmonton, AB T6G 2M7, Canada. RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1941-2711 EI 1941-2703 J9 J AEROSOL MED PULM D JI J. Aerosol Med. Pulm. Drug Deliv. PD JUN 1 PY 2015 VL 28 IS 3 MA P-070 BP A32 EP A32 PG 1 WC Respiratory System SC Respiratory System GA CV0IR UT WOS:000363934900105 ER PT J AU Hao, K Di Narzo, AF Ho, L Luo, W Li, SY Chen, R Li, TB Dubner, L Pasinetti, GM AF Hao, Ke Di Narzo, Antonio Fabio Ho, Lap Luo, Wei Li, Shuyu Chen, Rong Li, Tongbin Dubner, Lauren Pasinetti, Giulio Maria TI Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Alzheimer's disease; Type 2 diabetes; GWAS; Shared genomic component; eQTLs; Pathway ID METABOLIC SYNDROME; SUSCEPTIBILITY LOCI; SYNAPTIC PLASTICITY; SIGNALING PATHWAYS; INFLAMMATION; ASSOCIATION; ANNOTATION; INSIGHTS; COHORT; RISK AB Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer's disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS metaanalysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and coexpression networks. We found 927 SNPs associated with both AD and T2D with p-value <= 0.01, an overlap significantly larger than random chance (overlapping p-value of 6.93E-28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa. Collectively, our GWAS studies tentatively support the epidemiological observation of disease concordance between T2D and AD. Moreover, the studies provide the much needed information for the design of future novel therapeutic approaches, for a subpopulation of T2D subjects with genetic disposition to AD, that could benefit T2D and reduce the risk for subsequent development of AD. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Hao, Ke; Di Narzo, Antonio Fabio; Luo, Wei; Li, Shuyu; Chen, Rong] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Hao, Ke; Di Narzo, Antonio Fabio; Li, Shuyu; Chen, Rong] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Luo, Wei] Huaqiao Univ, Coll Comp Sci & Technol, Xiamen 361021, Peoples R China. [Li, Tongbin] AccuraSci LLC, Johnston, IA USA. [Pasinetti, Giulio Maria] James J Peters Vet Affairs Med Ctr, GRECC, Bronx, NY USA. RP Pasinetti, GM (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, One Gustave L Levy Pl, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU Icahn School of Medicine at Mount Sinai; Altschul Foundation; National Natural Science Foundation of China [21477087]; CADgenomics grant of Leduqc Foundation [0266-2493]; Fujian Province Overseas Studying Fellowship FX This study was supported by discretionary funding from the Icahn School of Medicine at Mount Sinai to Dr. Giulio Pasinetti and in part by the Altschul Foundation. In addition, Dr. Pasinetti holds a Career Scientist Award in the Research and Development unit and is the Director of the Basic and Biomedical Research and Training Program, GRECC, James J. Peters Veterans Affairs Medical Center. We acknowledge that the contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Hao K is partially supported by National Natural Science Foundation of China (Grant No. 21477087). Hao K is also partially supported by CADgenomics grant of Leduqc Foundation (Grant #0266-2493) as co-Investigator. Luo W is partially supported by Fujian Province Overseas Studying Fellowship. NR 46 TC 7 Z9 7 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 EI 1872-9452 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD JUN-OCT PY 2015 VL 43-44 SI SI BP 66 EP 76 DI 10.1016/j.mam.2015.06.006 PG 11 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA CV4VC UT WOS:000364263600007 PM 26116273 ER PT J AU Randolph, GW Sritharan, N Song, P Franco, R Kamani, D Woodson, G AF Randolph, Gregory W. Sritharan, Niranjan Song, Phil Franco, Ramon Kamani, Dipti Woodson, Gayle TI Y Thyroidectomy in the Professional Singer-Neural Monitored Surgical Outcomes SO THYROID LA English DT Article ID RECURRENT LARYNGEAL NERVE; PARATHYROID SURGERY; SINGING VOICE; INJURY; COMPLICATIONS; PARALYSIS; STATEMENT; DIAGNOSIS; SPEAKING; BRANCH AB Background: Voice changes commonly occur from thyroidectomy and may be due to neural or nonneural causes. Such changes can be a source of significant morbidity for any patient, but thyroidectomy in the professional singer carries special significance. We test the hypothesis that the career of singers and professional voice users is not impaired after neural monitored thyroid surgery. Methods: A quantitative analysis of pre- and postoperative neural monitored thyroid surgery voice outcomes utilizing three validated vocal instrumentsVoice Handicap Index (VHI), Singing Voice Handicap Index (SVHI), and Evaluation of Ability to Sing Easily (EASE)in a unique series of professional singers/voice users was performed. Additional quantitative analysis related to final intraoperative electromyography (EMG) amplitude, the time to return to performance, and vocal parameters affected during this interval was performed. Results: Twenty-seven vocal professionals undergoing thyroidectomy were identified, of whom 60% had surgery for thyroid cancer. Pre- and postsurgery flexible fiberoptic laryngeal exams were normal in all patients. Return to performance rate was 100%, and mean time to performance was 2.26 months (1.61). All three vocal instrument mean scores, pre-op vs. post-op, were unchanged: VHI, 4.15 (+/- 5.22) vs. 4.04 (+/- 3.85), p=0.9301; SVHI, 11.26 (+/- 14.41) vs.12.07 (+/- 13.09), p=0.8297; and EASE, 6.19 (+/- 9.19) vs. 6.00 (+/- 7.72), p=0.9348. The vocal parameters most affected from surgery until first performances were vocal fatigue (89%), high range (89%), pitch control and modulation (74%), and strength (81%). Final mean intraoperative EMG amplitude was within normal limits for intraoperative stimulation and had no relationship with time to first professional performance (p=0.7199). Conclusions: Neural monitored thyroidectomy, including for thyroid malignancy, in professional voice users is safe without any changes in three different voice/singing instruments, with 100% return to performance. Intraoperative EMG data at the conclusion of surgery and postoperative laryngeal exam were normal in all patients. Specific vocal parameters are transiently affected during the postoperative recovery phase, which is important to outline in the consent process of this unique patient population and may provide insight into the physiologic state of the larynx subsequent to thyroid surgery. C1 [Randolph, Gregory W.; Sritharan, Niranjan; Kamani, Dipti] Massachusetts Eye & Ear Infirm, Div Thyroid, Boston, MA 02114 USA. [Randolph, Gregory W.; Sritharan, Niranjan; Kamani, Dipti] Massachusetts Eye & Ear Infirm, Div Parathyroid Surg, Boston, MA 02114 USA. [Song, Phil; Franco, Ramon] Massachusetts Eye & Ear Infirm, Div Laryngol, Boston, MA 02114 USA. [Randolph, Gregory W.] Massachusetts Gen Hosp, Div Surg Oncol, Endocrine Surg Serv, Boston, MA 02114 USA. [Woodson, Gayle] Southern Illinois Sch Med, Div Otolaryngol Head & Neck Surg, Springfield, IL USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Gregory_Randolph@meei.harvard.edu FU John and Claire Bertucci Thyroid Research Fund FX This work was funded by the John and Claire Bertucci Thyroid Research Fund. NR 36 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JUN 1 PY 2015 VL 25 IS 6 BP 665 EP 671 DI 10.1089/thy.2014.0467 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU9WN UT WOS:000363897500008 PM 25790153 ER PT J AU McLean, DJ Diaz-Gil, D Farhan, HN Ladha, KS Kurth, T Eikermann, M AF McLean, Duncan J. Diaz-Gil, Daniel Farhan, Hassan N. Ladha, Karim S. Kurth, Tobias Eikermann, Matthias TI Dose-dependent Association between Intermediate-acting Neuromuscular-blocking Agents and Postoperative Respiratory Complications SO ANESTHESIOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; POSTANESTHESIA CARE-UNIT; NONCARDIAC SURGERY; NEOSTIGMINE REVERSAL; TRACHEAL INTUBATION; RESIDUAL PARALYSIS; PULMONARY-FUNCTION; BODY-WEIGHT; BLOCKADE; ANESTHESIA AB Background: Duration of action increases with repeated administration of neuromuscular-blocking agents, and intraoperative use of high doses of neuromuscular-blocking agent may affect respiratory safety. Methods: In a hospital-based registry study on 48,499 patients who received intermediate-acting neuromuscular-blocking agents, the authors tested the primary hypothesis that neuromuscular-blocking agents are dose dependently associated with the risk of postoperative respiratory complications. In the secondary analysis, the authors evaluated the association between neostigmine dose given for reversal of neuromuscular-blocking agents and respiratory complications. Post hoc, the authors evaluated the effects of appropriate neostigmine reversal (neostigmine 60 g/kg after recovery of train-of-four count of 2) on respiratory complications. The authors controlled for patient-, anesthesia-, and surgical complexity-related risk factors. Results: High doses of neuromuscular-blocking agents were associated with an increased risk of postoperative respiratory complications (n = 644) compared with low doses (n = 205) (odds ratio [OR], 1.28; 95% CI, 1.04 to 1.57). Neostigmine was associated with a dose-dependent increase in the risk of postoperative respiratory complications (OR, 1.51; 95% CI, 1.25 to 1.83). Post hoc analysis revealed that appropriate neostigmine reversal eliminated the dose-dependent association between neuromuscular-blocking agents and respiratory complications (for neuromuscular-blocking agent effects with appropriate reversal: OR, 0.98; 95% CI, 0.63 to 1.52). Conclusions: The use of neuromuscular-blocking agents was dose dependently associated with increased risk of postoperative respiratory complications. Neostigmine reversal was also associated with a dose-dependent increase in the risk of respiratory complications. However, the exploratory data analysis suggests that the proper use of neostigmine guided by neuromuscular transmission monitoring results can help eliminate postoperative respiratory complications associated with the use of neuromuscular-blocking agents. C1 [McLean, Duncan J.; Diaz-Gil, Daniel; Farhan, Hassan N.; Ladha, Karim S.; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Kurth, Tobias] INSERM, Res Ctr Epidemiol & Biostat, U897, Team Neuroepidemiol, Bordeaux, France. [Kurth, Tobias] Univ Bordeaux, Coll Hlth Sci, Bordeaux, France. [Kurth, Tobias] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Eikermann, Matthias] Univ Klinkum Duisburg Essen, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 FU Buzen Fund FX This project was supported by an unrestricted research grant from the Buzen Fund, established by Jeffrey Buzen, Ph.D., and Judith Buzen of Boston, Massachusetts. NR 60 TC 19 Z9 19 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUN PY 2015 VL 122 IS 6 BP 1201 EP 1213 DI 10.1097/ALN.0000000000000674 PG 13 WC Anesthesiology SC Anesthesiology GA CU4XJ UT WOS:000363534400007 PM 25919486 ER EF