FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chang, MS Barton, K Crockett, M Tuomala, RE Rutherford, AE Mutinga, ML Andersson, KL Brown, RS Oken, E Ukomadu, C AF Chang, Matthew S. Barton, Kerri Crockett, Molly Tuomala, Ruth E. Rutherford, Anna E. Mutinga, Muthoka L. Andersson, Karin L. Brown, Robert S., Jr. Oken, Emily Ukomadu, Chinweike TI Postpartum Laboratory Follow-up in Women With Hepatitis B in Massachusetts From 2007 to 2012 SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article; Proceedings Paper CT 55th Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract (SSAT) / Digestive Disease Week (DDW) CY MAY 02-06, 2014 CL Chicago, IL SP Soc Surg Alimentary Tract DE access; adherence; guidelines; surveillance ID VIRUS INFECTION; HEPATOCELLULAR-CARCINOMA; COST-EFFECTIVENESS; UNITED-STATES AB Background: Screening for HBV infection in pregnant women is standard of care. Guidelines recommend that patients with chronic HBV have ongoing care and laboratory testing, but little is known about postpartum maternal HBV care outcomes. Study: We conducted a retrospective cohort study using Massachusetts Virtual Epidemiologic Network, an electronic public health surveillance system maintained by the Massachusetts Department of Public Health. We identified women who tested hepatitis B surface antigen positive during their first reported (index) pregnancy in Massachusetts from 2007 to 2012 and measured HBV-related laboratory tests reported to Massachusetts Department of Public Health during and after pregnancy. Results: We identified 983 hepatitis B surface antigen positive pregnant women. Half (492/983) did not have evidence of additional postpartum HBV laboratory testing following their index pregnancy. Women who had postpartum laboratory tests reported were younger [mean age (SD): 29 (5.3) vs. 31 (5.5) y, P = 0.0001] and more likely to have >1 pregnancy during the study period (41% vs. 1%, P < 0.0001). There were no differences in race, ethnicity, and US born status. On multivariable logistic regression, older age predicted a lower likelihood of having postpartum laboratory testing (odds ratio, 0.77; 95% confidence interval, 0.70-0.90). Conclusions: Postpartum maternal HBV follow-up laboratory testing occurred in only half of Massachusetts women and did not vary by race, ethnicity, or US born status. Our results were limited to a single state surveillance database, which likely underestimates the number of tests ordered. C1 [Chang, Matthew S.; Rutherford, Anna E.; Mutinga, Muthoka L.; Ukomadu, Chinweike] Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy, 75 Francis St, Boston, MA 02115 USA. [Tuomala, Ruth E.] Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. [Barton, Kerri; Crockett, Molly] Massachusetts Dept Publ Hlth, Bureau Infect Dis, Boston, MA USA. [Andersson, Karin L.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Oken, Emily] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Oken, Emily] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Brown, Robert S., Jr.] Columbia Univ Coll Phys & Surg, Ctr Liver Dis & Transplantat, 630 W 168th St, New York, NY 10032 USA. [Ukomadu, Chinweike] Novartis Inst Biomed Res, Cambridge, MA USA. RP Chang, MS (reprint author), Stanford Univ, Sch Med, Div Gastroenterol & Hepatol, 300 Pasteur Dr,Rm M211, Palo Alto, CA 94304 USA. EM matthew.chang@stanford.edu FU NICHD NIH HHS [K24 HD069408] 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 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD JUL PY 2016 VL 50 IS 6 BP E60 EP E64 DI 10.1097/MCG.0000000000000530 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR1MH UT WOS:000379669100002 PM 27092430 ER PT J AU Vasconcelos, RM Sanfilippo, N Paster, BJ Kerr, AR Li, Y Ramalho, L Queiroz, EL Smith, B Sonis, ST Corby, PM AF Vasconcelos, R. M. Sanfilippo, N. Paster, B. J. Kerr, A. R. Li, Y. Ramalho, L. Queiroz, E. L. Smith, B. Sonis, S. T. Corby, P. M. TI Host-Microbiome Cross-talk in Oral Mucositis SO JOURNAL OF DENTAL RESEARCH LA English DT Review DE cancer; oral microbiome; Toll-like receptor; pathogen-associated molecular pattern; damage-associated molecular pattern; cancer complications ID STEM-CELL TRANSPLANTATION; NECK-CANCER PATIENTS; RECEIVING STOMATOTOXIC CHEMOTHERAPY; BONE-MARROW-TRANSPLANTATION; DOUBLE-BLIND; SELECTIVE ELIMINATION; INDUCTION CHEMOTHERAPY; CLINICAL-TRIAL; PHASE-III; HEAD AB Oral mucositis (OM) is among the most common, painful, and debilitating toxicities of cancer regimen-related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Novel discoveries in OM have focused on understanding the host-microbial interactions, because current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations, affecting tissue healing. Additional comprehensive and disciplined clinical investigation is needed to carefully characterize the relationship between the clinical trajectory of OM, the local levels of inflammatory changes (both clinical and molecular), and the ebb and flow of the oral microbiota. Answering such questions will increase our knowledge of the mechanisms engaged by the oral immune system in response to mucositis, facilitating their translation into novel therapeutic approaches. In doing so, directed clinical strategies can be developed that specifically target those times and tissues that are most susceptible to intervention. C1 [Vasconcelos, R. M.; Sanfilippo, N.; Smith, B.; Corby, P. M.] NYU, Sch Med, One Pk Ave, New York, NY 10010 USA. [Vasconcelos, R. M.; Kerr, A. R.; Li, Y.; Queiroz, E. L.; Corby, P. M.] NYU, Coll Dent, One Pk Ave, New York, NY 10010 USA. [Vasconcelos, R. M.; Ramalho, L.] Univ Fed Bahia, Fac Odontol, Salvador, BA, Brazil. [Sanfilippo, N.; Smith, B.] NYU, Perlmutter Canc Ctr, One Pk Ave, New York, NY 10010 USA. [Paster, B. J.] Forsyth Inst, Cambridge, MA USA. [Paster, B. J.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Sonis, S. T.] Biomodels LLC, Watertown, MA USA. [Sonis, S. T.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Sonis, S. T.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Corby, PM (reprint author), NYU, Sch Med, One Pk Ave, New York, NY 10010 USA.; Sonis, ST (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 75 Francis St, Boston, MA 02115 USA. EM ssonis@Biomodels.com; Patricia.Corby@nyumc.org FU New York University (NYU) Provost's Mega-Grants Initiative; National Institutes of Health National Center for Advancing Translational Sciences (CTSA) [1UL1 TR001445]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior [CAPES - 9162-13-5] FX This study was supported by the New York University (NYU) Provost's Mega-Grants Initiative, a Philanthropic Gift from Marty and Connie Silver (to study effects of radiation therapy in patients with head and neck cancer), the National Institutes of Health National Center for Advancing Translational Sciences (CTSA grant 1UL1 TR001445 to NYU), and the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES - 9162-13-5). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 52 TC 3 Z9 3 U1 7 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2016 VL 95 IS 7 BP 725 EP 733 DI 10.1177/0022034516641890 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DQ9UQ UT WOS:000379555200001 PM 27053118 ER PT J AU Kaye, EK Chen, N Cabral, HJ Vokonas, P Garcia, RI AF Kaye, E. K. Chen, N. Cabral, H. J. Vokonas, P. Garcia, R. I. TI Metabolic Syndrome and Periodontal Disease Progression in Men SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE periodontitis; bone loss; epidemiology; risk factors; systemic health/disease; Metabolic Syndrome X ID SCIENTIFIC STATEMENT; JAPANESE ADULTS; OLDER-ADULTS; ORAL-HEALTH; US ADULTS; ASSOCIATION; ADIPOSITY AB Metabolic syndrome, a cluster of 3 or more risk factors for cardiovascular disease, is associated with periodontal disease, but few studies have been prospective in design. This study's aim was to determine whether metabolic syndrome predicts tooth loss and worsening of periodontal disease in a cohort of 760 men in the Department of Veterans Affairs Dental Longitudinal Study and Normative Aging Study who were followed up to 33 y from 1981 to 2013. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer. Waist circumference was measured in units of 0.1 cm following a normal expiration. Fasting blood samples were measured in duplicate for glucose, triglyceride, and high-density lipoprotein. Calibrated periodontists served as dental examiners. Periodontal outcome events on each tooth were defined as progression to predefined threshold levels of probing pocket depth (>= 5 mm), clinical attachment loss (>= 5 mm), mobility (>= 0.5 mm), and alveolar bone loss (>= 40% of the distance from the cementoenamel junction to the root apex, on radiographs). Hazards ratios (95% confidence intervals) of tooth loss or a periodontitis event were estimated from tooth-level extended Cox proportional hazards regression models that accounted for clustering of teeth within individuals and used time-dependent status of metabolic syndrome. Covariates included age, education, smoking status, plaque level, and initial level of the appropriate periodontal disease measure. Metabolic syndrome as defined by the International Diabetes Federation increased the hazards of tooth loss (1.39; 1.08 to 1.79), pocket depth >= 5 mm (1.37; 1.14 to 1.65), clinical attachment loss >= 5 mm (1.19; 1.00 to 1.41), alveolar bone loss >= 40% (1.25; 1.00 to 1.56), and tooth mobility >= 0.5 mm (1.43; 1.07 to 1.89). The number of positive metabolic syndrome conditions was also associated with each of these outcomes. These findings suggest that the metabolic disturbances that comprise the metabolic syndrome may play a role in the development or worsening of periodontitis. C1 [Kaye, E. K.; Garcia, R. I.] Boston Univ, Henry M Goldman Sch Dent Med, Dept Hlth Policy & Hlth Serv Res, 560 Harrison Ave, Boston, MA 02118 USA. [Kaye, E. K.; Vokonas, P.; Garcia, R. I.] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA USA. [Chen, N.] Boston Univ, Sch Med, Dept Pediat, 560 Harrison Ave, Boston, MA 02118 USA. [Cabral, H. J.] Boston Univ, Sch Publ Hlth, Dept Biostat, 560 Harrison Ave, Boston, MA 02118 USA. [Vokonas, P.] Boston Univ, Sch Med, Dept Med, Div Prevent Med & Epidemiol, 560 Harrison Ave, Boston, MA 02118 USA. [Vokonas, P.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, 560 Harrison Ave, Boston, MA 02118 USA. RP Kaye, EK (reprint author), Boston Univ, Henry M Goldman Sch Dent Med, Dept Hlth Policy & Hlth Serv Res, 560 Harrison Ave, Boston, MA 02118 USA. EM kralle@bu.edu FU National Institute of Dental and Craniofacial Research [R03 DE021730]; US Department of Veterans Affairs Cooperative Studies Program FX This study was supported by the National Institute of Dental and Craniofacial Research (R03 DE021730). The Dental Longitudinal Study and the Normative Aging Study are components of the Massachusetts Veterans Epidemiology Research and Information Center, which is supported by the US Department of Veterans Affairs Cooperative Studies Program. Views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 29 TC 1 Z9 1 U1 5 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2016 VL 95 IS 7 BP 822 EP 828 DI 10.1177/0022034516641053 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DQ9UQ UT WOS:000379555200013 PM 27025874 ER PT J AU Fine, N Hassanpour, S Borenstein, A Sima, C Oveisi, M Scholey, J Cherney, D Glogauer, M AF Fine, N. Hassanpour, S. Borenstein, A. Sima, C. Oveisi, M. Scholey, J. Cherney, D. Glogauer, M. TI Distinct Oral Neutrophil Subsets Define Health and Periodontal Disease States SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE inflammation; chronic periodontitis; immunologic surface markers; cell degranulation; neutrophil extracellular traps; reactive oxygen species ID LOW-DENSITY GRANULOCYTES; HUMAN PERIPHERAL-BLOOD; EXTRACELLULAR TRAPS; DIAGNOSTIC MARKER; FLOW-CYTOMETRY; INFLAMMATION; EXPRESSION; QUANTIFICATION; IDENTIFICATION; PATHOGENESIS AB Neutrophils exit the vasculature and swarm to sites of inflammation and infection. However, these cells are abundant in the healthy, inflammation-free human oral environment, suggesting a unique immune surveillance role within the periodontium. We hypothesize that neutrophils in the healthy oral cavity occur in an intermediary parainflammatory state that allows them to interact with and contain the oral microflora without eliciting a marked inflammatory response. Based on a high-throughput screen of neutrophil CD ( cluster of differentiation) marker expression and a thorough literature review, we developed multicolor flow cytometry panels to determine the surface marker signatures of oral neutrophil subsets in periodontal health and disease. We define here 3 distinct neutrophil subsets: resting/naive circulatory neutrophils, parainflammatory neutrophils found in the healthy oral cavity, and proinflammatory neutrophils found in the oral cavity during chronic periodontal disease. Furthermore, parainflammatory neutrophils manifest as 2 distinct subpopulations-based on size, granularity, and expression of specific CD markers-and exhibit intermediate levels of activation as compared with the proinflammatory oral neutrophils. These intermediately activated parainflammatory populations occur in equal proportions in the healthy oral cavity, with a shift to one highly activated proinflammatory neutrophil population in chronic periodontal disease. This work is the first to identify and characterize oral parainflammatory neutrophils that interact with commensal biofilms without inducing an inflammatory response, thereby demonstrating that not all neutrophils trafficking through periodontal tissues are fully activated. In addition to establishing possible diagnostic and treatment monitoring biomarkers, this oral neutrophil phenotype model builds on existing literature suggesting that the healthy periodontium may be in a parainflammatory state. C1 [Fine, N.; Hassanpour, S.; Borenstein, A.; Oveisi, M.; Glogauer, M.] Univ Toronto, Matrix Dynam Grp, Dept Dent, Toronto, ON, Canada. [Sima, C.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Sima, C.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Scholey, J.; Cherney, D.] Univ Hlth Network, Dept Med, Div Nephrol, Toronto, ON, Canada. RP Glogauer, M (reprint author), Univ Toronto, Fac Dent, Matrix Dynam Grp, Fitzgerald Bldg,150 Coll St, Toronto, ON M5S 3E2, Canada. EM michael.glogauer@utoronto.ca FU Canadian Institutes of Health Research [TBO-122068] FX Cell sorting was performed by Dionne White at the flow cytometry facility at the University of Toronto, Department of Immunology. This research was funded by a Bone Team grant from the Canadian Institutes of Health Research to M.G. (TBO-122068). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 41 TC 1 Z9 1 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2016 VL 95 IS 8 BP 931 EP 938 DI 10.1177/0022034516645564 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DQ9US UT WOS:000379555400013 PM 27270666 ER PT J AU Dawson, AZ Walker, RJ Campbell, JA Egede, LE AF Dawson, Aprill Z. Walker, Rebekah J. Campbell, Jennifer A. Egede, Leonard E. TI Validation of theoretical pathway between discrimination, diabetes self-care and glycemic control SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Discrimination; Glycemic control; Self-care; Pathways; Stress ID PERCEIVED RACIAL-DISCRIMINATION; AFRICAN-AMERICANS; RATED HEALTH; STRESS; ADULTS; RESILIENCY; BEHAVIORS; SERVICES; MELLITUS; VALIDITY AB Aims: This study examined the mechanisms through which discrimination influences diabetes self-care and glycemic control in patients with diabetes by using structured equation modeling. Methods: 615 patients were recruited from two adult primary care clinics in the southeastern United States. Measures were based on a theoretical model and included perceived discrimination, social support, social cohesion, and perceived stress. Structured equation modeling examined the relationship with diabetes self-care and glycemic control. Results: The final model (chi2(211) = 328.82, p < 0.0001, R-2 = 0.99, RMSEA = 0.03 and CFI = 0.98) shows that higher stress is directly significantly related to a decreased self-care (r = -0.59, p <0.001) and increased HbA1c (r = 0.27, p < 0.05). There was no significant direct association between discrimination, social support or social cohesion, and glycemic control or self-care. There was, however, a direct significant association between increased discrimination (r = 0.46, p < 0.001), decreased social support (r = -0.34, p < 0.001), increased social cohesion (r = 0.14, p < 0.05) and increased stress. Conclusions: These results support the hypothesized pathway of discrimination on health outcomes, showing both a direct and indirect influence through stress on HbA1c in adults with diabetes. Understanding the pathways through which discrimination influences diabetes outcomes is important for providing more comprehensive and effective care. These results suggest future interventions targeting patients with diabetes should take discrimination-induced stress into account. (C) 2016 Elsevier Inc. All rights reserved. C1 [Dawson, Aprill Z.; Walker, Rebekah J.; Campbell, Jennifer A.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280, Charleston, SC 29425 USA. [Walker, Rebekah J.; Egede, Leonard E.] Ralph H Johnson VAMC, Charleston VA HSR&D COIN, HEROIC, 109 Bee St, Charleston, SC USA. [Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Dept Med, 135 Rutledge Ave, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280, Charleston, SC 29425 USA. EM dawson@musc.edu; walkerrj@musc.edu; campbja@musc.edu; egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Disease [K24DK093699-01] FX This study was supported by Grant K24DK093699-01 from The National Institute of Diabetes and Digestive and Kidney Disease (PI: Leonard Egede). NR 38 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD JUL PY 2016 VL 30 IS 5 BP 858 EP 863 DI 10.1016/j.jdiacomp.2016.03.014 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP8PI UT WOS:000378759700018 PM 27068266 ER PT J AU Jones, CN Hoang, AN Martel, JM Dimisko, L Mikkola, A Inoue, Y Kuriyama, N Yamada, M Hamza, B Kaneki, M Warren, HS Brown, DE Irimia, D AF Jones, Caroline N. Hoang, Anh N. Martel, Joseph M. Dimisko, Laurie Mikkola, Amy Inoue, Yoshitaka Kuriyama, Naohide Yamada, Marina Hamza, Bashar Kaneki, Masao Warren, H. Shaw Brown, Diane E. Irimia, Daniel TI Technical Advance: Microfluidic assay for precise measurements of mouse, rat, and human neutrophil chemotaxis in whole-blood droplets SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE neutrophil; migration; inbred lines ID MICE; RECEPTOR; ACTIVATION; GENERATION; C57BL/6J; PLATFORM; DISEASES; STRAINS; MODELS AB Animal models of human disease differ in innate immune responses to stress, pathogens, or injury. Precise neutrophil phenotype measurements could facilitate interspecies comparisons. However, such phenotype comparisons could not be performed accurately with the use of current assays, as they require the separation of neutrophils from blood using species-specific protocols, and they introduce distinct artifacts. Here, we report a microfluidic technology that enables robust characterization of neutrophil migratory phenotypes in a manner independent of the donor species and performed directly in a droplet of whole blood. The assay relies on the particular ability of neutrophils to deform actively during chemotaxis through microscale channels that block the advance of other blood cells. Neutrophil migration is measured directly in blood, in the presence of other blood cells and serum factors. Our measurements reveal important differences among migration counts, velocity, and directionality among neutrophils from 2 common mouse strains, rats, and humans. C1 [Jones, Caroline N.; Hoang, Anh N.; Martel, Joseph M.; Dimisko, Laurie; Inoue, Yoshitaka; Hamza, Bashar; Irimia, Daniel] Harvard Med Sch, Dept Surg, BioMEMS Resource Ctr, Massachusetts Gen Hosp, Boston, MA USA. [Kuriyama, Naohide; Yamada, Marina; Kaneki, Masao] Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA USA. [Warren, H. Shaw] Harvard Med Sch, Dept Pediat & Med, Infect Dis Unit, Massachusetts Gen Hosp, Boston, MA USA. [Brown, Diane E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Mikkola, Amy; Brown, Diane E.] Massachusetts Gen Hosp, Ctr Comparat Med, Boston, MA 02114 USA. [Jones, Caroline N.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. RP Irimia, D (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, BioMEMS Resource Ctr, MGH CNY 114 16th St,1404, Boston, MA 02129 USA.; Irimia, D (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, MGH CNY 114 16th St,1404, Boston, MA 02129 USA. EM dirimia@hms.harvard.edu FU U.S. National Institutes of Health [GM092804]; Shriners Burns Institute [8700]; Defense Advanced Research Projects Agency (DARPA) [W911NF-13-1] FX Microfabrication work was performed at the BioMEMS Research Center (EB002503). This work was supported by grants from the U.S. National Institutes of Health (GM092804; to D.I.), Shriners Burns Institute (8700; to H.S.W.), and Defense Advanced Research Projects Agency (DARPA; W911NF-13-1; to H.S.W.). NR 42 TC 0 Z9 0 U1 5 U2 9 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2016 VL 100 IS 1 BP 241 EP 247 DI 10.1189/jlb.5TA0715-310RR PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DR2MI UT WOS:000379738200025 PM 26819316 ER PT J AU Kluk, MJ Lindsley, RC Aster, JC Lindeman, NI Szeto, D Hall, D Kuo, FC AF Kluk, Michael. J. Lindsley, R. Coleman Aster, Jon C. Lindeman, Neal. I. Szeto, David Hall, Dimity Kuo, Frank C. TI Validation and Implementation of a Custom Next-Generation Sequencing Clinical Assay for Hematologic Malignancies SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MYELOPROLIFERATIVE NEOPLASMS; SOMATIC MUTATIONS; MYELODYSPLASTIC SYNDROMES; COHESIN COMPLEX; DIAGNOSTICS; INHIBITION; GENOME; CELL AB Targeted next-generation sequencing panels to identify genetic alterations in cancers are increasingly becoming an integral part of clinical practice. We report here the design, validation, and implementation of a comprehensive 95-gene next-generation sequencing panel targeted for hematologic malignancies that we named rapid heme panel. Rapid heme panel is amplicon based and covers hotspot regions of oncogenes and most of the coding regions of tumor suppressor genes. It is composed of 1330 amplicons and covers 175 kb of genomic sequence in total. Rapid heme panel's average coverage is 1500x with <5% of the amplicons with <50x coverage, and it reproducibly detects single nucleotide variants and small insertions/deletions at allele frequencies of >= 5%. Comparison with a capture-based next-generation sequencing assay showed that there is >95% concordance among a wide array of variants across a range of allele frequencies. Read count analyses that used rapid heme panel showed high concordance with karyotypic results when tumor content was >30%. The average turnaround time was 7 days over a 6-month span with an average volume of >= 40 specimens per week and a low sample fail rate (<= 1%), demonstrating its suitability for clinical application. C1 [Kluk, Michael. J.; Aster, Jon C.; Lindeman, Neal. I.; Szeto, David; Hall, Dimity; Kuo, Frank C.] Brigham & Womens Hosp, Ctr Adv Mol Diagnost, 75 Francis St, Boston, MA 02115 USA. [Lindsley, R. Coleman] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02115 USA. RP Kuo, FC (reprint author), Brigham & Womens Hosp, Dept Pathol, Ctr Adv Mol Diagnost, 75 Francis St, Boston, MA 02115 USA. EM fkuo@partners.org FU Department of Pathology at Brigham and Women's Hospital FX Supported by internal funds dedicated for test validation in the laboratory through the Department of Pathology at Brigham and Women's Hospital for assay development. NR 32 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2016 VL 18 IS 4 BP 507 EP 515 DI 10.1016/j.jmoldx.2016.02.003 PG 9 WC Pathology SC Pathology GA DR0ZM UT WOS:000379635600005 PM 27339098 ER PT J AU Corey, VR Pisano, VD Halpern, JH AF Corey, Vicka Rael Pisano, Vincent D. Halpern, John H. TI Effects of 3,4-Methylenedioxymethamphetamine on Patient Utterances in a Psychotherapeutic Setting SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE PTSD; MDMA; talk therapy; patient utterances ID POSTTRAUMATIC-STRESS-DISORDER; PTSD; MDMA; EPIDEMIOLOGY; VETERANS; EFFICACY AB 3,4-Methylenedioxymethamphetamine (MDMA) administered as an adjunct to talk therapy influences patient speech content and increases improvement in treatment-resistant posttraumatic stress disorder (PTSD). Data came from the recordings of Mithoefer et al. (2011). In the third therapeutic session studied, patientswere assigned, double blind, to anMDMAor a placebo group. Condition-blind scorers listened to therapy recordings and scored utterances where patients initiated topics that were empathic (regarding others' emotions), entactic (requesting or appreciating physical touch), or ensuic (describing a change in their sense of themselves). Patients who received MDMA produced high levels of ensuic, empathic, and entactic utterances compared with those who received the placebo. Interrater discourse scoring was reliable. The relationship between the number of scored utterances and the Clinician Administered PTSD Scale scores measuring PTSD severity after the treatment was significant, and reanalysis grouped bimodally into "many" or "few" such utterances remained significant. MDMA assisted these patients in having meaningful and disorder-resolving thoughts and discourse in talk therapy. C1 [Corey, Vicka Rael; Halpern, John H.] Harvard Med Sch, Boston, MA USA. [Corey, Vicka Rael; Halpern, John H.] McLean Hosp, Div Alcohol & Drug Abuse, Lab Integrat Psychiat, 115 Mill St, Belmont, MA 02178 USA. [Pisano, Vincent D.] Massachusetts Gen Hosp, Clin Trials Network Inst, Boston, MA 02114 USA. RP Corey, VR (reprint author), 35 Kidder Ave, Somerville, MA 02144 USA. EM vcorey@mclean.harvard.edu NR 21 TC 0 Z9 0 U1 12 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3018 EI 1539-736X J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD JUL PY 2016 VL 204 IS 7 BP 519 EP 523 DI 10.1097/NMD.0000000000000499 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DQ8GS UT WOS:000379447700006 PM 26998697 ER PT J AU Pronk, NP McLellan, DL McGrail, MP Olson, SM McKinney, ZJ Katz, JN Wagner, GR Sorensen, G AF Pronk, Nicolaas P. McLellan, Deborah L. McGrail, Michael P. Olson, Shawn M. McKinney, Zeke J. Katz, Jeffrey N. Wagner, Gregory R. Sorensen, Glorian TI Measurement Tools for Integrated Worker Health Protection and Promotion: Lessons Learned From the SafeWell Project SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID WORKPLACE HEALTH; BEHAVIOR-CHANGE; UNITED-STATES; CARE COSTS; SAFETY; ASSOCIATION; PROGRAMS; ORGANIZATIONS; INTERVENTIONS; PRODUCTIVITY AB Objectives: To describe (a) a conceptual approach, (b) measurement tools and data collection processes, (c) characteristics of an integrated feedback report and action plan, and (d) experiences of three companies with an integrated measurement approach to worker safety and health. Methods: Three companies implemented measurement tools designed to create an integrated view of health protection and promotion based on organizational-and individual-level assessments. Feedback and recommended actions were presented following assessments at baseline and 1-year follow-up. Measurement processes included group dialogue sessions, walk-through, online surveys, and focus groups. Results: The approach and measurement tools generated actionable recommendations and documented changes in the physical (eg, safety hazards) and psychosocial (eg, health and safety culture) work environment between baseline and 1-year follow-up. Conclusions: The measurement tools studied were feasible, acceptable, and meaningful to companies in the SafeWell study. C1 [Pronk, Nicolaas P.; Olson, Shawn M.; McKinney, Zeke J.] HealthPartners, Minneapolis, MN USA. [Pronk, Nicolaas P.; Olson, Shawn M.; McKinney, Zeke J.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Pronk, Nicolaas P.; McLellan, Deborah L.; Katz, Jeffrey N.; Wagner, Gregory R.; Sorensen, Glorian] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [McGrail, Michael P.] Aspirus, Wausau, WI USA. [McLellan, Deborah L.; Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Wagner, Gregory R.] NIOSH, Washington, DC USA. RP Pronk, NP (reprint author), HealthPartners, 8170 33rd Ave South, Bloomington, MN 55425 USA. EM nico.p.pronk@healthpartners.com FU National Institute for Occupational Safety and Health [U19 OH008861] FX This work was supported by a grant from the National Institute for Occupational Safety and Health (U19 OH008861) for the Harvard T.H. Chan School of Public Health Center for Work, Health and Well-being. NR 29 TC 1 Z9 1 U1 8 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JUL PY 2016 VL 58 IS 7 BP 651 EP 658 DI 10.1097/JOM.0000000000000752 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DR0RB UT WOS:000379613500007 PM 27206128 ER PT J AU van de Vondervoort, I Poelmans, G Aschrafi, A Pauls, DL Buitelaar, JK Glennon, JC Franke, B AF van de Vondervoort, Ilse Poelmans, Geert Aschrafi, Armaz Pauls, David L. Buitelaar, Jan K. Glennon, Jeffrey C. Franke, Barbara TI An integrated molecular landscape implicates the regulation of dendritic spine formation through insulin-related signalling in obsessive-compulsive disorder SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article ID GENOME-WIDE ASSOCIATION; DIABETES-MELLITUS; GENE; BEHAVIOR; EPIDEMIOLOGY; PROTEIN; MICE; PATHOPHYSIOLOGY; SYMPTOMATOLOGY; COMORBIDITY AB Background: Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with onset in childhood and is characterized by obsessions (recurrent, intrusive, persistent thoughts, impulses and/or ideas that often cause anxiety or distress) and compulsions (ritualized and stereotypic behaviours or mental acts that are often performed to relieve anxiety or distress associated with obsessions). Although OCD is a heritable disorder, its complex molecular etiology is poorly understood. Methods: We combined enrichment analyses and an elaborate literature review of the top-ranked genes emerging from the 2 published genome-wide association studies of OCD and candidate genes implicated through other evidence in order to identify biological processes that, when dysregulated, increase the risk for OCD. Results: The resulting molecular protein landscape was enriched for proteins involved in regulating postsynaptic dendritic spine formation - and hence synaptic plasticity -through insulin-dependent molecular signalling cascades. Limitations: This study is a first attempt to integrate molecuar information from different sources in order to identify biological mechanisms underlying OCD etiology. Our findings are constrained by the limited information from hypothesis-free studies and the incompleteness and existing limitations of the OCD literature and the gene function annotations of gene enrichment tools. As this study was solely based on in silico analyses, experimental validation of the provided hypotheses is warranted. Conclusion: Our work suggests a key role for insulin and insulin-related signalling in OCD etiology and - if confirmed by independent studies - could eventually pave the way for the development of novel OCD treatments. C1 [van de Vondervoort, Ilse; Poelmans, Geert; Buitelaar, Jan K.; Glennon, Jeffrey C.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, Nijmegen, Netherlands. [Poelmans, Geert; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101 HP 855, NL-6500 HB Nijmegen, Netherlands. [Poelmans, Geert] Radboud Univ Nijmegen, RIMLS, Donders Inst Brain Cognit & Behav, Dept Mol Anim Physiol, Nijmegen, Netherlands. [Aschrafi, Armaz] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Neuroinformat, Nijmegen, Netherlands. [Pauls, David L.] Harvard Med Sch, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA USA. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, Nijmegen, Netherlands. [Buitelaar, Jan K.] Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands. RP Franke, B (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101 HP 855, NL-6500 HB Nijmegen, Netherlands. EM Barbara.Franke@radboudumc.nl RI Franke, Barbara/D-4836-2009; Glennon, Jeffrey/D-2379-2013 OI Franke, Barbara/0000-0003-4375-6572; FU European Community [278948] FX The authors thank the families who made all the genetic studies of OCD possible and the many investigators whose work drives the OCD genetics field forward. The authors also thank the anonymous reviewers for their useful comments and suggestions regarding text revision. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no278948 (TACTICS). This funding organization has had no involvement with the conception, design, data analysis and interpretation, review and/or any other aspects relating to this paper. NR 50 TC 2 Z9 2 U1 2 U2 4 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 1180-4882 EI 1488-2434 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD JUL PY 2016 VL 41 IS 4 BP 280 EP 285 DI 10.1503/jpn.140327 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DR2RK UT WOS:000379751400010 PM 26854754 ER PT J AU Pedrelli, P Borsari, B Lipson, SK Heinze, JE Eisenberg, D AF Pedrelli, Paola Borsari, Brian Lipson, Sarah Ketchen Heinze, Justin E. Eisenberg, Daniel TI Gender Differences in the Relationships Among Major Depressive Disorder, Heavy Alcohol Use, and Mental Health Treatment Engagement Among College Students SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; SUBSTANCE USE BEHAVIORS; BINGE-DRINKING; QUESTIONNAIRE PHQ-9; SUICIDE PRONENESS; LATE ADOLESCENCE; UNITED-STATES; YOUNG-ADULTS; RISK-FACTORS; INJURY RISK AB Objective: Although major depressive disorder (MDD) and heavy episodic drinking (HED, 4+/5+ drinks in a single sitting for women/men) are common among young adults in college, the relationship between the two remains unclear. This study examined the association between MDD and HED in this population, the effect of gender on this association, and whether comorbid MDD and heavy alcohol use are associated with higher rates of mental health treatment engagement. Method: The study comprised 61,561 (65.3% female) undergraduate students who answered an online survey on depression, alcohol use, and treatment engagement in the past year. Hierarchical linear regressions examined the association between MDD and alcohol use (RED and peak blood alcohol concentration [pBAC]) and whether gender moderated these associations. Logistic regressions were then conducted to examine the influence of MDD, heavy alcohol use, and gender on treatment engagement. Results: Students with MDD reported more frequent HED and higher pBAC than did students without MDD; this was especially true for female students. Rates of treatment engagement were higher among women than men, among students with MDD than students without MDD, and among female students with HED than women without HED. Conclusions: The presence of an association between MDD and heavy alcohol use suggests the need for systematic screenings of both conditions. Low rates of treatment engagement in college students with MDD and heavy alcohol use calls for the development of strategies to engage this high-risk group in treatment. C1 [Pedrelli, Paola] Harvard Med Sch, Massachusetts Gen Hosp, Depress Clin Res Program, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA. [Borsari, Brian] San Francisco Veteran Affairs Med Ctr, San Francisco, CA USA. [Borsari, Brian] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Lipson, Sarah Ketchen] Univ Michigan, Sch Educ, Ctr Study Higher & Postsecondary Educ, Ann Arbor, MI 48109 USA. [Lipson, Sarah Ketchen; Eisenberg, Daniel] Univ Michigan, Sch Publ Hlth, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Heinze, Justin E.] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Eisenberg, Daniel] Univ Michigan, Inst Social Res, Ctr Populat Studies, Ann Arbor, MI 48109 USA. RP Pedrelli, P (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Depress Clin Res Program, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM ppedrelli@mgh.harvard.edu FU National Institute on Alcohol Abuse and Alcoholism [K23AA020064, R01AA017427]; VISN1 Career Development Award [V1CDA2012-18] FX This study was supported by National Institute on Alcohol Abuse and Alcoholism Grants K23AA020064 (to Paola Pedrelli) and R01AA017427 (to Brian Borsari), and VISN1 Career Development Award V1CDA2012-18 (to Brian Borsari). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism, the National Institutes of Health, the Department of Veterans Affairs, or the United States Government. NR 64 TC 0 Z9 0 U1 17 U2 25 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2016 VL 77 IS 4 BP 620 EP 628 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA DQ7HG UT WOS:000379376900017 PM 27340967 ER PT J AU Meyer, AND Murphy, DR Singh, H AF Meyer, Ashley N. D. Murphy, Daniel R. Singh, Hardeep TI Communicating Findings of Delayed Diagnostic Evaluation to Primary Care Providers SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article DE Algorithms; Ambulatory Care Facilities; Communication; Control Groups; Electronic Health Records; Electronic Mail; Follow-Up Studies; Humans; Neoplasms; Primary Care Providers; Telephone ID ELECTRONIC HEALTH RECORDS; INFORMATION OVERLOAD; PATIENT; COMMON AB Background: We previously found that an intervention involving electronic algorithms to detect delays in follow-up of cancer-related abnormal or "red-flag" findings and communicating this information to primary care providers (PCPs) led to more timely diagnostic evaluation. In this study, we examined the effectiveness of various communication strategies to inform PCPs about the delayed follow-up. Methods: After identifying follow-up delays through electronic health record-based algorithms and record reviews, we communicated this information to PCPs using 3 escalating steps. First, we sent secure E-mails. If no evidence of follow-up was found in a medical record review after 1 week, we made up to 3 attempts to reach the PCPs or their nurses via telephone. If they could not be reached, we informed clinic directors as the third and final step. In this analysis, we evaluate PCPs' follow-up in response to these methods of communication. Results: A total of 733 patients with follow-up delays were identified (369 patients in the intervention group and 364 patients in the control group). Communicating information to PCPs about possible follow-up delays led to decreased times to diagnostic evaluation, but communication related to delays did not always lead to follow-up for the patients in the intervention group. Specifically, secure E-mails led to follow-up in 11.1% of cases (41 of 369), telephone calls led to follow-up in 68.6% of cases (225 of 328), and contacting clinic directors led to follow-up in 5 of 11 cases in which communication escalated to this level. Conclusion: Strategies to communicate to PCPs information on delayed follow-up of findings suspicious for cancer were useful, but not fail-safe. Additional back-up strategies, such as using case coordinators, might be needed. C1 Michael E De Bakey Vet Affairs Med Ctr, Houston Vet Affairs Ctr Innovat Qual Effectivenes, Houston, TX USA. Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX USA. RP Meyer, AND (reprint author), Ctr Innovat Qual Effectiveness & Safety 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM ameyer@bcm.edu FU Agency for Health Care Research and Quality [R18HS017820, K08-HS022901, R01HS022087]; Houston Veterans Affairs Health Services Research & Development Center for Innovations in Quality, Effectiveness and Safety [CIN 13-413]; VA Health Services Research and Development Service [CRE 12-033, USA 14274]; VA National Center for Patient Safety FX This work was supported by the Agency for Health Care Research and Quality (grant no. R18HS017820) and the Houston Veterans Affairs Health Services Research & Development Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413). DRM is supported by a Mentored Career Development Award (grant K08-HS022901) from the Agency for Healthcare Research and Quality. HS is also supported by the VA Health Services Research and Development Service (CRE 12-033; Presidential Early Career Award for Scientists and Engineers USA 14274), the VA National Center for Patient Safety, and the Agency for Health Care Research and Quality (grant R01HS022087). NR 14 TC 1 Z9 1 U1 3 U2 3 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 EI 1558-7118 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD JUL-AUG PY 2016 VL 29 IS 4 BP 469 EP 473 DI 10.3122/jabfm.2016.04.150363 PG 5 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA DR0MC UT WOS:000379600600008 PM 27390378 ER PT J AU Taudorf, EH Lerche, CM Erlendsson, AM Philipsen, PA Hansen, SH Janfelt, C Paasch, U Anderson, RR Haedersdal, M AF Taudorf, E. H. Lerche, C. M. Erlendsson, A. M. Philipsen, P. A. Hansen, S. H. Janfelt, C. Paasch, U. Anderson, R. R. Haedersdal, M. TI Fractional laser-assisted drug delivery: Laser channel depth influences biodistribution and skin deposition of methotrexate SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE Er:Yag laser; fluorescence microscopy; Franz skin permeability Cells; high performance liquid chromatography; laser-assisted drug delivery ID ERBIUM-YAG LASER; TRANSDERMAL DELIVERY; INTRALESIONAL METHOTREXATE; TOPICAL METHOTREXATE; PHOTODYNAMIC THERAPY; PSORIASIS-VULGARIS; PHARMACOKINETICS; KERATOACANTHOMA; ABLATION; GEL AB Background and ObjectiveAblative fractional laser (AFXL) facilitates delivery of topical methotrexate (MTX). This study investigates impact of laser-channel depth on topical MTX-delivery. Materials and MethodsMTX (1% [w/v]) diffused for 21 hours through AFXL-exposed porcine skin in in vitro Franz Cells (n=120). A 2,940nm AFXL generated microscopic ablation zones (MAZs) into epidermis (11mJ/channel, MAZ-E), superficial-dermis (26mJ/channel, MAZ-DS), and mid-dermis (256mJ/channel, MAZ-DM). High performance liquid chromatography (HPLC) was used to quantify MTX deposition in full-thickness skin, biodistribution profiles at specific skin levels, and transdermal permeation. Fluorescence microscopy was used to visualize UVC-activated MTX-fluorescence (254nm) and semi-quantify MTX distribution in skin. ResultsAFXL increased topical MTX-delivery (P<0.001). Without laser exposure, MTX-concentration in full-thickness skin was 0.07mg/cm(2), increasing sixfold (MAZ-E), ninefold (MAZ-DS), and 11-fold (MAZ-DM) after AFXL (P<0.001). Deeper MAZs increased MTX-concentrations in all skin layers (P<0.038) and favored maximum accumulation in deeper skin layers (MAZ-E: 1.85mg/cm(3) at 500m skin-level vs. MAZ-DM: 3.75mg/cm(3) at 800m, P=0.002). Ratio of skin deposition versus transdermal permeation remained constant, regardless of MAZ depth (P=0.172). Fluorescence intensities confirmed MTX biodistribution through coagulation zones and into surrounding skin, regardless of thickness of coagulation zones (6-47m, P0.438). ConclusionAFXL greatly increases topical MTX-delivery. Deeper MAZs deliver higher MTX-concentrations than superficial MAZs, which indicates that laser channel depth may be important for topical delivery of hydrophilic molecules. Lasers Surg. Med. 48:519-529, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Taudorf, E. H.; Lerche, C. M.; Erlendsson, A. M.; Philipsen, P. A.; Haedersdal, M.] Univ Copenhagen, Bispebjerg Univ Hosp, Dept Dermatol, D-92,Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. [Hansen, S. H.; Janfelt, C.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2400 Copenhagen NV, Denmark. [Paasch, U.] Univ Leipzig, Dept Dermatol, Div Dermatopathol Aesthet & Laserdermatol, D-04109 Leipzig, Germany. [Anderson, R. R.; Haedersdal, M.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. RP Taudorf, EH (reprint author), Univ Copenhagen, Bispebjerg Univ Hosp, Dept Dermatol, D-92,Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. EM ehtaudorf@dadlnet.dk FU Pantec Biosolutions AG FX Merete Haedersdal received a research grant from Pantec Biosolutions AG. The company has had no influence on study design, study conduction or manuscript preparation. All other authors state no conflicts of interest. NR 45 TC 1 Z9 1 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD JUL PY 2016 VL 48 IS 5 BP 519 EP 529 DI 10.1002/lsm.22484 PG 11 WC Dermatology; Surgery SC Dermatology; Surgery GA DQ9GQ UT WOS:000379518800009 PM 26846733 ER PT J AU Senthil-Kumar, P Ni, T Randolph, MA Velmahos, GC Kochevar, IE Redmond, RW AF Senthil-Kumar, Prabhu Ni, Tao Randolph, Mark A. Velmahos, George C. Kochevar, Irene E. Redmond, Robert W. TI A light-activated amnion wrap strengthens colonic anastomosis and reduces peri-anastomotic adhesions SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE rose bengal; photochemistry; anastomosis; colon; crosslinking; amnion; anastomotic leak ID PHOTOCHEMICAL KERATODESMOS; CORNEAL INCISIONS; FIBRIN SEALANT; REPAIR; MODEL; SKIN; RAT; OMENTOPLASTY; MEMBRANE; DEFECTS AB Background and ObjectiveColonic anastomotic failure is a dreaded complication, and multiple surgical techniques have failed to eliminate it. Photochemical tissue bonding (PTB) is a method of sealing tissue surfaces by light-activated crosslinking. We evaluated if a human amniotic membrane (HAM), sealed over the anastomotic line by PTB, increases the anastomotic strength. Study DesignSprague-Dawley rats underwent midline laparotomy followed by surgical transection of the left colon. Animals were randomized to colonic anastomosis by one of the following methods (20 per group): single-layer continuous circumferential suture repair (SR); SR with a HAM wrap attached by suture (SR+HAM-S); SR with HAM bonded photochemically over the anastomotic site using 532nm light (SR+HAM-PTB); approximation of the bowel ends with only three sutures and sealing with HAM-PTB (3+ HAM-PTB). A control group underwent laparotomy alone with no colon resection (NR). Sub-groups (n=10) were sacrificed at days 3 and 7 post-operatively and adhesions were evaluated. A 6cm section of colon was then removed and strength of anastomosis evaluated by burst pressure (BP) measurement. ResultsA fourfold increase in BP was observed in the SR+HAM-PTB group compared to suture repair alone (943 vs. 25 +/- 8mmHg, P<0.0001) at day 3. At day 7 the burst pressures were 165 +/- 40 and 145 +/- 31mmHg (P=1), respectively. A significant decrease in peri-anastomotic adhesions was observed in the SR+HAM-PTB group compared to the SR group at both time points (P<0.001). ConclusionSealing sutured colonic anastomotic lines with HAM-PTB increases the early strength of the repair and reduces peri-anastomotic adhesions. Lasers Surg. Med. 48:530-537, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Senthil-Kumar, Prabhu; Ni, Tao; Kochevar, Irene E.; Redmond, Robert W.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Their 218, Boston, MA 02114 USA. [Senthil-Kumar, Prabhu; Randolph, Mark A.] Massachusetts Gen Hosp, Dept Surg, Plast Surg Res Lab, Boston, MA 02114 USA. [Ni, Tao] Shanghai Jiao Tong Univ, Dept Burns & Plast Surg, Peoples Hosp 3, Shanghai 201900, Peoples R China. [Ni, Tao] Shanghai Jiao Tong Univ, Inst Traumat Med, Sch Med, Shanghai 201900, Peoples R China. [Velmahos, George C.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Redmond, RW (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Their 218, Boston, MA 02114 USA. EM redmond@helix.mgh.harvard.edu FU CIMIT [W81XWH-09-2-0001] FX Contract grant sponsor: CIMIT; Contract grant number: W81XWH-09-2-0001. NR 35 TC 0 Z9 0 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD JUL PY 2016 VL 48 IS 5 BP 530 EP 537 DI 10.1002/lsm.22507 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA DQ9GQ UT WOS:000379518800010 PM 26996284 ER PT J AU Kositratna, G Hibert, ML Jaspan, M Welford, D Manstein, D AF Kositratna, Garuna Hibert, Matthew Louis Jaspan, Martin Welford, David Manstein, Dieter TI Effects of deviation from focal plane on lesion geometry for ablative fractional photothermolysis SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE focal plane; deviation; ablative fractional resurfacing; ablative fractional photothermolysis; complications; Rayleigh range; fill factor; thermal injury; lesion geometry ID ASSISTED DRUG-DELIVERY; RESURFACING DEVICE; TECHNOLOGY; ASIANS AB Background and ObjectiveFractional Photothermolysis (FP) is a method of skin treatment that generates a thermal damage pattern consisting of multiple columns of thermal damage, also known as microscopic treatment zones (MTZs). They are very small in diameter and are generated by application of highly focused laser beams. In order to obtain the smallest spot size, the treatment should be performed in the focal plane. Any deviation from the focal plane (DFP) results in an increase of spot size. FP devices typically utilize distance holders in order to facilitate exposures at this specific location. In spite of the use of distance holders, DFP can occur. In particular, variations of contact pressure to the skin surface and anatomical treatment areas of high surface curvature may be prone to DFP during FP treatments. The impact of such distance variation on lesion geometry, such as depth and diameter of the thermal injury, has not previously been evaluated. The objective of this study was to investigate the relation between DFP and the resulting lesion geometry for a selected ablative fractional device. Material and MethodsA handpiece of an ablative fractional laser (DeepFX, UltraPulse Encore, Lumenis, Yokneam, Israel) was mounted to a rigid stand. Full thickness human skin obtained from abdominoplasty was mounted to a separate stand perpendicular to the handpiece. The tissue stand allowed the distance between the handpiece and the tissue to be adjusted to produce a variation up to3mm from the focal plane. A 1x1cm(2) scanning area of 169 MTZs, 50mJ energy per MTZ, 120m nominal spot size, was applied at -3, -2, -1, 0, +1, +2, and +3mm deviated from the focal plane. Minus (-) and plus (+) signs indicate decreasing and increasing distance between the handpiece and the tissue, respectively. Depth and diameter of the laser induced tissue lesions were assessed and quantified. ResultsDFPs produced a significant alteration of the lesion geometry. DFPs of -3, -2, -1, 0, +1, +2, +3mm resulted in average lesion depths of 1,020 (-40%), 1,180 (-31%), 1,400 (-18%), styled-content style="text-decoration:underline"1,700 (0%)styled-content, 1,620 (-5%), 780 (-55%), 680 (-60%) mu m, and average lesion diameters of 314 (+26%), 311 (+25%), 273 (+10%), styled-content style="text-decoration:underline"248 (0%)styled-content, 256 (+3%), 316 (+27%), 359 (+44%) mu m, respectively. The underlined values represent the focal plane. The percentage changes relative to values at focal plane are in parentheses. ConclusionsA relatively minor DFP has a marked impact on the thermal injury profile, including lesion depth and diameter, of the laser-exposed tissue. Such marked changes of the thermal injury profile might affect the wound healing, safety, and efficacy of ablative fractional resurfacing procedures. Clinicians should carefully maintain the focal plane during ablative fractional treatment for reproducible results. The presented data are device specific and the clinical impact of such alteration of thermal injury profile warrants further investigation. Lasers Surg. Med. 48:555-561, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Kositratna, Garuna; Hibert, Matthew Louis; Manstein, Dieter] Massachusetts Gen Hosp, Res Inst, Cutaneous Biol Res Ctr, Dept Dermatol, Charlestown, MA 02129 USA. [Kositratna, Garuna; Manstein, Dieter] Harvard Med Sch, Boston, MA 02115 USA. [Jaspan, Martin; Welford, David] Endeavour Laser Technol Inc, Hathorne, MA 01937 USA. RP Kositratna, G (reprint author), Massachusetts Gen Hosp, Res Inst, Cutaneous Biol Res Ctr, Dept Dermatol, Charlestown, MA 02129 USA. EM gkositratna@mgh.harvard.edu NR 20 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD JUL PY 2016 VL 48 IS 5 BP 555 EP 561 DI 10.1002/lsm.22481 PG 7 WC Dermatology; Surgery SC Dermatology; Surgery GA DQ9GQ UT WOS:000379518800013 PM 26842919 ER PT J AU Amin, RM Bhayana, B Hamblin, MR Dai, TH AF Amin, Rehab M. Bhayana, Brijesh Hamblin, Michael R. Dai, Tianhong TI Antimicrobial blue light inactivation of Pseudomonas aeruginosa by photo-excitation of endogenous porphyrins: In vitro and in vivo studies SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE Pseudomonas aeruginosa; blue light; endogenous porphyrins; drug resistance; mouse ID RESISTANT ACINETOBACTER-BAUMANNII; PHOTODYNAMIC THERAPY; ANTIBIOTIC-RESISTANCE; WOUND INFECTIONS; MICE; MODEL; 21ST-CENTURY; PROPHYLAXIS; BACTERIA AB Pseudomonas aeruginosa is among the most common pathogens that cause nosocomial infections and is responsible for about 10% of all hospital-acquired infections. In the present study, we investigated the potential development of tolerance of P. aeruginosa to antimicrobial blue light by carrying 10 successive cycles of sublethal blue light inactivation. The high-performance liquid chromatographic (HPLC) analysis was performed to identify endogenous porphyrins in P. aeruginosa cells. In addition, we tested the effectiveness of antimicrobial blue light in a mouse model of nonlethal skin abrasion infection by using a bioluminescent strain of P. aeruginosa. The results demonstrated that no tolerance was developed to antimicrobial blue light in P. aeruginosa after 10 cycles of sub-lethal inactivation. HPLC analysis showed that P. aeruginosa is capable of producing endogenous porphyrins in particularly, coproporphyrin III, which are assumed to be responsible for the photodynamic effects of blue light alone. P. aeruginosa infection was eradicated by antimicrobial blue light alone (48J/cm(2)) without any added photosensitizer molecules in the mouse model. In conclusion, endogenous photosensitization using blue light should gain considerable attention as an effective and safe alternative antimicrobial therapy for skin infections. Lasers Surg. Med. 48:562-568, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Amin, Rehab M.; Bhayana, Brijesh; Hamblin, Michael R.; Dai, Tianhong] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Amin, Rehab M.; Bhayana, Brijesh; Hamblin, Michael R.; Dai, Tianhong] Harvard Med Sch, Dept Dermatol, Boston, MA 02114 USA. [Amin, Rehab M.] Cairo Univ, Natl Inst Laser Enhanced Sci, Giza 12613, Egypt. RP Amin, RM (reprint author), Cairo Univ, Natl Inst Laser Enhanced Sci, Giza 12613, Egypt.; Dai, TH (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM rehabamin@niles.edu.eg; rehabamin@niles.edu.eg FU ASLMS [BS.F04.14]; NIH [R21AI109172]; Binational Fulbright Commission in Egypt [AY2013-2014]; US NIH [R01AI050875] FX Contract grant sponsor: ASLMS; Contract grant number: BS.F04.14; Contract grant sponsor: NIH; Contract grant number: R21AI109172; Contract grant sponsor: Binational Fulbright Commission in Egypt; Contract grant number: AY2013-2014; Contract grant sponsor: US NIH grant; Contract grant number: R01AI050875. NR 28 TC 2 Z9 2 U1 7 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD JUL PY 2016 VL 48 IS 5 BP 562 EP 568 DI 10.1002/lsm.22474 PG 7 WC Dermatology; Surgery SC Dermatology; Surgery GA DQ9GQ UT WOS:000379518800014 PM 26891084 ER PT J AU Bhatnagar, B Blachly, JS Kohlschmidt, J Eisfeld, AK Volinia, S Nicolet, D Carroll, AJ Block, AW Kolitz, JE Stone, RM Mrozek, K Byrd, JC Bloomfield, CD AF Bhatnagar, B. Blachly, J. S. Kohlschmidt, J. Eisfeld, A-K Volinia, S. Nicolet, D. Carroll, A. J. Block, A. W. Kolitz, J. E. Stone, R. M. Mrozek, K. Byrd, J. C. Bloomfield, C. D. TI Clinical features and gene- and microRNA-expression patterns in adult acute leukemia patients with t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3) SO LEUKEMIA LA English DT Letter ID ACUTE MYELOID-LEUKEMIA; PROFILES C1 [Bhatnagar, B.; Blachly, J. S.; Byrd, J. C.; Bloomfield, C. D.] Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Bhatnagar, B.; Blachly, J. S.; Kohlschmidt, J.; Eisfeld, A-K; Nicolet, D.; Mrozek, K.; Byrd, J. C.; Bloomfield, C. D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Kohlschmidt, J.; Nicolet, D.] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA. [Kohlschmidt, J.; Nicolet, D.] Mayo Clin, Ctr Data, Rochester, MN USA. [Volinia, S.] Univ Ferrara, Dept Morphol Surg & Expt Med, Ferrara, Italy. [Carroll, A. J.] Univ Alabama Birmingham, Birmingham, AL USA. [Block, A. W.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Kolitz, J. E.] Hofstra North Shore Long Isl Jewish Sch Med, Monter Canc Ctr, Lake Success, NY USA. [Stone, R. M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bhatnagar, B (reprint author), Dept Internal Med, Div Hematol, Columbus, OH 43210 USA.; Bhatnagar, B (reprint author), Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. EM bhavana.bhatnagar@osumc.edu; clara.bloomfield@osumc.edu FU NCI NIH HHS [P30 CA016058, P50 CA140158, U10 CA180821, U10 CA180850, U10 CA180855, U10 CA180861, U10 CA180867, U10 CA180882, U24 CA114725] NR 15 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JUL PY 2016 VL 30 IS 7 BP 1586 EP 1589 DI 10.1038/leu.2015.345 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA DQ9BC UT WOS:000379504400017 PM 26669971 ER PT J AU Forman, DE Fix, GM McDannold, S McIntosh, N Schopfer, DW Whooley, MA Charns, MP AF Forman, Daniel E. Fix, Gemmae M. McDannold, Sarah McIntosh, Nathalie Schopfer, David W. Whooley, Mary A. Charns, Martin P. TI Decisive Bearing of Organizational Dynamics on the Application and Success of Hospital-Based Cardiac Rehabilitation SO MAYO CLINIC PROCEEDINGS LA English DT Letter ID HEART-ASSOCIATION; DISEASE C1 [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15238 USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. [Forman, Daniel E.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Fix, Gemmae M.; McDannold, Sarah] Edith Nourse Rogers Mem Vet Hosp, Bedford, MA USA. [Fix, Gemmae M.; McDannold, Sarah] Boston Univ, Sch Publ Hlth, Boston, MA USA. [McIntosh, Nathalie] VA Boston Healthcare Syst, Boston, MA USA. [Schopfer, David W.; Whooley, Mary A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Schopfer, David W.; Whooley, Mary A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Charns, Martin P.] Boston Univ, Sch Publ Hlth, VA Boston Healthcare Syst, Boston, MA USA. RP Forman, DE (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15238 USA.; Forman, DE (reprint author), Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA.; Forman, DE (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JUL PY 2016 VL 91 IS 7 BP 975 EP + DI 10.1016/j.mayocp.2016.04.019 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DR0BE UT WOS:000379572200026 PM 27378045 ER PT J AU Steensma, DP Kyle, RA Shampo, MA AF Steensma, David P. Kyle, Robert A. Shampo, Marc A. TI Elizabeth Blackburn and Maintenance of Telomeres SO MAYO CLINIC PROCEEDINGS LA English DT Biographical-Item C1 [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kyle, Robert A.; Shampo, Marc A.] Mayo Clin, Rochester, MN USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 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 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JUL PY 2016 VL 91 IS 7 BP E105 EP E105 DI 10.1016/j.mayocp.2016.01.026 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DR0BE UT WOS:000379572200004 PM 27378050 ER PT J AU Sweet, RA MacDonald, ML Kirkwood, CM Ding, Y Schempf, T Jones-Laughner, J Kofler, J Ikonomovic, MD Lopez, OL Garver, ME Fitz, NF Koldamova, R Yates, NA AF Sweet, Robert A. MacDonald, Matthew L. Kirkwood, Caitlin M. Ding, Ying Schempf, Tadhg Jones-Laughner, Jackie Kofler, Julia Ikonomovic, Milos D. Lopez, Oscar L. Garver, Megan E. Fitz, Nicholas F. Koldamova, Radosveta Yates, Nathan A. TI Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID AMYLOID-BETA; COGNITIVE IMPAIRMENT; ELDERLY SUBJECTS; TRANSGENIC MICE; FRONTAL-CORTEX; EXPRESSION; PATHOLOGY; DEFICITS; ISOFORM; BRAIN AB It has been hypothesized that Alzheimer disease (AD) is primarily a disorder of the synapse. However, assessment of the synaptic proteome in AD subjects has been limited to a small number of proteins and often included subjects with end-stage pathology. Protein from prefrontal cortex gray matter of 59 AD subjects with mild to moderate dementia and 12 normal elderly subjects was assayed using targeted mass spectrometry to quantify 191 synaptically expressed proteins. The profile of synaptic protein expression clustered AD subjects into two groups. One of these was characterized by reduced expression of glutamate receptor proteins, significantly increased synaptic protein network coexpression, and associated with Apolipoprotein E*4 (APOE*4) carrier status. The second group, by contrast, showed few differences from control subjects. A subset of AD subjects had altered prefrontal cortex synaptic proteostasis for glutamate receptors and their signaling partners. Efforts to therapeutically target glutamate receptors in AD may have outcomes dependent on APOE*4 genotype. C1 [Sweet, Robert A.; MacDonald, Matthew L.; Kirkwood, Caitlin M.; Schempf, Tadhg; Lopez, Oscar L.; Garver, Megan E.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Ding, Ying] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Jones-Laughner, Jackie; Yates, Nathan A.] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA USA. [Kofler, Julia] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Sweet, Robert A.; Ikonomovic, Milos D.; Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Fitz, Nicholas F.; Koldamova, Radosveta] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA USA. [Sweet, Robert A.] VISN 4 Mental Illness Res Educ & Clin Ctr MIRECC, Pittsburgh, PA USA. [Ikonomovic, Milos D.] VA Pittsburgh Healthcare Syst, GRECC, Pittsburgh, PA USA. RP Sweet, RA (reprint author), Biomedical Sci Tower,Rm W-1645,3811 OHara St, Pittsburgh, PA 15213 USA.; Sweet, RA (reprint author), Biomed Sci Tower,Rm W-1645,Lothrop & Terrace St, Pittsburgh, PA 15213 USA. EM sweetra@upmc.edu FU VAPHS [BX000452]; [MH16804]; [AG05133]; [AG014449]; [AG027224]; [AG037481]; [AG044490]; [P30CA047904] FX This work was supported by grants MH16804 (MLM), AG05133 (OLL), AG014449 (MDI), AG027224 (RAS), AG037481 (RK), AG044490 (NFF), and VAPHS grant BX000452 (RAS). The Biomedical Mass Spectrometry Center and UPCI Cancer Proteomics Facility are supported in part by award P30CA047904. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, the Department of Veterans Affairs, or the United States Government. NR 53 TC 0 Z9 0 U1 3 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUL PY 2016 VL 15 IS 7 BP 2252 EP 2262 DI 10.1074/mcp.M115.056580 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DQ9SS UT WOS:000379550200005 PM 27103636 ER PT J AU Gwathmey, KG Conaway, MR Sadjadi, R Joshi, A Barnett, C Bril, V Ng, E David, W Gable, K Guptill, JT Hobson-Webb, LD Dineen, J Hehir, M Brannagan, TH Byun, E Adler, M Burns, TM AF Gwathmey, Kelly G. Conaway, Mark R. Sadjadi, Reza Joshi, Amruta Barnett, Carolina Bril, Vera Ng, Eduardo David, William Gable, Karissa Guptill, Jeffrey T. Hobson-Webb, Lisa D. Dineen, Jennifer Hehir, Michael Brannagan, Thomas H. Byun, Esther Adler, Margaret Burns, Ted M. TI Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument SO MUSCLE & NERVE LA English DT Article DE CAP-PRI; chronic inflammatory demyelinating polyneuropathy; immune-mediated polyneuropathy; patient-reported outcome; quality of life ID INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY; TRIAL; ICE AB Introduction: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. Methods: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. Results: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. Conclusions: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve54: 9-17, 2016 C1 [Gwathmey, Kelly G.; Sadjadi, Reza; Joshi, Amruta; Burns, Ted M.] Univ Virginia, Dept Neurol, POB 800394, Charlottesville, VA 22908 USA. [Conaway, Mark R.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Barnett, Carolina; Bril, Vera; Ng, Eduardo] Univ Toronto, Div Neurol, Dept Med, Ellen & Martin Prosserman Ctr Neuromuscular Dis, Toronto, ON, Canada. [Barnett, Carolina; Bril, Vera; Ng, Eduardo] Univ Hlth Network, Toronto, ON, Canada. [David, William] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Gable, Karissa; Guptill, Jeffrey T.; Hobson-Webb, Lisa D.] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Dineen, Jennifer] Harvard Med Sch, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Hehir, Michael] Univ Vermont, Dept Neurol, Burlington, VT USA. [Brannagan, Thomas H.] Columbia Univ, Dept Neurol, New York, NY USA. [Byun, Esther] Jerry L Pettis VA Med Ctr, Dept Neurol, Loma Linda, CA USA. [Adler, Margaret] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. RP Burns, TM (reprint author), Univ Virginia, Dept Neurol, POB 800394, Charlottesville, VA 22908 USA. EM tmb8r@virginia.edu FU NINDS NIH HHS [K23 NS085049] NR 18 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 2016 VL 54 IS 1 BP 9 EP 17 DI 10.1002/mus.24985 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DQ2HP UT WOS:000379023700002 PM 26600438 ER PT J AU Liang, F Zhang, YY Hong, WY Dong, YL Xie, ZC Quan, QM AF Liang, Feng Zhang, Yiying Hong, Wooyoung Dong, Yuanlin Xie, Zhongcong Quan, Qimin TI Direct Tracking of Amyloid and Tau Dynamics in Neuroblastoma Cells Using Nanoplasmonic Fiber Tip Probes SO NANO LETTERS LA English DT Article DE nanoplasmonic fiber tip probe (nFTP); protein dynamics; A beta; tau; Alzheimer's disease; photonic crystal nanosensor ID CRYSTAL NANOBEAM CAVITIES; ALZHEIMERS-DISEASE; SINGLE-CELL; LIVING CELLS; HYPOTHESIS; HYPERPHOSPHORYLATION; PHOSPHOPROTEOMICS; MECHANISMS; STRATEGIES; BIOPROBES AB Amyloid plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease. However, there has been a long-standing discussion on the dynamic relations between A beta and tau proteins, partially due to the lack of a tool to track protein dynamics in individual live neurons' at the early stage of A beta generation and tau phosphorylation. Here, we developed nanoplasmonic fiber tip probe (nFTP) technology to simultaneously monitor A beta 42 generation and 0 tau phosphorylation (at serine 262) in living, single neuroblastoma cells over 12 h. We observed that A beta 42 generation, under clinically relevant anesthetic treatment, preceded tau phosphorylation, which then facilitated A beta(4)2 generation. This observation is also supported by measuring proteins in cell lysates using the ultrasensitive label-free photonic crystal nanosensors. nFTP therefore provides an advanced method to investigate protein expression and post-translational modification in live cells and determine outcomes of intervention of Alzheimer's disease and other neurodegenerative disorders. C1 [Liang, Feng; Hong, Wooyoung; Quan, Qimin] Harvard Univ, Rowland Inst, Cambridge, MA 02142 USA. [Zhang, Yiying; Dong, Yuanlin; Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. [Zhang, Yiying; Dong, Yuanlin; Xie, Zhongcong] Harvard Med Sch, Charlestown, MA 02129 USA. [Hong, Wooyoung] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RP Quan, QM (reprint author), Harvard Univ, Rowland Inst, Cambridge, MA 02142 USA.; Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA.; Xie, ZC (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA. EM zxie@mgh.harvard.edu; quan@rowland.harvard.edu RI liang, feng/S-4539-2016 FU Rowland Junior Fellowship Award at Rowland Institute at Harvard University, Cambridge, Massachusetts; National Institutes of Health, Bethesda, Maryland [R01 GM088801, R01 AG041274, R01 HD086977] FX The authors are thankful for helpful discussions with Diane Schaak at Rowland Institute at Harvard University. The authors thank Fang Fang and Lining Huang from Massachusetts General Hospital and Harvard Medical School for their help in harvesting cortex neurons of mice. The cost of isoflurane was generously provided by the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School. The research was supported in part by the Rowland Junior Fellowship Award at Rowland Institute at Harvard University, Cambridge, Massachusetts (to Q.Q.), and in part by R01 GM088801, R01 AG041274, and R01 HD086977 from the National Institutes of Health, Bethesda, Maryland (to Z.X.). NR 36 TC 1 Z9 1 U1 11 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD JUL PY 2016 VL 16 IS 7 BP 3989 EP 3994 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DR3HL UT WOS:000379794200004 PM 27266855 ER PT J AU Richards, DJ Tan, Y Coyle, R Li, Y Xu, RY Yeung, N Parker, A Menick, DR Tian, BZ Mei, Y AF Richards, Dylan J. Tan, Yu Coyle, Robert Li, Yang Xu, Ruoyu Yeung, Nelson Parker, Arran Menick, Donald R. Tian, Bozhi Mei, Ying TI Nanowires and Electrical Stimulation Synergistically Improve Functions of hiPSC Cardiac Spheroids SO NANO LETTERS LA English DT Article DE Silicon nanowires; electrical stimulation; cardiac spheroids; human induced pluripotent stem cell-derived cardiomyocytes ID CELL-DERIVED CARDIOMYOCYTES; PLURIPOTENT STEM-CELLS; MYOCARDIAL-INFARCTION; HEART-FAILURE; IN-VITRO; GAP-JUNCTIONS; RAT HEARTS; MATURATION; TISSUE; EXPRESSION AB The advancement of human induced pluripotent stem-cell-derived cardiomyocyte (hiPSC-CM) technology has shown promising potential to provide a patient-specific, regenerative cell therapy strategy to treat cardiovascular disease. Despite the progress, the unspecific, underdeveloped phenotype of hiPSC-CMs has shown arrhythmogenic risk and limited functional improvements after transplantation. To address this, tissue engineering strategies have utilized both exogenous and endogenous stimuli to accelerate the development of hiPSC-CMs. Exogenous electrical stimulation provides a biomimetic pacemaker-like stimuli that has been shown to advance the electrical properties of tissue engineered cardiac constructs. Recently, we demonstrated that the incorporation of electrically conductive silicon nanowires to hiPSC cardiac spheroids led to advanced structural and functional development of hiPSC-CMs by improving the endogenous electrical microenvironment. Here, we reasoned that the enhanced endogenous electrical microenvironment of nanowired hiPSC cardiac spheroids would synergize with exogenous electrical stimulation to further advance the functional development of nanowired hiPSC cardiac spheroids. For the first time, we report that the combination of nanowires and electrical stimulation enhanced cell cell junction formation, improved development of contractile machinery, and led to a significant decrease in the spontaneous beat rate of hiPSC cardiac spheroids. The advancements made here address critical challenges for the use of hiPSC-CMs in cardiac developmental and translational research and provide an advanced cell delivery vehicle for the next generation of cardiac repair. C1 [Richards, Dylan J.; Tan, Yu; Coyle, Robert; Li, Yang; Yeung, Nelson; Parker, Arran; Mei, Ying] Clemson Univ, Bioengn Dept, Clemson, SC 29634 USA. [Xu, Ruoyu; Tian, Bozhi] Univ Chicago, James Franck Inst, Dept Chem, Chicago, IL 60637 USA. [Xu, Ruoyu; Tian, Bozhi] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA. [Menick, Donald R.] Med Univ South Carolina, Gazes Cardiac Res Inst, Div Cardiol, Dept Med, Charleston, SC 29425 USA. [Mei, Ying] Med Univ South Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Menick, Donald R.] Med Univ South Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Mei, Y (reprint author), Clemson Univ, Bioengn Dept, Clemson, SC 29634 USA.; Mei, Y (reprint author), Med Univ South Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. EM mei@clemson.edu FU National Institutes of Health [8P20 GM103444, U54 GM104941]; Clemson University; National Science Foundation [NSF - EPS-0903795]; NIH Cardiovascular Training Grant [T32 HL007260]; US Department of Veterans Affairs Merit Review [I01 BX002327]; NIH-NIGMS [P30 GM103342] FX The work is supported by the National Institutes of Health (8P20 GM103444, U54 GM104941), the startup funds from Clemson University, the National Science Foundation (NSF - EPS-0903795), the NIH Cardiovascular Training Grant (T32 HL007260), and US Department of Veterans Affairs Merit Review (I01 BX002327). This study used the services of the Morphology, Imaging, and Instrumentation Core, which is supported by NIH-NIGMS P30 GM103342 to the South Carolina COBRE for Developmentally Based Cardiovascular Diseases. NR 56 TC 1 Z9 1 U1 17 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD JUL PY 2016 VL 16 IS 7 BP 4670 EP 4678 DI 10.1021/acs.nanolett.6b02093 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DR3HL UT WOS:000379794200101 PM 27328393 ER PT J AU Ben-David, U Ha, G Khadka, P Jin, X Wong, B Franke, L Golub, TR AF Ben-David, Uri Ha, Gavin Khadka, Prasidda Jin, Xin Wong, Bang Franke, Lude Golub, Todd R. TI The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis SO NATURE COMMUNICATIONS LA English DT Article ID COPY-NUMBER ALTERATION; COMPREHENSIVE MOLECULAR PORTRAITS; GENE-EXPRESSION PROFILES; PLURIPOTENT STEM-CELLS; GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR; MAMMARY-TUMORS; 14-3-3 SIGMA; SENSITIVITY; IDENTIFICATION AB Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tumorigenesis, and observe marked differences in CNA prevalence between mouse mammary tumours initiated with distinct drivers. Some aberrations are recurrent and unique to specific GEMMs, suggesting distinct driver-dependent routes to tumorigenesis. Synteny-based comparison of mouse and human tumours narrows critical regions in CNAs, thereby identifying candidate driver genes. We experimentally validate that loss of Stratifin (SFN) promotes HER2-induced tumorigenesis in human cells. These results demonstrate the power of GEMM CNA analysis to inform the pathogenesis of human cancer. C1 [Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Golub, Todd R.] Harvard & MIT, Broad Inst, Canc Program, Cambridge, MA 02142 USA. [Ha, Gavin; Golub, Todd R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9711 Groningen, Netherlands. [Golub, Todd R.] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20811 USA. RP Golub, TR (reprint author), Harvard & MIT, Broad Inst, Canc Program, Cambridge, MA 02142 USA.; Golub, TR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Golub, TR (reprint author), Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA.; Golub, TR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20811 USA. EM golub@broadinstitute.org RI Franke, Lude/P-7036-2016 OI Franke, Lude/0000-0002-5159-8802 FU Human Frontiers Science Program postdoctoral fellowship FX We thank Pablo Tamayo, Steven Schumacher, Craig Bielski and John Mercer for assistance with the data assembly; Dihua Yu for the MCF10A cells; and Gad Getz, Rameen Beroukhim and Zuzana Tothova for the helpful discussions. U.B.-D. is supported by a Human Frontiers Science Program postdoctoral fellowship. NR 51 TC 3 Z9 3 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2016 VL 7 AR 12160 DI 10.1038/ncomms12160 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR4ZJ UT WOS:000379912200001 PM 27374210 ER PT J AU Rambout, X Detiffe, C Bruyr, J Mariavelle, E Cherkaoui, M Brohee, S Demoitie, P Lebrun, M Soin, R Lesage, B Guedri, K Beullens, M Bollen, M Farazi, TA Kettmann, R Struman, I Hill, DE Vidal, M Kruys, V Simonis, N Twizere, JC Dequiedt, F AF Rambout, Xavier Detiffe, Cecile Bruyr, Jonathan Mariavelle, Emeline Cherkaoui, Majid Brohee, Sylvain Demoitie, Pauline Lebrun, Marielle Soin, Romuald Lesage, Bart Guedri, Katia Beullens, Monique Bollen, Mathieu Farazi, Thalia A. Kettmann, Richard Struman, Ingrid Hill, David E. Vidal, Marc Kruys, Veronique Simonis, Nicolas Twizere, Jean-Claude Dequiedt, Franck TI The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID BINDING PROTEINS; MAMMALIAN-CELLS; STRESS GRANULES; GENE-EXPRESSION; FISSION YEAST; P-BODIES; DEGRADATION; COMPLEX; FAMILY; STABILITY AB Control of mRNA levels, a fundamental aspect in the regulation of gene expression, is achieved through a balance between mRNA synthesis and decay. E26-related gene (Erg) proteins are canonical transcription factors whose previously described functions are confined to the control of mRNA synthesis. Here, we report that ERG also regulates gene expression by affecting mRNA stability and identify the molecular mechanisms underlying this function in human cells. ERG is recruited to mRNAs via interaction with the RNA-binding protein RBPMS, and it promotes mRNA decay by binding CNOT2, a component of the CCR4-NOT deadenylation complex. Transcriptome-wide mRNA stability analysis revealed that ERG controls the degradation of a subset of mRNAs highly connected to Aurora signaling, whose decay during S phase is necessary for mitotic progression. Our data indicate that control of gene expression by mammalian transcription factors may follow a more complex scheme than previously anticipated, integrating mRNA synthesis and degradation. C1 [Rambout, Xavier; Detiffe, Cecile; Bruyr, Jonathan; Mariavelle, Emeline; Cherkaoui, Majid; Demoitie, Pauline; Lebrun, Marielle; Guedri, Katia; Kettmann, Richard; Struman, Ingrid; Twizere, Jean-Claude; Dequiedt, Franck] Univ Liege ULg, Interdisciplinary Cluster Appl Genoprote GIGA R, Liege, Belgium. [Rambout, Xavier; Detiffe, Cecile; Bruyr, Jonathan; Mariavelle, Emeline; Cherkaoui, Majid; Demoitie, Pauline; Guedri, Katia; Kettmann, Richard; Twizere, Jean-Claude; Dequiedt, Franck] ULg, GIGA Mol Biol Dis, Liege, Belgium. [Brohee, Sylvain; Simonis, Nicolas] ULB, BiGRe, Brussels, Belgium. [Brohee, Sylvain] ULB, Comp Sci Dept, Brussels, Belgium. [Lebrun, Marielle] ULg, GIGA Inflammat Infect & Immun, Liege, Belgium. [Soin, Romuald; Kruys, Veronique] ULB, Fac Sci, Gosselies, Belgium. [Lesage, Bart; Beullens, Monique; Bollen, Mathieu] Univ Leuven KUL, Dept Cellular & Mol Med, Leuven, Belgium. [Farazi, Thalia A.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Struman, Ingrid] ULg, GIGA Canc, Liege, Belgium. [Hill, David E.; Vidal, Marc] DFCI, Dept Canc Biol, CCSB, Boston, MA USA. [Hill, David E.; Vidal, Marc] Harvard Med Sch, Dept Genet, Boston, MA USA. RP Dequiedt, F (reprint author), Univ Liege ULg, Interdisciplinary Cluster Appl Genoprote GIGA R, Liege, Belgium.; Dequiedt, F (reprint author), ULg, GIGA Mol Biol Dis, Liege, Belgium. EM fdequiedt@ulg.ac.be FU University of Liege; Fonds Leon Fredericq; Belgian Foundation against Cancer (Special Equipment Fund); Belgian National Fund for Scientific Research (FNRS), Televie; Interuniversity Attraction Poles Program-Belgian Science Policy (IUAP-BELSPO) [PVI/28, PVII/13]; National Human Genome research Institute [R01HG001715] FX We thank the Vidal laboratory at the Center for Cancer Systems Biology at the Dana-Farber Cancer Institute (CCSB, DFCI) for supplying reagents, advice and technical support for the HT-Y2H screen. We thank the Tuschl laboratory (Howard Hughes Medical Institute, Rockefeller University) for sharing reagents. We are grateful to E. Izaurralde (European Molecular Biology Laboratory) for kindly providing HA-tagged CNOT2, CNOT3, CNOT6 and CNOT. We would like to thank the laboratories of the Molecular Biology in Diseases Unit (GIGA-R, ULg) for helpful discussions and C. Vindry from the Kruys laboratory for technical assistance. We thank the GIGA interactomics, imaging and flow cytometry and genotranscriptomics platforms for their technical support. This work was supported by grants from the University of Liege, the Fonds Leon Fredericq, the Belgian Foundation against Cancer (Special Equipment Fund), the Belgian National Fund for Scientific Research (FNRS), Televie, the Interuniversity Attraction Poles Program-Belgian Science Policy IUAP-BELSPO PVI/28 and PVII/13 to F.D. and M. Bollen) and the National Human Genome research Institute (grant R01HG001715 to M.V. and D.E.H.). X.R., J-C.T. and N.S. are supported as an FNRS Research Fellow, Research Associate and Postdoctoral Fellow, respectively. C.D. and K.G. are supported as Televie-FNRS PhD students. NR 52 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 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUL PY 2016 VL 23 IS 7 BP 663 EP 672 DI 10.1038/nsmb.3243 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DQ7DX UT WOS:000379368200008 PM 27273514 ER PT J AU Sivaraman, KR Jivrajka, RV Soin, K Bouchard, CS Movahedan, A Shorter, E Jain, S Jacobs, DS Djalilian, AR AF Sivaraman, Kavitha R. Jivrajka, Renu V. Soin, Ketki Bouchard, Charles S. Movahedan, Asadolah Shorter, Ellen Jain, Sandeep Jacobs, Deborah S. Djalilian, Ali R. TI Superior Limbic Keratoconjunctivitis-like Inflammation in Patients with Chronic Graft-Versus-Host Disease SO OCULAR SURFACE LA English DT Article DE Limbal stem cell dysfunction; ocular chronic graft-versus-host disease; prosthetic replacement of the ocular surface (PROSE); superior limbic keratoconjunctivitis ID STEM-CELL TRANSPLANTATION; EYE DISEASE; DRY EYE; MANAGEMENT; PATHOGENESIS; DIAGNOSIS; BLINK; LENS AB Purpose: Describe the presentation and management of superior limbic keratoconjunctivitis (SLK)-like inflammation and secondary limbal stem cell dysfunction in the setting of ocular chronic graft-versus-host disease (cGVHD). Methods: Retrospective observational case series in a multicenter clinical practice. Participants were 13 patients (26 eyes) with ocular cGVHD and SLK-like inflammation presenting to the University of Illinois at Chicago and BostonSight (R) between January 1, 2009 and July 1, 2013. Main outcome measures: 1) Reversal or worsening of SLK, and 2) development of limbal stem cell dysfunction. Results: All eyes showed evidence of SLK-like inflammation and superior limbal stem cell dysfunction manifested by conjunctival injection and superior conjunctival and corneal staining. In addition to aggressive lubrication, management strategies for SLK included topical steroids (20/26), punctal occlusion (18/26), topical cyclosporine (24/26), autologous serum tears (12/26), therapeutic soft contact lens (13/26 eyes) and scleral lenses (4/26 eyes). SLK and limbal stem cell dysfunction were reversed in 23/26 eyes. Three eyes of two patients with long-standing disease demonstrated frank limbal stem cell deficiency (LSCD) and corneal pannus, with one patient requiring multiple reconstructive surgical procedures. Conclusions: SLK-like inflammation is an under-recognized condition in patients with severe dry eyes secondary to ocular cGVHD. Untreated SLK can potentially lead to permanent LSCD over time. Early recognition and management of SLK in ocular cGVHD can improve vision, reverse signs, and may prevent these long-term consequences. C1 [Sivaraman, Kavitha R.; Jivrajka, Renu V.; Soin, Ketki; Movahedan, Asadolah; Shorter, Ellen; Jain, Sandeep; Djalilian, Ali R.] Univ Illinois, Illinois Eye & Ear Infirm, Dept Ophthalmol & Visual Sci, Chicago, IL USA. [Bouchard, Charles S.] Loyola Univ, Dept Ophthalmol, Maywood, IL USA. [Jacobs, Deborah S.] BostonSight, Needham Hts, MA USA. [Jacobs, Deborah S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Djalilian, AR (reprint author), 1855 W Taylor St M-C 648, Chicago, IL 60612 USA. EM adjalili@uic.edu FU National Institutes of Health (Bethesda, Maryland) [EY01792]; Research to Prevent Blindness FX Core grant EY01792 from the National Institutes of Health (Bethesda, Maryland), Career development grant (Ali R. Djalilian) and unrestricted grant from Research to Prevent Blindness. The sponsors or funding organizations had no role in the design or conduct of this research. NR 23 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1542-0124 EI 1937-5913 J9 OCUL SURF JI Ocul. Surf. PD JUL PY 2016 VL 14 IS 3 BP 393 EP 400 PG 8 WC Ophthalmology SC Ophthalmology GA DQ9CI UT WOS:000379507600009 PM 27179980 ER PT J AU Grunmuller, L Thierauf, J Weissinger, SE Bergmann, C Bankfalvi, A Veit, J Hoffmann, TK Moller, P Lennerz, JK AF Gruenmueller, Lisa Thierauf, Julia Weissinger, Stephanie E. Bergmann, Christoph Bankfalvi, Agnes Veit, Johannes Hoffmann, Thomas K. Moeller, Peter Lennerz, Jochen K. TI Biopanel identifies expression status of targetable proteins in sinonasal melanoma SO PERSONALIZED MEDICINE LA English DT Article DE biopanel; biomarker; prognostic; trial design ID MUCOSAL MALIGNANT-MELANOMA; GROWTH-FACTOR RECEPTOR; METASTATIC MELANOMA; BRAF MUTATIONS; THERAPEUTIC TARGET; CLINICAL-PRACTICE; PHASE-II; C-MET; HEAD; NECK AB Background: Advanced stage at presentation, lack of BRAF mutations and overall rarity pose unique challenges to the therapy and trial design in sinonasal melanoma. Methods: Here, we assessed the expression status of 12 proteins in two independent cohorts of sinonasal melanoma (n = 20). Results: Each case showed expression of at least one protein (KIT, TP53, MYC, HER2, EGFR, MET, VEGFR, BRAF V600E and/or MDM2), whereas lack of ALK, FLI1 and PDGFR alpha expression underscores differences to cutaneous melanoma. Comparison of marker frequencies to a metareview of the literature indicates that MYC, HER2, EGFR and MET had not been previously assessed. Conclusion: Expression of at least one potentially targetable protein per case illustrates proteome pathway profiling as one starting point for marker stratified trial design. C1 [Gruenmueller, Lisa; Weissinger, Stephanie E.; Moeller, Peter; Lennerz, Jochen K.] Univ Ulm, Inst Pathol, Ulm, Germany. [Thierauf, Julia; Veit, Johannes; Hoffmann, Thomas K.] Univ Med Ctr Ulm, Dept Otorhinolaryngol Head & Neck Surg, Ulm, Germany. [Bergmann, Christoph] Univ Hosp Essen, Dept Otorhinolaryngol, Essen, Germany. [Bankfalvi, Agnes] Univ Hosp Essen, Dept Pathol, Essen, Germany. [Lennerz, Jochen K.] Harvard Med Sch, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Lennerz, JK (reprint author), Univ Ulm, Inst Pathol, Ulm, Germany.; Lennerz, JK (reprint author), Harvard Med Sch, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM jlennerz@partners.org FU Else-Kroner Fresenius Foundation; Dres. Bayer foundation (Ravensburg, Germany); Hertha Nathorff Program (University Ulm, Ulm Germany) FX The Else-Kroner Fresenius Foundation supported JK Lennerz; SE Weissinger is supported by the Dres. Bayer foundation (Ravensburg, Germany) and the Hertha Nathorff Program (University Ulm, Ulm Germany). All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript. 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 71 TC 0 Z9 0 U1 2 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PD JUL PY 2016 VL 13 IS 4 BP 291 EP 301 DI 10.2217/pme-2016-0023 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ6ZA UT WOS:000379354800003 ER PT J AU Hardiman, G Savage, SJ Hazard, ES Wilson, RC Courtney, SM Smith, MT Hollis, BW Halbert, CH Gattoni-Celli, S AF Hardiman, Gary Savage, Stephen J. Hazard, E. Starr Wilson, Robert C. Courtney, Sean M. Smith, Michael T. Hollis, Bruce W. Halbert, Chanita Hughes Gattoni-Celli, Sebastiano TI Systems analysis of the prostate transcriptome in African-American men compared with European-American men SO PHARMACOGENOMICS LA English DT Article DE African-American; health disparities; prostate; RNA-seq; transcription; vitamin D ID VITAMIN-D-RECEPTOR; DIFFERENTIAL EXPRESSION ANALYSIS; CANCER PREVENTION TRIAL; 1,25-DIHYDROXYVITAMIN D-3; 25-HYDROXYVITAMIN D; WHITE MEN; SUPPLEMENTATION; CELLS; RISK; GENE AB Aim: African-Americans (AA) have increased prostate cancer risk and a greater mortality rate than European-Americans (EA). AA exhibit a high prevalence of vitamin D deficiency. We examined the global prostate transcriptome in AA and EA, and the effect of vitamin D-3 supplementation. Patients & methods: Twenty-seven male subjects (ten AA and 17 EA), slated to undergo prostatectomy were enrolled in the study. Fourteen subjects received vitamin D-3 (4000 IU daily) and 13 subjects received placebo for 2 months prior to surgery. Results: AA show higher expression of genes associated with immune response and inflammation. Conclusion: Systems level analyses support the concept that Inflammatory processes may contribute to disease progression in AA. These transcripts can be modulated by a short course of vitamin D-3 supplementation. C1 [Hardiman, Gary] Med Univ South Carolina, Dept Med & Publ Hlth, Charleston, SC 29425 USA. [Hardiman, Gary; Hazard, E. Starr; Wilson, Robert C.; Courtney, Sean M.] Med Univ South Carolina, Ctr Genom Med, Charleston, SC 29425 USA. [Hazard, E. Starr] Med Univ South Carolina, Lib Sci & Informat, Charleston, SC USA. [Savage, Stephen J.] Ralph H Johnson VA Med Ctr, Dept Urol, Charleston, SC USA. [Savage, Stephen J.; Halbert, Chanita Hughes; Gattoni-Celli, Sebastiano] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Wilson, Robert C.; Smith, Michael T.] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC USA. [Hollis, Bruce W.] Med Univ South Carolina, Dept Pediat, Charleston, SC USA. [Halbert, Chanita Hughes] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Gattoni-Celli, Sebastiano] Med Univ South Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. RP Hardiman, G (reprint author), Med Univ South Carolina, Dept Med & Publ Hlth, Charleston, SC 29425 USA.; Hardiman, G (reprint author), Med Univ South Carolina, Ctr Genom Med, Charleston, SC 29425 USA.; Gattoni-Celli, S (reprint author), Ralph H Johnson VA Med Ctr, Charleston, SC USA.; Gattoni-Celli, S (reprint author), Med Univ South Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. EM hardiman@musc.edu; gattonis@musc.edu FU Veterans Administration (VA) CSRD Merit Award [CX000753]; MUSC Center for Genomic Medicine; MUSCCOM; Genomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina; Hollings Cancer Center, Medical University of South Carolina [P30 CA 138313] FX This research was funded by Veterans Administration (VA) CSR&D Merit Award CX000753 and a Pilot Project grant from the MUSC Center for Genomic Medicine to SG-C and MUSCCOM start-up funds to GTH. The authors also acknowledge support from the Genomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina. This shared resource is supported in part by the Hollings Cancer Center, Medical University of South Carolina Support Grant (P30 CA 138313). 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 46 TC 2 Z9 2 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUL PY 2016 VL 17 IS 10 BP 1129 EP 1143 DI 10.2217/pgs-2016-0025 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR3XC UT WOS:000379835000003 PM 27359067 ER PT J AU Mastroianni, M Lin, AM Smith, BL Austen, WG Colwell, AS AF Mastroianni, Melissa Lin, Alex M. Smith, Barbara L. Austen, William G., Jr. Colwell, Amy S. TI Nipple Loss following Nipple-Sparing Mastectomy SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID BREAST RECONSTRUCTION; OUTCOMES; CANCER; AREOLA; SKIN; COMPLICATIONS; INVOLVEMENT AB Background: Nipple preservation at the time of mastectomy is increasingly performed to enhance the overall result from the reconstruction. Unfortunately, some of these patients may lose their nipples for oncologic reasons or because of necrosis. Several studies have investigated risk factors associated with nipple loss, but few data exist on the incidence of cancer in the nipple specimen, nipple removal for cosmesis or symmetry, and whether these patients subsequently pursue nipple reconstruction. Methods: A retrospective review was performed on nipple-sparing mastectomies and immediate reconstruction from 2007 to 2013. Results: Of 443 patients (775 breasts), 51 nipples (6.6 percent) were removed. Of the 51 nipple losses, 76 percent had total nipple or nipple-areola complex loss and 24 percent had partial loss. Twenty-five of the nipples (49 percent) required excision for oncologic reasons, 18 nipples (35 percent) were either partially or totally lost because of necrosis, and one nipple (2 percent) was excised for cosmetic reasons. In cases of bilateral reconstruction and unilateral nipple loss, 65 percent of contralateral normal nipples were retained and 35 percent (n = 7) were removed for symmetry. Fourteen nipples had residual cancer or atypia, whereas 37 had normal pathologic findings. Twenty-one nipples (40 percent) were reconstructed and 30 were not. Conclusions: In this series, the incidence of nipple loss following nipple-sparing mastectomy was 6.6 percent and related primarily to positive oncologic margins. The rate of removal for cosmesis was low, suggesting that for most patients the nipple lies in an acceptable position. After removal, 40 percent of patients had nipple reconstruction. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Oncol, Boston, MA USA. RP Colwell, AS (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WACC 435, Boston, MA 02114 USA. EM acolwell@partners.org NR 16 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD JUL PY 2016 VL 138 IS 1 BP 24E EP 30E DI 10.1097/PRS.0000000000002296 PG 7 WC Surgery SC Surgery GA DQ6RG UT WOS:000379332200004 PM 27348682 ER PT J AU Gassman, AA Lewis, MS Lee, JC AF Gassman, Andrew A. Lewis, Michael S. Lee, Justine C. TI Remote Ischemic Preconditioning Recipient Tissues Improves the Viability of Murine Fat Transfer SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID REPERFUSION INJURY; RAT MODEL; BREAST; RECONSTRUCTION; TRANSPLANTATION; SURVIVAL; HARVEST; CELLS; HEART; SIZE AB Background: Local ischemia before the development of recipient circulation may contribute to the highly variable long-term results of fat grafting. Remote ischemic preconditioning before adipose procurement augments the retention of fat grafts and limits subsequent liposclerosis. However, there is no literature examining what role remote ischemic preconditioning has on the fat graft recipient site. Methods: Subcutaneous adipose tissue from transgenic mice expressing green fluorescent protein/luciferase was injected into skin folds of wild-type mice. Donors and recipients experienced intermittent temporary hindlimb tourniquet application before harvest and transfer, respectively. The viability of the transferred tissue was examined over 28 days by luciferin bioluminescence and subsequent histologic analysis. Results: There was a difference in bioluminescence at days 0, 14, and 28. The remote ischemic preconditioning donor or recipient mouse-alone groups demonstrated an approximately 2- to 3-fold increase in bioluminescence. Donor and recipient remote ischemic preconditioning had a 9-fold increase in bioluminescence. Histologic analysis at 28 days confirmed the presence of donor adipocytes, and they were gradually replaced by recipient inflammation and scar tissue. However, the amount of interstitial fibrosis was substantially less in the remote ischemic preconditioning groups. These findings were more pronounced when remote ischemic preconditioning was used for both donor and recipient mice. Conclusions: Remote ischemic preconditioning has the ability to increase the viability of donor adipocytes and limit interstitial fibrosis. More specifically, remote ischemic preconditioning treatment of both donated adipose tissue and recipient wound beds demonstrates the greatest overall adipose cellular viability and native architecture. C1 [Gassman, Andrew A.] Univ Texas Southwestern Med Ctr, Dept Plast Surg, 1801 Inwood Rd, Dallas, TX 75390 USA. Univ Calif Los Angeles, David Geffen Sch Med, Div Plast & Reconstruct Surg, Los Angeles, CA 90095 USA. Greater Los Angeles VA Healthcare Syst, Dept Pathol, Los Angeles, CA USA. RP Gassman, AA (reprint author), Univ Texas Southwestern Med Ctr, Dept Plast Surg, 1801 Inwood Rd, Dallas, TX 75390 USA. EM andrew.gassman@utsouthwestern.edu FU Plastic Surgery Foundation [274376]; Jean Perkins Foundation FX This work was supported by the Plastic Surgery Foundation (Pilot Research Grant number 274376) (to A.A.G.) and the Jean Perkins Foundation (to J.C.L.). NR 24 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 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD JUL PY 2016 VL 138 IS 1 BP 55E EP 63E DI 10.1097/PRS.0000000000002295 PG 9 WC Surgery SC Surgery GA DQ6RG UT WOS:000379332200008 PM 27348686 ER PT J AU Liao, EC AF Liao, Eric C. TI Different Acellular Dermal Matrix Preparations, Different Surgeons, Different Outcomes: What Factors Matter? SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter ID POSTMASTECTOMY BREAST RECONSTRUCTION C1 [Liao, Eric C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg, Boston, MA USA. RP Liao, EC (reprint author), Harvard Univ, Sch Med, WACC Suite 435,15 Parkman St, Boston, MA 02114 USA. EM cliao@partners.org NR 6 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 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD JUL PY 2016 VL 138 IS 1 BP 145E EP 146E DI 10.1097/PRS.0000000000002273 PG 2 WC Surgery SC Surgery GA DQ6RG UT WOS:000379332200020 PM 27351472 ER PT J AU Mattos, D Liao, EC AF Mattos, David Liao, Eric C. TI Reply: Lifetime Costs of Prophylactic Mastectomies and Reconstruction versus Surveillance SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter C1 [Mattos, David; Liao, Eric C.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Liao, EC (reprint author), 15 Parkman St,WACC 435, Boston, MA 02114 USA. EM cliao@partners.org NR 2 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 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD JUL PY 2016 VL 138 IS 1 BP 152E EP 153E DI 10.1097/PRS.0000000000002279 PG 3 WC Surgery SC Surgery GA DQ6RG UT WOS:000379332200027 PM 27351478 ER PT J AU Siddiqui, IJ Luz, J Borg-Stein, J O'Connor, K Bockbrader, M Rainey, H Way, D Colachis, S Bahner, DP Kohler, MJ AF Siddiqui, Imran J. Luz, Jennifer Borg-Stein, Joanne O'Connor, Kevin Bockbrader, Marcia Rainey, Heather Way, David Colachis, Sam Bahner, David P. Kohler, Minna J. TI The Current State of Musculoskeletal Ultrasound Education in Physical Medicine and Rehabilitation Residency Programs SO PM&R LA English DT Article ID COMPETENCE ASSESSMENT; UNITED-STATES; RHEUMATOLOGY; ULTRASONOGRAPHY; SONOGRAPHY; CURRICULUM; KNOWLEDGE; FELLOWS AB Background: Exposure to musculoskeletal ultrasound (MSUS) is now a mandatory component of physical medicine and rehabilitation (PM&R) residency training. However, reports on the extent of the implementation and efficacy of MSUS education are lacking in the literature. Objective: To determine the extent to which PM&R residencies are implementing MSUS education. Design: Cross-sectional. Setting: Institutional. Participants: Thirty-six of the 78 United States PM&R residency programs accredited by the Accreditation Council for Graduate Medical Education. Methods: All 78 programs were solicited with an online survey via the residency program director and coordinator in July 2014. The 25 questions on the survey were aimed at determining program MSUS educational characteristics and their effectiveness. Main Outcome Measures: Description of teaching methods used for MSUS, residency demographics, characteristics of MSUS faculty expertise, and faculty-perceived competency in MSUS examinations and procedures among residents. Data were analyzed using both descriptive statistics and tests for independence to identify correlations between program characteristics and resident MSUS competency. Results: A response was received from 36 of the 78 residency programs (46.2%). Of the 36 residency programs that responded, 97.2% provide exposure to MSUS (a figure that drops to 44.9% when nonrespondents are included); 61% had mandatory MSUS training (28.2% when including nonrespondents); and 44.4% had a formal curriculum (20.5% when including nonrespondents). The most common MSUS educational tools used were lecture (88.9%), outpatient clinic (86.1%), and hands-on workshops (86.1%). Sixty-one percent of responding programs evaluate residents with formal assessment tools. Overall, faculty at 38.8% and 44.4% of programs believed that at least 50% of residents who graduate are competent in diagnostic and interventional MSUS, respectively. These rates were significantly associated with the use of formal assessment. Conclusion: MSUS education is growing in PM&R, but many programs still have not adopted a formal educational curriculum. Formal assessment to evaluate resident MSUS skills significantly improves faculty-perceived MSUS competency. C1 [Siddiqui, Imran J.; Luz, Jennifer; Borg-Stein, Joanne; O'Connor, Kevin] Harvard Med Sch, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Boston, MA USA. [Siddiqui, Imran J.] Regenerat Orthoped & Sports Med, Washington, DC USA. [Bockbrader, Marcia; Rainey, Heather; Way, David; Colachis, Sam] Ohio State Univ, Wexner Med Ctr, Dept Phys Med & Rehabil, Columbus, OH 43210 USA. [Bahner, David P.] Ohio State Univ, Dept Emergency Med, Wexner Med Ctr, Columbus, OH 43210 USA. [Kohler, Minna J.] Harvard Med Sch, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, 55 Fruit St,Yawkey 2C, Boston, MA 02114 USA. RP Kohler, MJ (reprint author), Harvard Med Sch, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, 55 Fruit St,Yawkey 2C, Boston, MA 02114 USA. EM mkohler@mgh.harvard.edu RI Bockbrader, Marcia/J-6203-2013; OI Bockbrader, Marcia/0000-0001-6419-0630; Way, David/0000-0002-1896-3425 FU Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institute of Health); Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institute of Health) [UL138 TR001102]; Harvard University FX This work was conducted with support from Harvard Catalyst/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 UL138 TR001102) and financial contributions from Harvard University and its affiliated academic health care 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 health care centers, or the National Institutes of Health. NR 30 TC 0 Z9 0 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD JUL PY 2016 VL 8 IS 7 BP 660 EP 666 DI 10.1016/j.pmrj.2015.11.010 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DR1RB UT WOS:000379681500007 PM 26690020 ER PT J AU Nagpal, A Xu, R Pangarkar, S Dworkin, I Singh, JR AF Nagpal, Ameet Xu, Rachel Pangarkar, Sanjog Dworkin, Ian Singh, Jaspal R. TI Driving Under the Influence of Opioids SO PM&R LA English DT Editorial Material ID CHRONIC NONMALIGNANT PAIN; DRUG-ABUSING VOLUNTEERS; NEUROPSYCHOLOGICAL PERFORMANCE; PRESCRIPTION OPIOIDS; ORAL OXYCODONE; NONCANCER PAIN; UNITED-STATES; MORPHINE; PSYCHOMOTOR; THERAPY C1 [Nagpal, Ameet; Xu, Rachel] Univ Texas Hlth Sci Ctr San Antonio, Dept Anesthesiol, San Antonio, TX 78229 USA. [Pangarkar, Sanjog] Vet Hlth Serv, Inpatient Pain Serv, Dept Phys Med & Rehabil, Los Angeles, CA USA. [Dworkin, Ian] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Dept Phys Med & Rehabil, Los Angeles, CA USA. [Singh, Jaspal R.] Weill Cornell Med Coll, Phys Med & Rehabil, 525 E 68th St,Baker 16, New York, NY 10065 USA. RP Singh, JR (reprint author), Weill Cornell Med Coll, Phys Med & Rehabil, 525 E 68th St,Baker 16, New York, NY 10065 USA. EM jrs9012@med.cornell.edu NR 43 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 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD JUL PY 2016 VL 8 IS 7 BP 698 EP 705 DI 10.1016/j.pmrj.2016.05.010 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DR1RB UT WOS:000379681500011 PM 27406008 ER PT J AU Schapira, MM Imbert, D Oh, E Byhoff, E Shea, JA AF Schapira, Marilyn M. Imbert, Diana Oh, Eric Byhoff, Elena Shea, Judy A. TI Public engagement with scientific evidence in health: A qualitative study among primary-care patients in an urban population SO PUBLIC UNDERSTANDING OF SCIENCE LA English DT Article DE decision making in science; health communication; patients; public understanding of science ID STATISTICAL LITERACY; INFORMATION; NUMERACY; RISK; COMMUNICATION; MEDICINE; PERCEPTIONS; CONFIDENCE; EXPERIENCE; CHOICE AB The purpose of this study is to explore the experience and perspective of patients regarding scientific evidence in health and the degree that this information impacts health behavior and medical decision making. A focus group study was conducted. Participants were recruited from an urban primary-care practice. The focus group discussions were audio-recorded, transcribed verbatim, and coded by two independent investigators. Emergent themes were identified. Participants (n=30) ranged in age from 30 to 79years, 60% were female, 77% were black, and 50% had at least some college experience. Three thematic areas informed a wide range in level of interest regarding scientific study design and result information: (1) scientific literacy, (2) medical decision making style, and (3) impact of culture and community on decision making. Our findings indicate that communication strategies that incorporate key elements of scientific study design, methods, and results will most effectively translate findings from comparative effectiveness research to patient-informed decision making regarding evidence-based health interventions. C1 [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Schapira, Marilyn M.; Imbert, Diana; Byhoff, Elena; Shea, Judy A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Oh, Eric] Swarthmore Coll, Swarthmore, PA 19081 USA. RP Schapira, MM (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Gen Internal Med, 1110 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM mschap@upenn.edu FU Robert Wood Johnson Foundation Health & Society Scholars program at the University of Pennsylvania FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from the Robert Wood Johnson Foundation Health & Society Scholars program at the University of Pennsylvania. NR 40 TC 0 Z9 0 U1 6 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0963-6625 EI 1361-6609 J9 PUBLIC UNDERST SCI JI Public Underst. Sci. PD JUL PY 2016 VL 25 IS 5 BP 612 EP 626 DI 10.1177/0963662514560489 PG 15 WC Communication; History & Philosophy Of Science SC Communication; History & Philosophy of Science GA DR3EW UT WOS:000379786400008 PM 25491359 ER PT J AU Grandhige, AP Timmer, M O'Neill, MJ Binney, ZO Quest, TE AF Grandhige, Anjali P. Timmer, Marjorie O'Neill, Michael J. Binney, Zachary O. Quest, Tammie E. TI Respiratory Therapists' Experiences and Attitudes Regarding Terminal Extubations and End-of-Life Care SO RESPIRATORY CARE LA English DT Article DE palliative care; respiratory therapist; ventilator; end of life ID WITHDRAWAL; SUPPORT; OUTCOMES; UNIT AB BACKGROUND: Respiratory therapists (RTs) routinely care for patients with life- limiting illnesses and in some hospitals are responsible for terminal extubations. Data on how such experiences affect RTs are scarce. The objective of this work was to survey RTs at 2 academic medical centers about their experiences caring for patients with terminal extubations. METHODS: An online survey was distributed to the hospitals' RTs. Survey data included demographics and experiences with end-of-life care and terminal extubations. The survey was derived from previously published questionnaires plus input from hospital RT leaders. RESULTS: Sixty-five of 173 RTs (37.6%) responded. Of these, 42.4% were >= 50 y old, and 62.7% were female. 20.3% had <= 5 y experience; 52.5% had >= 16 y. 93.8% self-reported being involved in at least one terminal extubation; of those, 36.1% reported performing >= 20. Nearly half (47.5%) wanted to be involved in family meetings discussing terminal extubations, but just 6.6% were frequently involved. Only 32.3% felt that they received adequate education regarding terminal illness in RT school; 32.3% reported gathering this knowledge while working. 60.0% wanted more formal education around terminal patient care. 27.9% reported sometimes being uncomfortable with performing a terminal extubation; most of these rarely felt that they had the option not to perform the extubation. CONCLUSIONS: RTs are rarely involved in end-of-life discussions despite a desire to be, and they experience situations that generate discomfort. There is demand for more formal RT training around care for terminal patients. Clinical protocols that involve RTs in meetings before ventilator withdrawal should be considered. C1 [Grandhige, Anjali P.; O'Neill, Michael J.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Timmer, Marjorie] Emory Univ Hosp, Dept Resp Care, Atlanta, GA USA. [Grandhige, Anjali P.; O'Neill, Michael J.; Binney, Zachary O.; Quest, Tammie E.] Emory Univ, Emory Palliat Care Ctr, Atlanta, GA USA. [Binney, Zachary O.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA. [Quest, Tammie E.] US Dept Vet Affairs, Med Ctr, Atlanta, GA USA. [Quest, Tammie E.] Emory Univ, Sch Med, Dept Emergency Med, Atlanta, GA USA. RP Grandhige, AP (reprint author), Emory Univ, Sch Med, Dept Med, Atlanta, GA USA.; Grandhige, AP (reprint author), Emory Univ, Emory Palliat Care Ctr, Atlanta, GA USA. EM anjali.grandhige@emory.edu NR 14 TC 1 Z9 1 U1 4 U2 4 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD JUL PY 2016 VL 61 IS 7 BP 891 EP 896 DI 10.4187/respcare.04168 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ5EU UT WOS:000379228600002 PM 27274094 ER PT J AU McConnell, RA Kerlin, MP Schweickert, WD Ahmad, F Patel, MS Fuchs, BD AF McConnell, Ryan A. Kerlin, Meeta Prasad Schweickert, William D. Ahmad, Faraz Patel, Mitesh S. Fuchs, Barry D. TI Using a Post-Intubation Checklist and Time Out to Expedite Mechanical Ventilation Monitoring: Observational Study of a Quality Improvement Intervention SO RESPIRATORY CARE LA English DT Article DE blood gas analysis; acidosis; artificial respiration; mechanical ventilators; checklist; quality improvement ID SURGICAL SAFETY CHECKLIST; CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; BLOOD-GAS-ANALYSIS; INTRAHOSPITAL TRANSPORT; HOSPITAL MORTALITY; MEDICAL TEAM; ARTERIAL; COMMUNICATION; OXYGEN AB BACKGROUND: Delayed mechanical ventilation monitoring may impede recognition of life-threatening acidemia. Coordination of multidisciplinary processes can be improved by using a checklist and time-out procedure. The study objective was to evaluate process-related outcomes after implementation of a post-intubation checklist and time out. METHODS: An observational study of a 24-bed medical ICU in Philadelphia, Pennsylvania, was conducted from January to December 2011. A random sample of mechanically ventilated adults was selected from the pre-intervention (n = 80) and post-intervention (n = 144) periods. The primary outcome was the proportion of subjects with an arterial blood gas (ABG) result within 60 min of mechanical ventilation initiation. Secondary outcomes included rates of respiratory acidosis, moderate-severe acidemia (pH < 7.25), checklist initiation, and project sustainability. Chi-square analysis was used to evaluate differences in outcomes between time periods. RESULTS: After the intervention, the proportion of subjects with an ABG result within 60 min increased (56% vs 37%, P = .01), and time to ABG result improved (58 min vs 79 min, P = .004). Adjusting for illness severity, the proportion with an ABG result within 60 min remained significantly higher in the post-intervention period (odds ratio 2.42, 95% CI 1.25-4.68, P = .009). Checklist adherence was higher with ICU intubations than for intubations performed outside the ICU (71% vs 27% checklist initiation rate, P < .001). Transfer from referring institutions (23% checklist initiation rate, P = .006) negatively impacted checklist use. Implementation challenges included frequent stakeholder turnover, undefined process ownership, and lack of real-time performance feedback. CONCLUSIONS: A post-intubation checklist and time out improved the timeliness of mechanical ventilation monitoring through more rapid assessment of arterial blood gases. Implementing this peri-intubation procedure may reduce the risks associated with transitioning to full mechanical ventilatory support. Optimal implementation necessitates strategies to surmount organizational and behavioral barriers to change. C1 [McConnell, Ryan A.] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA 94143 USA. [Kerlin, Meeta Prasad; Schweickert, William D.; Fuchs, Barry D.] Univ Penn, Dept Med, Div Pulm Allergy & Crit Care, Philadelphia, PA 19104 USA. [Ahmad, Faraz] Northwestern Univ, Dept Med, Div Cardiol, Chicago, IL 60611 USA. [Patel, Mitesh S.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Patel, Mitesh S.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP McConnell, RA (reprint author), Univ Calif San Francisco, Div Gastroenterol, 513 Parnassus Ave,S-357, San Francisco, CA 94143 USA. EM ryan.mcconnell@ucsf.edu NR 38 TC 1 Z9 1 U1 2 U2 2 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD JUL PY 2016 VL 61 IS 7 BP 902 EP 912 DI 10.4187/respcare.04191 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ5EU UT WOS:000379228600004 PM 26932381 ER PT J AU Saadi, A Patenaude, B Nirola, DK Deki, S Tshering, L Clark, S Shaull, L Sorets, T Fink, G Mateen, F AF Saadi, Altaf Patenaude, Bryan Nirola, Damber Kumar Deki, Sonam Tshering, Lhab Clark, Sarah Shaull, Lance Sorets, Tali Fink, Guenther Mateen, Farrah TI Quality of life in epilepsy in Bhutan SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Article DE Quality of life; Epilepsy; Asia; Education; Global health ID INVENTORY QOLIE-31; PSYCHOMETRIC PROPERTIES; SEIZURE FREQUENCY; HEALTH; RELIABILITY; VALIDITY; VERSION; STIGMA; COUNTRIES; PEOPLE AB Purpose: To assess the quality of life in epilepsy (QOLIE) among adults in the lower middle-income country of Bhutan and assess the potential demographic and clinical associations with better QOLIE. Methods: People with clinically diagnosed epilepsy were prospectively enrolled at the Jigme Dorji Wangchuck National Referral Hospital in Thimphu (2014-2015). Regression models were constructed to assess the potential impact of age, sex, residence in the capital city, wealth quintile, educational attainment, seizure in the prior year, seizures with loss of consciousness, self-reported stigma score, and need for multiple antiepileptic drugs. Results: The mean Bhutanese QOLIE-31 score among 172 adults (mean age 31.1 years, 93 female) was 48.9/100 +/- 17.7. Younger age, lower educational attainment level, and increased self-perceived stigma were each observed to have an independent, negative association with QOLIE (p < 0.05), while a patient's wealth quintile, sex, seizure frequency, seizure type and number of antiepileptic drugs were not. Education appeared to be most strongly associated with QOL at the high school and college levels. Conclusions: There are potentially modifiable associations with low QOLIE. Addressing the educational level and self-perceived stigma of PWE may have an especial impact. The low QOLIE in Bhutan may reflect cultural approaches to epilepsy, health services, or other factors including those outside of the health sector. (C) 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. C1 [Saadi, Altaf] Massachusetts Gen Hosp, Partners Neurol Residency, Boston, MA 02114 USA. [Saadi, Altaf] Brigham & Womans Hosp, Boston, MA USA. [Patenaude, Bryan; Fink, Guenther] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Nirola, Damber Kumar; Deki, Sonam; Tshering, Lhab] Jigme Dorji Wangchuck Natl Referral Hosp, Thimphu, Bhutan. [Clark, Sarah; Shaull, Lance; Sorets, Tali; Mateen, Farrah] Massachusetts Gen Hosp, 165 Cambridge St 627, Boston, MA 02114 USA. [Mateen, Farrah] Harvard Med Sch, Boston, MA USA. RP Mateen, F (reprint author), Massachusetts Gen Hosp, 165 Cambridge St 627, Boston, MA 02114 USA. EM asaadi@partners.org; bryanpatenaude@gmail.com; drnirola@yahoo.com; somlcey90@gmail.com; tsheringlhab999@gmail.com; sclark0929@gmail.com; Irshaull@gmail.com; tsorets@bbns.org; gfink@hsph.harvard.edu; fmateen@mgh.harvard.edu OI Nirola, Damber/0000-0003-3941-6081 FU Government of Canada FX Grand Challenges Canada, funded by the Government of Canada. NR 39 TC 2 Z9 2 U1 7 U2 7 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 EI 1532-2688 J9 SEIZURE-EUR J EPILEP JI Seizure PD JUL PY 2016 VL 39 BP 44 EP 48 DI 10.1016/j.seizure.2016.05.001 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DQ7FG UT WOS:000379371700009 PM 27257785 ER PT J AU Smock, KJ Plumhoff, EA Meijer, P Hsu, PH Zantek, ND Heikal, NM Van Cott, EM AF Smock, Kristi J. Plumhoff, Elizabeth A. Meijer, Piet Hsu, Peihong Zantek, Nicole D. Heikal, Nahla M. Van Cott, Elizabeth M. TI Protein S testing in patients with protein S deficiency, factor V Leiden, and rivaroxaban by North American Specialized Coagulation Laboratories SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Protein S; proficiency testing; NASCOLA; factor V Leiden; direct oral anticoagulants ID VENOUS THROMBOSIS; RISK-FACTOR; ASSAYS; ANTITHROMBIN; DABIGATRAN; DIAGNOSIS; FAMILIES; SEX; AGE AB In 2010-2012, the North American Specialized Coagulation Laboratory Association (NASCOLA) distributed 12 proficiency testing challenges to evaluate laboratory testing for protein S (PS). Results were analysed to assess the performance of PS activity, PS free antigen, and PS total antigen testing. Statistical analysis was performed on the numeric results and qualitative classification submitted for each method. There were 2,106 total results: 716 results from PS activity assays, 833 results from PS free antigen assays, and 557 results from PS total antigen assays. The three assay types performed well in the classification of five normal samples and nine abnormal samples, although certain PS activity methods were more likely to classify normal samples as abnormal and one PS total antigen assay was more likely to classify abnormal samples as normal. PS activity methods were affected by interfering substances such as heterozygous or homozygous factor V Leiden mutation (underestimation) and the anticoagulant drug rivaroxaban (overestimation). In conclusion, NASCOLA laboratories using a variety of PS assays performed well in the classification of clearly normal and abnormal samples. Laboratories performing PS activity assays should be aware of potential interferences in samples positive for FV Leiden or containing certain anticoagulant medications. C1 [Smock, Kristi J.; Heikal, Nahla M.] Univ Utah, Dept Pathol, ARUP Labs, 500 Chipeta Way,Mail Stop 115-G04, Salt Lake City, UT 84108 USA. [Plumhoff, Elizabeth A.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Meijer, Piet] ECAT Fdn, Voorschoten, Netherlands. [Hsu, Peihong] Northwell Hlth Syst, Dept Pathol & Lab Med, Lake Success, NY USA. [Hsu, Peihong] Hofstra Northwell Sch Med, Lake Success, NY USA. [Zantek, Nicole D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN USA. [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Smock, KJ (reprint author), Univ Utah, Dept Pathol, ARUP Labs, 500 Chipeta Way,Mail Stop 115-G04, Salt Lake City, UT 84108 USA. EM Kristi.smock@hsc.utah.edu FU Sekisui Diagnostics, Inc. FX NDZ has received research funding from Sekisui Diagnostics, Inc. The other authors declare no conflicts of interest related to the content of the manuscript. NR 22 TC 2 Z9 2 U1 0 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2016 VL 116 IS 1 BP 50 EP 57 DI 10.1160/TH15-12-0918 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DQ8XM UT WOS:000379495000006 PM 27075008 ER PT J AU Carreras, ET Hochholzer, W Frelinger, AL Nordio, F O'Donoghue, ML Wiviott, SD Angiolillo, DJ Michelson, AD Sabatine, MS Mega, JL AF Carreras, Edward T. Hochholzer, Willibald Frelinger, Andrew L., III Nordio, Francesco O'Donoghue, Michelle L. Wiviott, Stephen D. Angiolillo, Dominick J. Michelson, Alan D. Sabatine, Marc S. Mega, Jessica L. TI Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel Insights from the ELEVATE-TIMI 56 Trial SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Diabetes mellitus; ischaemic heart disease; platelet pharmacology; polymorphisms ID CORONARY-ARTERY-DISEASE; OPTIMIZING ANTIPLATELET THERAPY; PLATELET REACTIVITY; CARDIOVASCULAR OUTCOMES; CLINICAL-OUTCOMES; COMBINED ASPIRIN; INTERVENTION; RESPONSIVENESS; IMPACT; POLYMORPHISM AB Both diabetes mellitus (DM) and carriage of the CYP2C19*2 allele are associated with a reduced response to clopidogrel. The relative contributions of these factors and whether higher clopidogrel doses can overcome both factors remain unknown. The objective of this study was to test the ability of clopidogrel doses up to 300 mg daily to decrease platelet reactivity in patients with DM and/or CYP2C19*2. ELEVATE-TIMI 56 randomised 333 patients with coronary artery disease to different maintenance doses of clopidogrel in four treatment periods, each lasting approximately 14 days. On-treatment platelet reactivity was compared between patients stratified by DM, CYP2C19*2 status and clopidogrel dose. Both DM and CYP2C19*2 were independently associated with elevated on-treatment platelet reactivity with clopidogrel 75 mg daily (p<0.0001 for each). With 75 mg, mean on-treatment PRU was progressively higher (p trend < 0.001) when evaluating patients: with neither DM nor CYP2C19*2 (150.7; 95 % CI 140.5-162.6), with only DM (187.2; 95 % CI, 171.3-206.9), with only CYP2C19*2 (227.9; 95 % CI, 205.1-250.8), and with both DM and CYP2C19*2 (239.9; 95 % CI, 209.7-270.1). Notably, with 75 mg, patients with only CYP2C19*2 had higher on-treatment platelet reactivity than those with only DM (p=0.0068). To achieve on-treatment platelet reactivity similar to that seen with clopidogrel 75 mg in patients with neither DM nor CYP2C19*2, the following doses were required: 150 mg with only DM, 225 mg with only CYP2C19*2, and 300 mg with both DM and CYP2C19*2. Patients with both DM and CYP2C19*2 required a four-fold increase in clopidogrel maintenance dose as compared to patients without these factors to achieve a similar antiplatelet response. C1 [Carreras, Edward T.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Hochholzer, Willibald] Univ Heart Ctr Freiburg, Dept Cardiol & Angiol 2, Bad Krozingen, Germany. [Frelinger, Andrew L., III; Michelson, Alan D.] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Div Hematol Oncol,Ctr Platelet Res Studies, Boston, MA USA. [Nordio, Francesco; O'Donoghue, Michelle L.; Wiviott, Stephen D.; Sabatine, Marc S.; Mega, Jessica L.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Nordio, Francesco; O'Donoghue, Michelle L.; Wiviott, Stephen D.; Sabatine, Marc S.; Mega, Jessica L.] Harvard Med Sch, Boston, MA USA. [Angiolillo, Dominick J.] Univ Florida, Coll Med, Jacksonville, FL USA. [Mega, Jessica L.] Verily Life Sci, Mountain View, CA USA. RP Carreras, ET; Sabatine, MS (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ecarreras@partners.org; msabatine@partners.org FU Bristol-Myers Squibb/sanofi-aventis; National Institutes of Health [K99/R00 HL098461]; German Heart Foundation FX The ELEVATE-TIMI 56 trial was funded by an investigator-initiated grant from Bristol-Myers Squibb/sanofi-aventis. Research supplies were provided by Accumetrics and Nanosphere. Dr. Mega was supported in part by grant K99/R00 HL098461 from the National Institutes of Health. Dr. Hochholzer is supported in part by the German Heart Foundation. NR 30 TC 0 Z9 1 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2016 VL 116 IS 1 BP 69 EP 77 DI 10.1160/TH15-12-0981 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DQ8XM UT WOS:000379495000008 PM 27009617 ER PT J AU Hodak, S Tuttle, RM Maytal, G Nikiforov, YE Randolph, G AF Hodak, Steven Tuttle, R. Michael Maytal, Guy Nikiforov, Yuri E. Randolph, Gregory TI Changing the Cancer Diagnosis: The Case of Follicular Variant of Papillary Thyroid Cancer-Primum Non Nocere and NIFTP SO THYROID LA English DT Editorial Material ID BRAF V600E; CARCINOMA; RISK; OVERDIAGNOSIS; MANAGEMENT; TUMORS C1 [Hodak, Steven] NYU, Dept Endocrinol, New York, NY USA. [Tuttle, R. Michael] Mem Sloan Kettering Canc Ctr, Dept Endocrinol, 1275 York Ave, New York, NY 10021 USA. [Maytal, Guy] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Nikiforov, Yuri E.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Randolph, Gregory] Massachusetts Gen Hosp, Dept Otolaryngol Head Neck Surg, Massachusetts Eye & Ear Infirm, Surg Oncol, Boston, MA 02114 USA. RP Randolph, G (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Thyroid & Parathyroid Surg, 243 Charles St, Boston, MA 02114 USA. EM Gregory_Randolph@meei.harvard.edu NR 21 TC 1 Z9 1 U1 1 U2 2 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 JUL PY 2016 VL 26 IS 7 BP 869 EP 871 DI 10.1089/thy.2016.0205 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR0PU UT WOS:000379610200001 PM 27184034 ER PT J AU Daniels, GH AF Daniels, Gilbert H. TI Follicular Variant of Papillary Thyroid Carcinoma: Hybrid or Mixture? SO THYROID LA English DT Editorial Material ID GENERATION SEQUENCING ASSAY; DIAGNOSIS; IMPACT; CANCER; CYTOLOGY; NODULES; MALIGNANCY; MUTATIONS; INVASION; LESIONS C1 [Daniels, Gilbert H.] Massachusetts Gen Hosp, Ctr Canc, Thyroid Unit, Boston, MA 02114 USA. [Daniels, Gilbert H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Daniels, Gilbert H.] Harvard Med Sch, Boston, MA USA. RP Daniels, GH (reprint author), Massachusetts Gen Hosp, Thyroid Unit ACC 730, Boston, MA 02114 USA. EM gdaniels@partners.org NR 23 TC 2 Z9 2 U1 1 U2 2 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 JUL PY 2016 VL 26 IS 7 BP 872 EP 874 DI 10.1089/thy.2016.0244 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR0PU UT WOS:000379610200002 PM 27214083 ER PT J AU Winter, CC Katiyar, KS Hernandez, NS Song, YJ Struzyna, LA Harris, JP Cullen, DK AF Winter, Carla C. Katiyar, Kritika S. Hernandez, Nicole S. Song, Yeri J. Struzyna, Laura A. Harris, James P. Cullen, D. Kacy TI Transplantable living scaffolds comprised of micro-tissue engineered aligned astrocyte networks to facilitate central nervous system regeneration SO ACTA BIOMATERIALIA LA English DT Article DE Tissue engineering; Living scaffold; Glial cell transplant; Biomaterials; Regeneration; Neurotrauma; Neurodegeneration; Traumatic brain injury; Cell migration; Axon pathfinding; Neural stem cells ID SPINAL-CORD-INJURY; ROSTRAL MIGRATORY STREAM; NEURAL STEM-CELLS; NEURITE OUTGROWTH; IN-VITRO; SUBSTRATE CURVATURE; SUBVENTRICULAR ZONE; NEURONAL MIGRATION; BRAIN-INJURY; TRACT AXONS AB Neurotrauma, stroke, and neurodegenerative disease may result in widespread loss of neural cells as well as the complex interconnectivity necessary for proper central nervous system function, generally resulting in permanent functional deficits. Potential regenerative strategies involve the recruitment of endogenous neural stem cells and/or directed axonal regeneration through the use of tissue engineered "living scaffolds" built to mimic features of three-dimensional (3-D) in vivo migratory or guidance pathways. Accordingly, we devised a novel biomaterial encasement scheme using tubular hydrogel-collagen micro-columns that facilitated the self-assembly of seeded astrocytes into 3-D living scaffolds consisting of long, cable-like aligned astrocytic networks. Here, robust astrocyte alignment was achieved within a micro-column inner diameter (ID) of 180 mu m or 300-350 mu m but not 1.0 mm, suggesting that radius of curvature dictated the extent of alignment. Moreover, within small ID micro-columns, >70% of the astrocytes assumed a bi-polar morphology, versus similar to 10% in larger micro-columns or planar surfaces. Cell-cell interactions also influenced the aligned architecture, as extensive astrocyte-collagen contraction was achieved at high (9-12 x 10(5) cells/mL) but not lower (2-6 x 10(5) cells/mL) seeding densities. This high density micro-column seeding led to the formation of ultra-dense 3-D "bundles" of aligned bi-polar astrocytes within collagen measuring up to 150 mu m in diameter yet extending to a remarkable length of over 2.5 cm. Importantly, co-seeded neurons extended neurites directly along the aligned astrocytic bundles, demonstrating permissive cues for neurite extension. These transplantable cable-like astrocytic networks structurally mimic the glial tube that guides neuronal progenitor migration in vivo along the rostral migratory stream, and therefore may be useful to guide progenitor cells to repopulate sites of widespread neurodegeneration. Statement of Significance This manuscript details our development of novel micro-tissue engineering techniques to generate robust networks of longitudinally aligned astrocytes within transplantable micro-column hydrogels. We report a novel biomaterial encasement scheme that facilitated the self-assembly of seeded astrocytes into long, aligned regenerative pathways. These miniature "living scaffold" constructs physically emulate the glial tube - a pathway in the brain consisting of aligned astrocytes that guide the migration of neuronal progenitor cells - and therefore may facilitate directed neuronal migration for central nervous system repair. The small size and self-contained design of these aligned astrocyte constructs will permit minimally invasive transplantation in models of central nervous system injury in future studies. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Winter, Carla C.; Katiyar, Kritika S.; Hernandez, Nicole S.; Song, Yeri J.; Struzyna, Laura A.; Harris, James P.; Cullen, D. Kacy] Univ Penn, Perelman Sch Med, Ctr Brain Injury & Repair, Dept Neurosurg, Philadelphia, PA 19104 USA. [Winter, Carla C.; Struzyna, Laura A.] Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA. [Winter, Carla C.; Katiyar, Kritika S.; Struzyna, Laura A.; Harris, James P.; Cullen, D. Kacy] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Katiyar, Kritika S.] Drexel Univ, Sch Biomed Engn, Philadelphia, PA 19104 USA. [Hernandez, Nicole S.; Song, Yeri J.; Cullen, D. Kacy] Univ Penn, Perelman Sch Med, Neurosci Grad Grp, Philadelphia, PA 19104 USA. RP Cullen, DK (reprint author), 105E Hayden Hall 3320 Smith Walk, Philadelphia, PA 19104 USA. EM dkacy@mail.med.upenn.edu FU Penn Medicine Neuroscience Center; National Science Foundation [DGE-1321851]; National Institutes of Health [T32-NS043126, F31-NS090746]; Michael J. Fox Foundation (Therapeutic Pipeline Program) [9998]; Department of Veterans Affairs (RRD Merit Review) [B1097-I]; U.S. Army Medical Research and Materiel Command through the Joint Warfighter Medical Research Program [W81XWH-13-207004]; Penn's Center for Undergraduate Research Fellowships FX Financial support was provided by the Penn Medicine Neuroscience Center, National Science Foundation (Graduate Research Fellowship DGE-1321851), National Institutes of Health (T32-NS043126; F31-NS090746), Michael J. Fox Foundation (Therapeutic Pipeline Program #9998), Department of Veterans Affairs (RR&D Merit Review #B1097-I), U.S. Army Medical Research and Materiel Command through the Joint Warfighter Medical Research Program (#W81XWH-13-207004), and Penn's Center for Undergraduate Research & Fellowships. We thank Patricia Murphy for technical assistance in these studies. NR 56 TC 1 Z9 1 U1 18 U2 31 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 EI 1878-7568 J9 ACTA BIOMATER JI Acta Biomater. PD JUL 1 PY 2016 VL 38 BP 44 EP 58 DI 10.1016/j.actbio.2016.04.021 PG 15 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DQ1LZ UT WOS:000378963800005 PM 27090594 ER PT J AU Stoeckel, LE Chai, XQJ Zhang, JH Whitfield-Gabrieli, S Evins, AE AF Stoeckel, Luke E. Chai, Xiaoqian J. Zhang, Jiahe Whitfield-Gabrieli, Susan Evins, A. Eden TI Lower gray matter density and functional connectivity in the anterior insula in smokers compared with never smokers SO ADDICTION BIOLOGY LA English DT Article DE Executive function; functional connectivity; nicotine addiction; salience; voxel-based morphometry ID GLOBAL SIGNAL REGRESSION; PREFRONTAL CORTEX; WITHDRAWAL SYMPTOMS; BRAIN; NICOTINE; NETWORK; ADDICTION; ORGANIZATION; SMOKING; FMRI AB Although nicotine addiction is characterized by both structural and functional abnormalities in brain networks involved in salience and cognitive control, few studies have integrated these data to understand how these abnormalities may support addiction. This study aimed to (1) evaluate gray matter density and functional connectivity of the anterior insula in cigarette smokers and never smokers and (2) characterize how differences in these measures were related to smoking behavior. We compared structural magnetic resonance imaging (MRI) (gray matter density via voxel-based morphometry) and seed-based functional connectivity MRI data in 16 minimally deprived smokers and 16 matched never smokers. Compared with controls, smokers had lower gray matter density in left anterior insula extending into inferior frontal and temporal cortex. Gray matter density in this region was inversely correlated with cigarettes smoked per day. Smokers exhibited negative functional connectivity (anti-correlation) between the anterior insula and regions involved in cognitive control (left lPFC) and semantic processing/emotion regulation (lateral temporal cortex), whereas controls exhibited positive connectivity between these regions. There were differences in the anterior insula, a central region in the brain's salience network, when comparing both volumetric and functional connectivity data between cigarette smokers and never smokers. Volumetric data, but not the functional connectivity data, were also associated with an aspect of smoking behavior (daily cigarettes smoked). C1 [Stoeckel, Luke E.; Evins, A. Eden] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Stoeckel, Luke E.; Evins, A. Eden] Harvard Med Sch, Boston, MA USA. [Chai, Xiaoqian J.; Zhang, Jiahe; Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, E25-618, Cambridge, MA 02139 USA. RP Stoeckel, LE (reprint author), Massachusetts Gen Hosp, Ctr Addict Med, 60 Staniford St, Boston, MA 02114 USA. EM lstoeckel@mgh.harvard.edu FU Harvard Medical School Norman E. Zinberg Fellowship in Addiction Psychiatry Research; Brain and Behavior Research Foundation NARSAD; Charles A. King Trust; NIH [K23DA032612, K24 DA030443] FX We wish to acknowledge Ms. Vanessa Calderon, Alice Coakley, Caroline Chan, Janani Raveendran, Satrajit Ghosh, Carlo de los Angeles, Jodi Gilman, Gretchen Reynolds and Julia Stern for imaging study support, discussion of methods, assistance with manuscript preparation and critical review of the manuscript. This research was carried out at the Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology. Finally, the study was supported by the Harvard Medical School Norman E. Zinberg Fellowship in Addiction Psychiatry Research (L.E.S.), a Brain and Behavior Research Foundation NARSAD Young Investigator Award (L.E.S.), the Charles A. King Trust (L.E.S.), NIH K23DA032612 (L.E.S.) and NIH K24 DA030443 (A.E.E.). NR 53 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2016 VL 21 IS 4 BP 972 EP 981 DI 10.1111/adb.12262 PG 10 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA DQ4CP UT WOS:000379151100020 PM 25990865 ER PT J AU Elsesser, SA Oldenburg, CE Biello, KB Mimiaga, MJ Safren, SA Egan, JE Novak, DS Krakower, DS Stall, R Mayer, KH AF Elsesser, Steven A. Oldenburg, Catherine E. Biello, Katie B. Mimiaga, Matthew J. Safren, Steven A. Egan, James E. Novak, David S. Krakower, Douglas S. Stall, Ron Mayer, Kenneth H. TI Seasons of Risk: Anticipated Behavior on Vacation and Interest in Episodic Antiretroviral Pre-exposure Prophylaxis (PrEP) Among a Large National Sample of US Men Who have Sex with Men (MSM) SO AIDS AND BEHAVIOR LA English DT Article DE PrEP; MSM; Episodic PrEP; Epi-PrEP; HIV ID BISEXUAL MEN; TRANSGENDER WOMEN; LIMITED KNOWLEDGE; HIV PREVENTION; GAY; PERSPECTIVES; INTERMITTENT; INFECTION; EDUCATION; BARRIERS AB The current analysis evaluates interest in and acceptability of daily PrEP during short episodes of anticipated increased risk (i.e. Epi-PrEP). In 2013, U.S. members of an internet-based MSM sexual networking site were invited to complete a survey about HIV prevention practices in the context of vacationing. 7305 MSM responded to the survey. Of respondents who had vacationed in the past year, 25.6 % reported condomless anal sex (CAS) with new male sex partners while vacationing. Most (92.6 %) respondents agreed that having to use PrEP every day was a barrier to PrEP use and 74.3 % indicated they would take PrEP if they knew it would be helpful for short periods of anticipated increased risk. MSM who reported increased CAS while on vacation in the past year were more likely to indicate that they would take PrEP if it were helpful when used for short periods than respondents who did not (aOR = 2.02, 95 % CI 1.59-2.56, p < 0.001). Studies designed to evaluate uptake, adherence, and protective benefit of short PrEP courses are warranted. C1 [Elsesser, Steven A.; Oldenburg, Catherine E.; Biello, Katie B.; Mimiaga, Matthew J.; Safren, Steven A.; Krakower, Douglas S.; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, 8th Floor,1340 Boylston St, Boston, MA 02115 USA. [Oldenburg, Catherine E.; Biello, Katie B.; Mimiaga, Matthew J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Mimiaga, Matthew J.; Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Safren, Steven A.; Mayer, Kenneth H.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Egan, James E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA USA. [Novak, David S.] Online Buddies Inc, OLB Res Inst, Cambridge, MA USA. [Krakower, Douglas S.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Stall, Ron] Univ Pittsburgh, Dept Behav & Social Sci, Pittsburgh, PA USA. [Mayer, Kenneth H.] Harvard Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. RP Mayer, KH (reprint author), Fenway Hlth, Fenway Inst, 8th Floor,1340 Boylston St, Boston, MA 02115 USA.; Mayer, KH (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Mayer, KH (reprint author), Harvard Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. EM kmayer@fenwayhealth.org FU Gilead Sciences FX This work was funded by an unrestricted research grant from Gilead Sciences. NR 40 TC 2 Z9 2 U1 4 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2016 VL 20 IS 7 BP 1400 EP 1407 DI 10.1007/s10461-015-1238-0 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DQ1ZS UT WOS:000379000500003 PM 26538056 ER PT J AU Kuhns, LM Reisner, SL Mimiaga, MJ Gayles, T Shelendich, M Garofalo, R AF Kuhns, Lisa M. Reisner, Sari L. Mimiaga, Matthew J. Gayles, Travis Shelendich, Michael Garofalo, Robert TI Correlates of PrEP Indication in a Multi-Site Cohort of Young HIV-Uninfected Transgender Women SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Transgender; PrEP; Young adults ID PREEXPOSURE PROPHYLAXIS; RISK; MEN; SEX AB Transgender women are at high risk of HIV infection, with younger transgender women (YTW) particularly vulnerable. Pre-Exposure Prophylaxis (PrEP) has shown efficacy in reducing HIV acquisition, but little is known about PrEP indication or initiation among YTW. Baseline data from 180 YTW age 18-29 years enrolled in Project LifeSkills, an on-going HIV prevention intervention for YTW, were analyzed to examine factors associated with PrEP indication. The sample (mean age = 23.4, SD = 3.2) was comprised largely of women of color (69 %) and of low socioeconomic status (71 % unemployed). Overall, 62 % met criteria for PrEP indication, but only 5 % reported ever taking PrEP. Factors associated with increased odds of PrEP indication were: PrEP interest (aOR 3.24; 95 % CI 1.44, 7.33), number of recent anal sex partners (aOR 1.23; 95 % CI 1.04, 1.46), and lower collective self-esteem scores (aOR 0.67; 95 % CI 0.47, 0.94). Despite high levels of PrEP indication, there remain low levels of PrEP awareness and uptake among YTW. C1 [Kuhns, Lisa M.; Gayles, Travis; Garofalo, Robert] Ann & Robert H Lurie Childrens Hosp, Div Adolescent Med, 225 E Chicago Ave,Box 161, Chicago, IL 60611 USA. [Kuhns, Lisa M.; Gayles, Travis; Shelendich, Michael; Garofalo, Robert] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Reisner, Sari L.; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Reisner, Sari L.; Mimiaga, Matthew J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Kuhns, LM (reprint author), Ann & Robert H Lurie Childrens Hosp, Div Adolescent Med, 225 E Chicago Ave,Box 161, Chicago, IL 60611 USA.; Kuhns, LM (reprint author), Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. EM lkuhns@luriechildrens.org FU National Institute of Mental Health of the National Institutes of Health [R01MH094323]; Northwestern University Clinical and Translational Science Institute from the National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (CTSA) [UL1TR000150] FX We thank members of the LifeSkills Study Team in Boston and Chicago for their contribution to sample accrual and data collection and Abigail Muldoon for preparation of data for analysis. Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH094323. The project described was also supported, in part, by the Northwestern University Clinical and Translational Science Institute, Grant Number UL1TR000150 from the National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (CTSA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The CTSA is a registered trademark of the U.S. Department of Health and Human Services (DHHS). ClinicalTrials.gov registration number NCT01575938. NR 24 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2016 VL 20 IS 7 BP 1470 EP 1477 DI 10.1007/s10461-015-1182-z PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DQ1ZS UT WOS:000379000500011 PM 26336946 ER PT J AU Calabrese, SK Underhill, K Earnshaw, VA Hansen, NB Kershaw, TS Magnus, M Krakower, DS Mayer, KH Betancourt, JR Dovidio, JF AF Calabrese, Sarah K. Underhill, Kristen Earnshaw, Valerie A. Hansen, Nathan B. Kershaw, Trace S. Magnus, Manya Krakower, Douglas S. Mayer, Kenneth H. Betancourt, Joseph R. Dovidio, John F. TI Framing HIV Pre-Exposure Prophylaxis (PrEP) for the General Public: How Inclusive Messaging May Prevent Prejudice from Diminishing Public Support SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Pre-exposure prophylaxis (PrEP); Framing; Public opinion; Prejudice; Black/African American; Men who have sex with men (MSM) ID SOCIAL CONSTRUCTION; ANTIRETROVIRAL PROPHYLAXIS; TRANSGENDER WOMEN; UNITED-STATES; BLACK-MEN; HIGH-RISK; SEX; INFECTION; ATTITUDES; POLICY AB Strategic framing of public messages about HIV pre-exposure prophylaxis (PrEP) may influence public support for policies and programs affecting access. This survey study examined how public attitudes toward PrEP differed based on the social group PrEP was described as benefiting ("beneficiary'') and the moderating effect of prejudice. Members of the general public (n = 154) recruited online were randomly assigned to three beneficiary conditions: general population, gay men, or Black gay men. All participants received identical PrEP background information before completing measures of PrEP attitudes (specifying beneficiary), racism, and heterosexism. Despite anticipating greater PrEP adherence among gay men and Black gay men and perceiving PrEP as especially beneficial to the latter, participants expressed lower support for policies/programs making PrEP affordable for these groups vs. the general population. This disparity in support was stronger among participants reporting greater prejudice. Inclusive framing of PrEP in public discourse may prevent prejudice from undermining implementation efforts. C1 [Calabrese, Sarah K.; Kershaw, Trace S.] Yale Univ, Dept Chron Dis Epidemiol, Yale Sch Publ Hlth, 135 Coll St,Suite 358, New Haven, CT 06510 USA. [Calabrese, Sarah K.; Underhill, Kristen; Earnshaw, Valerie A.; Hansen, Nathan B.; Kershaw, Trace S.; Dovidio, John F.] Yale Univ, Ctr Interdisciplinary Res AIDS, New Haven, CT 06520 USA. [Underhill, Kristen] Yale Univ, Yale Law Sch, New Haven, CT USA. [Earnshaw, Valerie A.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. [Hansen, Nathan B.] Univ Georgia, Coll Publ Hlth, Dept Hlth Promot & Behav, Athens, GA 30602 USA. [Magnus, Manya] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Epidemiol & Biostat, Washington, DC USA. [Krakower, Douglas S.; Mayer, Kenneth H.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Krakower, Douglas S.; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Betancourt, Joseph R.] Harvard Med Sch, Dispar Solut Ctr, Massachusetts Gen Hosp, Boston, MA USA. [Dovidio, John F.] Yale Univ, Dept Psychol, New Haven, CT USA. RP Calabrese, SK (reprint author), Yale Univ, Dept Chron Dis Epidemiol, Yale Sch Publ Hlth, 135 Coll St,Suite 358, New Haven, CT 06510 USA.; Calabrese, SK (reprint author), Yale Univ, Ctr Interdisciplinary Res AIDS, New Haven, CT 06520 USA. EM sarah.calabrese@yale.edu FU National Institute of Mental Health (NIMH) [K01-MH103080, P30-MH062294]; Yale University Fund for Lesbian and Gay Studies Award; NIMH [K01-MH093273, K23-MH098795]; Agency for Healthcare Research and Quality (AHRQ) [K12-HS022986] FX This research was supported by Award Numbers K01-MH103080 and P30-MH062294 from the National Institute of Mental Health (NIMH) and the Yale University Fund for Lesbian and Gay Studies Award. Kristen Underhill and Douglas S. Krakower were supported by NIMH Award Numbers K01-MH093273 and K23-MH098795, respectively. Valerie A. Earnshaw was supported by the Agency for Healthcare Research and Quality (AHRQ) Award Number K12-HS022986. Mentorship was received from the Social and Behavioral Sciences Research Network (SBSRN) of the National Institutes of Health Centers for AIDS Research (2013 SBSRN National Scientific Meeting Mentoring Day) and P30-AI060354. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the SBSRN, the National Institutes of Health, the AHRQ, or Yale Lesbian and Gay Studies. The authors wish to thank Valen Grandelski for programming the survey, Suzanne Horowitz for her technical assistance on the survey, and Adam Eldahan for his support with reference management software and proofreading. The authors are also grateful to the individuals who generously contributed their time and effort by participating in this study. NR 91 TC 0 Z9 0 U1 6 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2016 VL 20 IS 7 BP 1499 EP 1513 DI 10.1007/s10461-016-1318-9 PG 15 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DQ1ZS UT WOS:000379000500014 PM 26891840 ER PT J AU Jain, S Oldenburg, CE Mimiaga, MJ Mayer, KH AF Jain, Sachin Oldenburg, Catherine E. Mimiaga, Matthew J. Mayer, Kenneth H. TI High Levels of Concomitant Behavioral Health Disorders Among Patients Presenting for HIV Non-occupational Post-exposure Prophylaxis at a Boston Community Health Center Between 1997 and 2013 SO AIDS AND BEHAVIOR LA English DT Article DE HIV; PEP; nPEP; Syndemic; Mental illness ID CHILDHOOD SEXUAL-ABUSE; SEVERE MENTAL-ILLNESS; RISK BEHAVIOR; ANTIRETROVIRAL PROPHYLAXIS; TRANSMISSION RISK; SUBSTANCE USE; SOUTH-AFRICA; YOUNG MEN; FOLLOW-UP; INFECTION AB A paucity of information regarding mental health exists for patients presenting for HIV non-occupational post-exposure prophylaxis (nPEP). We reviewed electronicmedical records of 894 adult nPEP patients seen at a large Boston community health center between 1997 and 2013. Of 821 patients with consensual sexual exposures, 88.3 % were men who have sex with men, and 40.0 % had a mental health diagnosis. Diagnoses included: depression (24.4 %), anxiety (21.9 %), attention deficit disorder (7.8 %), post-traumatic stress disorder (3.3 %), and psychotic disorders (3.3 %). Of 129 patients with substance use disorders, alcohol dependence (65.9 %) and crystal methamphetamine (43.4 %) predominated. Unprotected receptive anal intercourse was associated with psychotic disorders (aOR = 4.86; 95 % CI: 1.76-13.5) and substance use disorders (aOR = 1.89; 95 % CI: 1.28-2.80). Substance use at the time of exposure was associated with: depression (aOR = 1.95; 95 % CI: 1.36-2.80), anxiety (aOR = 2.22; 95 % CI: 1.51-3.25), attention deficit disorder (aOR = 1.96; 95 % CI: 1.18-3.27), and substance use disorder (aOR = 4.78; 95 % CI: 3.30-6.93). Mental illness should be screened for and addressed at nPEP visits to optimize HIV risk-reduction. C1 [Jain, Sachin] Montefiore Med Ctr, Albert Einstein Coll Med, Div Infect Dis, Bronx, NY 10467 USA. [Oldenburg, Catherine E.; Mimiaga, Matthew J.; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Oldenburg, Catherine E.; Mimiaga, Matthew J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Jain, S (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, Div Infect Dis, Bronx, NY 10467 USA. EM sajain@montefiore.org FU Harvard University Center For AIDS Research (CFAR), an NIH [P30 AI060354]; National Institute of Allergy and Infectious Disease T32 NRSA Grant [T32AI007535]; National Institute of Drug Abuse T32 NRSA Grant [T32DA013911] FX The Fenway Institute Data Team, including Chris Grasso, Ken Levine, and Shayne Zaslow, screened eligible patients for this study, aided with construction of the data abstraction tool, and provided database support. The Harvard University Center For AIDS Research (CFAR), an NIH funded program (P30 AI060354; PI: Walker), provided statistical consultation and contributes to Mayer's funding. Oldenburg is supported by a National Institute of Allergy and Infectious Disease T32 NRSA Grant (T32AI007535; PI: Seage) and a National Institute of Drug Abuse T32 NRSA Grant (T32DA013911; PI: Flanigan). NR 53 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2016 VL 20 IS 7 BP 1556 EP 1563 DI 10.1007/s10461-015-1021-2 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DQ1ZS UT WOS:000379000500020 PM 25689892 ER PT J AU Duncan, DT Rienti, M Kulldorff, M Aldstadt, J Castro, MC Frounfelker, R Williams, JH Sorensen, G Johnson, RM Hemenway, D Williams, DR AF Duncan, Dustin T. Rienti, Michael, Jr. Kulldorff, Martin Aldstadt, Jared Castro, Marcia C. Frounfelker, Rochelle Williams, James H. Sorensen, Glorian Johnson, Renee M. Hemenway, David Williams, David R. TI Local spatial clustering in youths' use of tobacco, alcohol, and marijuana in Boston SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE Spatial clustering; drug use; tobacco use; alcohol use; marijuana use; youth ID AFRICAN-AMERICAN ADOLESCENTS; SUBSTANCE USE DISORDERS; ILLICIT DRUG-USE; CIGARETTE-SMOKING; NATURAL-HISTORY; SOCIAL NETWORK; UNITED-STATES; HIGH-SCHOOL; URBAN; STRESS AB Background: Understanding geographic variation in youth drug use is important for both identifying etiologic factors and planning prevention interventions. However, little research has examined Spatial clustering of drug use among youths by using rigorous statistical methods. Objectives: The purpose of this study was to examine spatial clustering of youth use of tobacco, alcohol, and marijuana. Methods! Responses on, tobacco, alcohol, and Marijuana use from 1,292 high school students ages 13-19 who provided complete residential addresses were drawn from the 2008 Boston Youth Survey Geospatial Dataset. Response options on past month use included "none," "1-2," "3-9," and "10 or more." The response rate for each substance was approximately 94%. Spatial clustering Of youth drug use was assessed using the spatial Bernoulli model in. the SatScan (TM) Software package. Results Approximately 12%, 3:6%, and 18% of youth reported any past-month use of tobacco, alcohol, and/or Marijuana, respectively. Two clusters of elevated past tobacco use among: Boston youths were generated, one of which was statistically significant. This cluster, located in the South Boston neighborhood, had a relative risk of 5:37 with,a p-Value of 0.00014. There was no significant localized spatial clustering in youth past alcohol or marijuana use in either the unadjusted or adjusted. Models. Conclusion: Significant Spatial-clustering in youth tobacco use was-found.. Finding a significant cluster in the South Boston neighborhood provides reason for further investigation into neighborhood characteristics that may shape adolescents' substance use behaviors. This type of research can be used to evaluate the underlying reasons behind spatial clustering of youth substance and to target local drug abuse prevention interventions and use. C1 [Duncan, Dustin T.; Williams, James H.] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Duncan, Dustin T.] NYU, Coll Global Publ Hlth, New York, NY USA. [Duncan, Dustin T.] NYU, Coll Nursing, Ctr Drug Use & HIV Res, New York, NY USA. [Duncan, Dustin T.] NYU, Coll Arts & Sci, Populat Ctr, New York, NY USA. [Duncan, Dustin T.] NYU, Ctr Data Sci, New York, NY USA. [Rienti, Michael, Jr.; Aldstadt, Jared] SUNY Buffalo, Dept Geog, Buffalo, NY USA. [Rienti, Michael, Jr.] SUNY Buffalo, Ctr Hlth & Social Res, Buffalo, NY USA. [Kulldorff, Martin] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Kulldorff, Martin] Harvard Med Sch, Boston, MA USA. [Castro, Marcia C.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Castro, Marcia C.] Harvard Univ, Harvard Ctr Populat & Dev Studies, Cambridge, MA 02138 USA. [Frounfelker, Rochelle; Williams, David R.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Sorensen, Glorian; Williams, David R.] Harvard TH Chan Sch Publ Hlth, Lung Canc Dispar Ctr, Boston, MA USA. [Sorensen, Glorian; Johnson, Renee M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Hemenway, David] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Williams, David R.] Harvard Univ, Dept African & African Amer Studies, Cambridge, MA 02138 USA. [Williams, David R.] Harvard Univ, Dept Sociol, Cambridge, MA 02138 USA. RP Duncan, DT (reprint author), New York Univ, Dept Populat Hlth, Spatial Epidemiol Lab, Sch Med, 227 East 30th St,Off 621, New York, NY 10016 USA. EM Dustin.Duncan@nyumc.org OI Johnson, Renee/0000-0001-5083-8686 FU New York University School of Medicine Start-Up Research Fund; National Institutes of Health [R01CA165057]; Centers for Disease Control and Prevention [U49CE00740]; Robert Wood Johnson Foundation's Active Living Research Program [67129]; Robert Wood Johnson Foundation Health; Society Scholars Seed Grant Program Harvard Center for Population and Development Studies, Harvard School of Public Health FX Dr. Dustin Duncan was supported by his New York University School of Medicine Start-Up Research Fund to work on this project. Dr. Martin Kulldorff was supported in part by a grant from the National Institutes of Health (grant # R01CA165057). The 2008 Boston Youth Survey was funded by a grant from the Centers for Disease Control and Prevention (grant U49CE00740) to the Harvard Youth Violence Prevention Center at Harvard School of Public Health (David Hemenway, PhD, Principal Investigator). A grant to Dustin Duncan from Robert Wood Johnson Foundation's Active Living Research Program (grant # 67129) supported the development of the Boston Youth Survey Geospatial Dataset. This study was supported by the Robert Wood Johnson Foundation Health and Society Scholars Seed Grant Program (grant to Dustin Duncan), Harvard Center for Population and Development Studies, Harvard School of Public Health. NR 58 TC 0 Z9 0 U1 4 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0095-2990 EI 1097-9891 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD JUL PY 2016 VL 42 IS 4 BP 412 EP 421 DI 10.3109/00952990.2016.1151522 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DQ1MW UT WOS:000378966100007 PM 27096932 ER PT J AU Vijayan, A Faubel, S Askenazi, DJ Cerda, J Fissell, WH Heung, M Humphreys, BD Koyner, JL Liu, KD Mour, G Nolin, TD Bihorac, A AF Vijayan, Anitha Faubel, Sarah Askenazi, David J. Cerda, Jorge Fissell, William H. Heung, Michael Humphreys, Benjamin D. Koyner, Jay L. Liu, Kathleen D. Mour, Girish Nolin, Thomas D. Bihorac, Azra CA Amer Soc Nephrology Acute Kidney Injury Advisory Grp TI Clinical Use of the Urine Biomarker [TIMP-2] x [ IGFBP7] for Acute Kidney Injury Risk Assessment SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Acute kidney injury (AKI); biomarker; [TIMP-2] x [IGFBP7]; diagnosis; critically ill; tissue inhibitor of metalloproteinase 2; insulin-like growth factor binding protein 7; NephroCheck; early detection; risk assessment; renal dysfunction; decreased kidney function ID ACUTE-RENAL-FAILURE; CYCLE ARREST BIOMARKERS; CRITICALLY-ILL PATIENTS; FUROSEMIDE STRESS TEST; ACID-BINDING PROTEIN; CARDIAC-SURGERY; CARDIOPULMONARY BYPASS; TISSUE INHIBITOR; NEPHROLOGY CONSULTATION; POOR OUTCOMES AB Acute kidney injury (AKI) is a serious complication, commonly occurring in the critically ill population, with devastating short- and long-term consequences. Despite standardization of the definition and staging of AKI, early recognition remains challenging given that serum creatinine level is a marker, albeit imperfect, of kidney function and not kidney injury. Furthermore, the delay in increase in serum creatinine level after loss of glomerular filtration also prevents timely detection of decreased kidney function in patients with AKI. During the past decade, numerous clinical investigations have evaluated the utility of several biomarkers in the early diagnosis and risk stratification of AKI. In 2014, the US Food and Drug Administration approved the marketing of a test based on the combination of urine concentrations of tissue inhibitor of metalloproteinase 2 and insulinlike growth factor binding protein 7 ([TIMP-2] 3 [ IGFBP7]) to determine whether certain critically ill patients are at risk for developing moderate to severe AKI. The optimal role of this biomarker in the diagnosis, management, and prognosis of AKI in different clinical settings requires further clarification. In this perspective, we summarize the biological actions of these 2 cell-cycle arrest biomarkers and present important considerations regarding the clinical application, interpretation, and limitations of this novel test for the early detection of AKI. Am J Kidney Dis. 68(1): 19-28. (C) 2016 by the National Kidney Foundation, Inc. C1 [Vijayan, Anitha; Humphreys, Benjamin D.] Washington Univ, Dept Med, Div Renal, St Louis, MO USA. [Faubel, Sarah] Univ Colorado, Div Renal, Denver, CO 80202 USA. [Faubel, Sarah] Denver VA Med Ctr, Denver, CO USA. [Askenazi, David J.] Univ Alabama Birmingham, Div Pediat Nephrol, Birmingham, AL USA. [Cerda, Jorge] Albany Med Coll, Albany, NY 12208 USA. [Fissell, William H.] Vanderbilt Univ, Dept Med, Div Nephrol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Heung, Michael] Univ Michigan, Dept Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Koyner, Jay L.] Univ Chicago, Dept Med, Sect Nephrol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Liu, Kathleen D.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Liu, Kathleen D.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA USA. [Mour, Girish] Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15260 USA. [Nolin, Thomas D.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Bihorac, Azra] Univ Florida, Dept Med, Gainesville, FL USA. [Bihorac, Azra] Univ Florida, Dept Anesthesiol, Gainesville, FL USA. [Bihorac, Azra] Univ Florida, Dept Surg, Gainesville, FL USA. RP Vijayan, A (reprint author), Washington Univ, Div Renal, Campus Box 8129,660 S Euclid Ave, St Louis, MO 63110 USA. EM avijayan@dom.wustl.edu FU Spectral Medical Inc and AM-Pharma; Astute Medical Inc; NIH [U01DK104308, U01DK085649]; Abbott; Achaogen Inc; Chemocentryx Inc; Durect Corporation; Center for Sepsis and Critical Illness Award from the National Institute of General Medical Sciences [P50 GM-111152]; Society of Critical Care Medicine FX Dr Vijayan was a clinical adjudicator for the Topaz trial and has research support from Spectral Medical Inc and AM-Pharma. Dr Askenazi is a speaker for the AKI Foundation. Dr Heung reports receiving grant funding from Astute Medical Inc, the manufacturer of NEPHROCHECK. Dr Humphreys is a Co-Principal Investigator on an NIH grant to develop novel biomarkers of chronic kidney disease (CKD) (U01DK104308). Dr Koyner reports receiving grant funding from Abbott and Astute Medical Inc for enrolling patients in observational AKI biomarker studies and consulting fees from Astute Medical Inc. Dr Liu was a clinical adjudicator for the Topaz trial and reports consultancy agreements with Achaogen Inc, Astute Medical Inc, Chemocentryx Inc, and Durect Corporation. She is a Co-Principal Investigator on an NIH grant to test novel biomarkers of CKD (U01DK085649). Dr Nolin is member of the Independent Data Monitoring Committee for Thrasos Innovation Inc. Dr Bihorac is supported by Center for Sepsis and Critical Illness Award P50 GM-111152 from the National Institute of General Medical Sciences and has received research grants from the Society of Critical Care Medicine, Astute Medical Inc, and the I. Heermann Anesthesia Foundation Inc. The remaining authors declare that they have no relevant financial interests. NR 74 TC 8 Z9 8 U1 4 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2016 VL 68 IS 1 BP 19 EP 28 DI 10.1053/j.ajkd.2015.12.033 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DP6VB UT WOS:000378636100010 PM 26948834 ER PT J AU Kraut, JA AF Kraut, Jeffrey A. TI Approach to the Treatment of Methanol Intoxication SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Toxic alcohols; serum osmolal gap; serum anion gap; fomepizole; methanol; methanol intoxication; ethanol; hemodialysis ID ETHYLENE-GLYCOL; OSMOLAL GAP; FORMATE KINETICS; ANION-GAP; EXTRACORPOREAL TREATMENTS; METABOLIC-ACIDOSIS; SERUM OSMOLALITY; DIAGNOSIS; FOMEPIZOLE; HEMODIALYSIS AB Methanol intoxication is an uncommon but serious poisoning. Its adverse effects are due primarily to the impact of its major metabolite formic acid and lactic acid resulting from cellular hypoxia. Symptoms including abdominal pain and loss of vision can appear a few hours to a few days after exposure, reflecting the time necessary for accumulation of the toxic byproducts. In addition to a history of exposure, increases in serum osmolal and anion gaps can be clues to its presence. However, increments in both parameters can be absent depending on the nature of the toxic alcohol, time of exposure, and coingestion of ethanol. Definitive diagnosis requires measurement with gas or liquid chromatography, which are laborious and expensive procedures. Tests under study to detect methanol or its metabolite formate might facilitate the diagnosis of this poisoning. Treatment can include administration of ethanol or fomepizole, both inhibitors of the enzyme alcohol dehydrogenase to prevent formation of its metabolites, and hemodialysis to remove methanol and formate. In this Acid-Base and Electrolyte Teaching Case, a patient with methanol intoxication due to ingestion of model airplane fuel is described, and the value and limitations of current and new diagnostic and treatment measures are discussed. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Kraut, Jeffrey A.] UCLA Membrane Biol Lab, Med & Res Serv Vet Adm Greater Los Angeles Health, Los Angeles, CA USA. [Kraut, Jeffrey A.] Vet Adm Greater Los Angeles Healthcare Syst, Div Nephrol, Los Angeles, CA USA. [Kraut, Jeffrey A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Kraut, JA (reprint author), VHAGLA Healthcare Syst, Div Nephrol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jkraut@ucla.edu FU UCLA Academic Senate; Veterans Administration FX Support: The manuscript was supported by funds from the UCLA Academic Senate and Veterans Administration. NR 55 TC 1 Z9 1 U1 3 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 2016 VL 68 IS 1 BP 161 EP 167 DI 10.1053/j.ajkd.2016.02.058 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DP6VB UT WOS:000378636100026 PM 27180631 ER PT J AU Badhwar, V Rankin, JS Jacobs, JP Shahian, DM Habib, RH D'Agostino, RS Thourani, VH Suri, RM Prager, RL Edwards, FH AF Badhwar, Vinay Rankin, J. Scott Jacobs, Jeffrey P. Shahian, David M. Habib, Robert H. D'Agostino, Richard S. Thourani, Vinod H. Suri, Rakesh M. Prager, Richard L. Edwards, Fred H. TI The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2016 Update on Research SO ANNALS OF THORACIC SURGERY LA English DT Article ID AORTIC-VALVE-REPLACEMENT; NATIONAL DATABASE; OUTCOMES; QUALITY; RISK AB The Society of Thoracic Surgeons Adult Cardiac Database (ACSD) is an international voluntary effort that is the foundation of our specialty's efforts in clinical performance assessment and quality improvement. Containing nearly 6,000,000 patient records, the ACSD is a robust resource for clinical research. Seven major original publications and four review articles were generated from the ACSD in 2015. The risk-adjusted outcome analyses and quality measures reported in these studies have made substantial contributions to inform daily clinical practice. This report summarizes the ACSD-based research efforts published in 2015. (C) 2016 by The Society of Thoracic Surgeons C1 W Virginia Univ, Div Cardiothorac Surg, Morgantown, WV 26506 USA. Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, St Petersburg, FL USA. Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, Tampa, FL USA. Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, Orlando, FL USA. Florida Hosp Children, St Petersburg, FL USA. Florida Hosp Children, Tampa, FL USA. Florida Hosp Children, Orlando, FL USA. Johns Hopkins Univ, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD 21205 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Qual & Safety, Massachusetts Gen Hosp, Boston, MA 02115 USA. Soc Thorac Surg Res Ctr, Chicago, IL USA. Lahey Hosp & Med Ctr, Dept Thorac & Cardiovasc Surg, Burlington, MA USA. Emory Univ, Div Cardiothorac Surg, Atlanta, GA 30322 USA. Cleveland Clin, Div Thorac & Cardiovasc Surg, Cleveland, OH 44106 USA. Univ Michigan, Dept Cardiac Surg, Ann Arbor, MI 48109 USA. Univ Florida, Div Cardiothorac Surg, Jacksonville, FL USA. RP Badhwar, V (reprint author), W Virginia Univ, 1 Med Ctr Dr, Morgantown, WV 26506 USA. EM vinay.badhwar@wvumedicine.org FU BioStable Science and Engineering; Admedus Corp; AtriCure USA FX Dr Rankin discloses a financial relationship with BioStable Science and Engineering, Admedus Corp, and AtriCure USA. NR 14 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2016 VL 102 IS 1 BP 7 EP 13 DI 10.1016/j.athoracsur.2016.05.009 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DP6UL UT WOS:000378634400029 PM 27262913 ER PT J AU Stephens, EH Robich, MP Walters, DM DeNino, WF Aftab, M Tchantchaleishvili, V Eilers, AL Rice, RD Goldstone, AB Shlestad, RC Malas, T Cevasco, M Gillaspie, EA Fiedler, AG LaPar, DJ Shah, AA AF Stephens, Elizabeth H. Robich, Michael P. Walters, Dustin M. DeNino, Walter F. Aftab, Muhammad Tchantchaleishvili, Vakhtang Eilers, Amanda L. Rice, Robert D. Goldstone, Andrew B. Shlestad, Ryan C. Malas, Tarek Cevasco, Marisa Gillaspie, Erin A. Fiedler, Amy G. LaPar, Damien J. Shah, Asad A. TI Gender and Cardiothoracic Surgery Training: Specialty Interests, Satisfaction, and Career Pathways SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 23-27, 2016 CL Phoenix, AZ SP Soc Thorac Surg ID GENERAL-SURGERY; WOMEN; PERCEPTIONS; PERFORMANCE; RESIDENTS AB Background. The cardiothoracic surgical workforce is changing. Although 5% of practicing surgeons are women, 20% of current cardiothoracic surgery residents are women. The purpose of this study was to evaluate the influence of gender on specialty interest, satisfaction, and career pathways of current residents. Methods. Responses to the mandatory 2015 Thoracic Surgery Residents Association/Thoracic Surgery Directors Association in-training examination survey taken by 354 residents (100% response rate) were evaluated. The influence of gender was assessed with the use of standard univariate analyses. Results. Women accounted for 20% of residents, and the percentage did not vary with postgraduate year or program type (traditional versus integrated). Although no differences were found between the genders related to specialty interest, academic versus private practice career, or pursuit of additional training, women were more likely to pursue additional training in minimally invasive thoracic surgery (10% versus 2.5%, p = 0.001) and less likely to perform research in their careers (65% versus 88%, p = 0.043). Although women were equally satisfied with their career choice, had similar numbers of interviews and job offers, and felt equally prepared for their boards, graduating women felt less prepared technically (77% versus 90%, p = 0.01) and for practicing independently (71% versus 87%, p = 0.01). Women were less likely to be married (26% versus 62%, p < 0.001) and have children (19% versus 49%, p < 0.001). Conclusions. Although career satisfaction and specialty interest were similar between the genders, women were less likely to intend to perform research during their careers despite similar previous research experience. Women also demonstrated lower rates of marriage and childbearing compared with their male counterparts. (C) 2016 by The Society of Thoracic Surgeons C1 Columbia Univ, New York, NY USA. Maine Med Ctr, Cardiovasc Inst, Dept Cardiothorac Surg, Portland, ME 04102 USA. Univ Washington, Seattle, WA 98195 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Colorado, Denver, CO 80202 USA. Univ Rochester, Rochester, NY USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Mem Hermann Heart & Vasc Inst, Houston, TX USA. Univ Penn, Philadelphia, PA 19104 USA. Ottawa Heart Inst, Ottawa, ON, Canada. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Virginia, Charlottesville, VA USA. Duke Univ, Med Ctr, Div Cardiovasc & Thorac Surg, Durham, NC USA. RP Shah, AA (reprint author), Duke Univ, Med Ctr, Div Cardiovasc & Thorac Surg, DUMC 3443, Durham, NC 27710 USA. EM asad.shah@duke.edu NR 24 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2016 VL 102 IS 1 BP 200 EP 206 DI 10.1016/j.athoracsur.2016.03.043 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DP6UL UT WOS:000378634400055 PM 27157051 ER PT J AU Raymond, DP Seder, CW Wright, CD Magee, MJ Kosinski, AS Cassivi, SD Grogan, EL Blackmon, SH Allen, MS Park, BJ Burfeind, WR Chang, AC DeCamp, MM Wormuth, DW Fernandez, FG Kozower, BD AF Raymond, Daniel P. Seder, Christopher W. Wright, Cameron D. Magee, Mitchell J. Kosinski, Andrzej S. Cassivi, Stephen D. Grogan, Eric L. Blackmon, Shanda H. Allen, Mark S. Park, Bernard J. Burfeind, William R. Chang, Andrew C. DeCamp, Malcolm M. Wormuth, David W. Fernandez, Felix G. Kozower, Benjamin D. TI Predictors of Major Morbidity or Mortality After Resection for Esophageal Cancer: A Society of Thoracic Surgeons General Thoracic Surgery Database Risk Adjustment Model SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the Southern-Thoracic-Surgical-Association CY NOV 04-07, 2015 CL Orlando, FL SP So Thorac Surg Assoc ID OUTCOMES AB Background. The purpose of this analysis was to revise the model for perioperative risk for esophagectomy for cancer utilizing The Society of Thoracic Surgeons General Thoracic Surgery Database to provide enhanced risk stratification and quality improvement measures for contributing centers. Methods. The Society of Thoracic Surgeons General Thoracic Surgery Database was queried for all patients treated for esophageal cancer with esophagectomy between July 1, 2011, and June 30, 2014. Multivariable risk models for major morbidity, perioperative mortality, and combined morbidity and mortality were created with the inclusion of surgical approach as a risk factor. Results. In all, 4,321 esophagectomies were performed by 164 participating centers. The most common procedures included Ivor Lewis (32.5%), transhiatal (21.7%), minimally invasive esophagectomy, Ivor Lewis type (21.4%), and McKeown (10.0%). Sixty-nine percent of patients received induction therapy. Perioperative mortality (inpatient and 30day) was 135 of 4,321 (3.4%). Major morbidity occurred in 1,429 patients (33.1%). Major morbidities include unexpected return to operating (15.6%), anastomotic leak (12.9%), reintubation (12.2%), initial ventilation beyond 48 hours (3.5%), pneumonia (12.2%), renal failure (2.0%), and recurrent laryngeal nerve paresis (2.0%). Statistically significant predictors of combined major morbidity or mortality included age more than 65 years, body mass index 35 kg/m(2) or greater, preoperative congestive heart failure, Zubrod score greater than 1, McKeown esophagectomy, current or former smoker, and squamous cell histology. Conclusion. Thoracic surgeons participating in The Society of Thoracic Surgeons General Thoracic Surgery Database perform esophagectomy with low morbidity and mortality. McKeown esophagectomy is an independent predictor of combined postoperative morbidity or mortality. Revised predictors for perioperative outcome were identified to facilitate quality improvement processes and hospital comparisons. (C) 2016 by The Society of Thoracic Surgeons C1 [Raymond, Daniel P.] Cleveland Clin Fdn, Thorac & Cardiovasc Surg, 9500 Euclid Ave,J4-1, Cleveland, OH 44195 USA. [Seder, Christopher W.] Rush Med Univ, Univ Thorac Surg, Chicago, IL USA. [Wright, Cameron D.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Magee, Mitchell J.] HCA North Texas Div, Dallas, TX USA. [Kosinski, Andrzej S.] Duke Clin Res Inst, Durham, NC USA. [Cassivi, Stephen D.; Blackmon, Shanda H.; Allen, Mark S.] Mayo Clin, Dept Thorac Surg, Rochester, MN USA. [Grogan, Eric L.] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, Nashville, TN USA. [Park, Bernard J.] Mem Sloan Kettering Canc Ctr, Thorac Serv, 1275 York Ave, New York, NY 10021 USA. [Burfeind, William R.] St Lukes Hlth Network, Cardiovasc & Thorac Surg Associates, Bethlehem, PA USA. [Chang, Andrew C.] Univ Michigan Hlth Syst, Thorac Surg Sect, Ann Arbor, MI USA. [DeCamp, Malcolm M.] NW Mem Hosp, Div Thorac Surg, Chicago, IL 60611 USA. [Wormuth, David W.] Upstate Surg Grp, Syracuse, NY USA. [Fernandez, Felix G.] Emory Univ, Div Cardiothorac Surg, Atlanta, GA 30322 USA. [Kozower, Benjamin D.] Univ Virginia Hlth Syst, Dept Gen Thorac Surg, Charlottesville, VA USA. RP Raymond, DP (reprint author), Cleveland Clin Fdn, Thorac & Cardiovasc Surg, 9500 Euclid Ave,J4-1, Cleveland, OH 44195 USA. EM raymond3@ccf.org FU NCI NIH HHS [P30 CA008748] NR 18 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2016 VL 102 IS 1 BP 207 EP 214 DI 10.1016/j.athoracsur.2016.04.055 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DP6UL UT WOS:000378634400056 PM 27240449 ER PT J AU Rodriguez, E Nifong, LW Bonatti, J Casula, R Falk, V Folliguet, TA Kiaii, BB Mack, MJ Mihaljevic, T Smith, JM Suri, RM Bavaria, JE MacGillivray, TE Chitwood, WR AF Rodriguez, Evelio Nifong, L. Wiley Bonatti, Johannes Casula, Roberto Falk, Volkmar Folliguet, Thierry A. Kiaii, Bob B. Mack, Michael J. Mihaljevic, Tomislav Smith, J. Michael Suri, Rakesh M. Bavaria, Joseph E. MacGillivray, Thomas E. Chitwood, W. Randolph, Jr. TI Pathway for Surgeons and Programs to Establish and Maintain a Successful Robot-Assisted Adult Cardiac Surgery Program SO ANNALS OF THORACIC SURGERY LA English DT Review ID MITRAL-VALVE REPAIRS; MULTICENTER TRIAL; BYPASS SURGERY; ARTERY; EXPERIENCE; SAFETY; GRAFT C1 [Rodriguez, Evelio] St Thomas Heart Hosp, 4230 Harding Rd,Ste 430, Nashville, TN 37205 USA. [Nifong, L. Wiley] East Carolina Heart Inst, Dept Cardiovasc Sci, Greenville, NC USA. [Bonatti, Johannes] Cleveland Clin, Abu Dhabi Heart & Vasc Inst, Abu Dhabi, U Arab Emirates. [Casula, Roberto] Imperial Coll Healthcare NHS Trust, London, England. [Casula, Roberto] St Marys Hosp, Dept Cardiothorac Surg, London, England. [Falk, Volkmar] Charite, Deutsch Herzzentrum Berlin, Berlin, Germany. [Folliguet, Thierry A.] Ctr Hosp Univ Brabois ILCV, Vandoeuvre Les Nancy, France. [Kiaii, Bob B.] London Hlth Sci Ctr, Dept Cardiovasc & Thorac Surg, London, ON, Canada. [Mack, Michael J.] Heart Hosp, Baylor Hlth Care Syst, Plano, TX USA. [Mihaljevic, Tomislav] Cleveland Clin Abu Dhabi, Abu Dhabi, U Arab Emirates. [Smith, J. Michael] Good Samaritan Hosp, Cincinnati, OH USA. [Suri, Rakesh M.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Bavaria, Joseph E.] Hosp Univ Penn, Div Cardiovasc Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. [MacGillivray, Thomas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chitwood, W. Randolph, Jr.] Vidant Med Ctr, Greenville, NC USA. [Chitwood, W. Randolph, Jr.] E Carolina Univ, Greenville, NC USA. RP Rodriguez, E (reprint author), St Thomas Heart Hosp, 4230 Harding Rd,Ste 430, Nashville, TN 37205 USA. EM evelio.rodriguez@sth.org NR 14 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2016 VL 102 IS 1 BP 340 EP 344 DI 10.1016/j.athoracsur.2016.02.085 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DP6UL UT WOS:000378634400076 PM 27343505 ER PT J AU Grajo, JR Patino, M Prochowski, A Sahani, DV AF Grajo, Joseph R. Patino, Manuel Prochowski, Andrea Sahani, Dushyant V. TI Dual energy CT in practice: Basic principles and applications SO APPLIED RADIOLOGY LA English DT Article ID IODINE OVERLAY TECHNIQUE; RENAL MASSES; COMPUTED-TOMOGRAPHY; MULTIDETECTOR CT; PHANTOM; IMAGES; CONTRAST C1 [Grajo, Joseph R.] Univ Florida, Coll Med, Gainesville, FL 32611 USA. [Patino, Manuel; Prochowski, Andrea; Sahani, Dushyant V.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA USA. RP Grajo, JR (reprint author), Univ Florida, Coll Med, Gainesville, FL 32611 USA. NR 27 TC 0 Z9 0 U1 0 U2 0 PU ANDERSON PUBLISHING, INC PI SCOTCH PLAINS PA 180 GLENSIDE AVE, SCOTCH PLAINS, NJ 07076 USA SN 0160-9963 EI 1879-2898 J9 APPL RADIOL JI Appl. Radiol. PD JUL PY 2016 VL 45 IS 7 BP 6 EP 12 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DQ5AH UT WOS:000379216300001 ER PT J AU Kamaraj, DC Dicianno, BE Mahajan, HP Buhari, AM Cooper, RA AF Kamaraj, Deepan C. Dicianno, Brad E. Mahajan, Harshal P. Buhari, Alhaji M. Cooper, Rory A. TI Interrater Reliability of the Power Mobility Road Test in the Virtual Reality-Based Simulator-2 SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Durable medical equipment; Neurological rehabilitation; Process assessment (health care); Rehabilitation; Reproducibility of results; Simulation training; Virtual reality exposure therapy; Wheelchairs ID WHEELCHAIR DRIVING PERFORMANCE; TRAUMATIC BRAIN-INJURY; SPINAL-CORD-INJURY; COMMUNITY; USERS; AGREEMENT; VALIDITY; JOYSTICK; PEOPLE; SKILLS AB Objective: To assess interrater reliability of the Power Mobility Road Test (PMRT) when administered through the Virtual Reality based SIMulator-version 2 (VRSIM-2). Design: Within-subjects repeated-measures design. Setting: Participants interacted with VRSIM-2 through 2 display options (desktop monitor vs immersive virtual reality screens) using 2 control interfaces (roller system vs conventional movement-sensing joystick), providing 4 different driving scenarios (driving conditions 1-4). Participants performed 3 virtual driving sessions for each of the 2 display screens and 1 session through a real-world driving course (driving condition 5). The virtual PMRT was conducted in a simulated indoor office space, and an equivalent course was charted in an open space for the real-world assessment. After every change in driving condition, participants completed a self-reported workload assessment questionnaire, the Task Load Index, developed by the National Aeronautics and Space Administration. Participants: A convenience sample of electric-powered wheelchair (EPW) athletes (N=21) recruited at the 31st National Veterans Wheelchair Games. Interventions: Not applicable. Main Outcome Measures: Total composite PMRT score. Results: The PMRT had high interrater reliability (intraclass correlation coefficient [ICC]>.75) between the 2 raters in all 5 driving conditions. Post hoc analyses revealed that the reliability analyses had >80% power to detect high ICCs in driving conditions 1 and 4. Conclusions: The PMRT has high interrater reliability in conditions 1 and 4 and could be used to assess EPW driving performance virtually in VRSIM-2. However, further psychometric assessment is necessary to assess the feasibility of administering the PMRT using the different interfaces of VRSIM-2. (C) 2016 by the American Congress of Rehabilitation Medicine C1 [Kamaraj, Deepan C.; Dicianno, Brad E.; Mahajan, Harshal P.; Buhari, Alhaji M.; Cooper, Rory A.] Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, Ctr Excellence Wheelchairs & Related Technol, Pittsburgh, PA 15206 USA. [Kamaraj, Deepan C.; Cooper, Rory A.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Dicianno, Brad E.; Cooper, Rory A.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Cooper, Rory A.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Dicianno, BE (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, 6425 Penn Ave,Ste 400, Pittsburgh, PA 15206 USA. EM dicianno@pitt.edu OI Kamaraj, Dr.C/0000-0003-0639-8518; Kamaraj, Deepan C/0000-0003-1241-1723 FU Department of Veteran Affairs Research and Development Merit Review Award [A6035R] FX Supported by the Department of Veteran Affairs Research and Development Merit Review Award (grant no. A6035R) with resources and facilities at the Human Engineering Research Laboratories, VA Pittsburgh HealthCare System The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. NR 50 TC 0 Z9 0 U1 5 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUL PY 2016 VL 97 IS 7 BP 1078 EP 1084 DI 10.1016/j.apmr.2016.02.005 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DQ1RZ UT WOS:000378979400005 PM 26921680 ER PT J AU Kamaraj, DC Dicianno, BE Mahajan, HP Buhari, AM Cooper, RA AF Kamaraj, Deepan C. Dicianno, Brad E. Mahajan, Harshal P. Buhari, Alhaji M. Cooper, Rory A. TI Stability and Workload of the Virtual Reality-Based Simulator-2 SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Durable medical equipment; Process assessment (health care); Rehabilitation; Reproducibility of results; Simulation training; Virtual reality exposure therapy; Wheelchairs ID SPINAL-CORD-INJURY; WHEELCHAIR SKILLS; ADVERSE CONSEQUENCES; MOBILITY DEVICES; PEOPLE; RELIABILITY; PERFORMANCE; VALIDITY; REPAIRS; PROGRAM AB Objective: To assess the stability of clinicians' and users' rating of electric-powered wheelchair (EPW) driving while using 4 different human machine interfaces (HMIs) within the Virtual Reality-based SIMulator-version 2 (VRSIM-2) and in the real world (accounting for a total of 5 unique driving conditions). Design: Within-subjects repeated-measures design. Setting: Simulation-based assessment in a research laboratory. Participants: A convenience sample of EPW athletes (N=21) recruited at the 31st National Veterans Wheelchair Games. Interventions: Not applicable. Main Outcome Measures: Composite PMRT scores from the Power Mobility Road Test (PMRT); Raw Task Load Index; and the 6 subscale scores from the Task Load Index developed by the National Aeronautics and Space Administration (NASA-TLX). Results: There was moderate stability (intraclass correlation coefficient between .50 and .75) in the total composite PMRT scores (P<001) and the users' self-reported performance scores (P<.001) among the 5 driving conditions. There was a significant difference in the workload among the 5 different driving conditions as reflected by the Raw Task Load Index (P=.009). Subanalyses revealed this difference was due to the difference in the mental demand (P=.007) and frustration (P=.007) subscales. Post hoc analyses revealed that these differences in the NASA-TLX subscale scores were due to the differences between real-world and virtual driving scores, particularly attributable to the conditions (1 and 3) that lacked the rollers as a part of the simulation. Conclusions: Further design improvements in the simulator to increase immersion experienced by the EPW user, along with a standardized training program for clinicians to deliver PMRT in VRSIM-2, could improve the stability between the different HMIs and real-world driving. (C) 2016 by the American Congress of Rehabilitation Medicine C1 [Kamaraj, Deepan C.; Dicianno, Brad E.; Mahajan, Harshal P.; Buhari, Alhaji M.; Cooper, Rory A.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Excellence Wheelchairs & Related Technol, 6425 Penn Ave,Ste 400, Pittsburgh, PA 15206 USA. [Kamaraj, Deepan C.; Dicianno, Brad E.; Mahajan, Harshal P.; Buhari, Alhaji M.; Cooper, Rory A.] Human Engn Res Labs, Pittsburgh, PA USA. [Kamaraj, Deepan C.; Cooper, Rory A.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Dicianno, Brad E.; Cooper, Rory A.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Cooper, Rory A.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Dicianno, BE (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Excellence Wheelchairs & Related Technol, 6425 Penn Ave,Ste 400, Pittsburgh, PA 15206 USA. EM dicianno@pitt.edu OI Kamaraj, Dr.C/0000-0003-0639-8518; Kamaraj, Deepan C/0000-0003-1241-1723 FU Department of Veteran Affairs Research and Development Merit Review Award [A6035R] FX Supported by the Department of Veteran Affairs Research and Development Merit Review Award (grant no. A6035R) with resources and facilities at the Human Engineering Research Laboratories, VA Pittsburgh HealthCare System The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. NR 31 TC 0 Z9 0 U1 5 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUL PY 2016 VL 97 IS 7 BP 1085 EP 1092 DI 10.1016/j.apmr.2016.01.032 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DQ1RZ UT WOS:000378979400006 PM 26921682 ER PT J AU Hiremath, SV Intille, SS Kelleher, A Cooper, RA Ding, D AF Hiremath, Shivayogi V. Intille, Stephen S. Kelleher, Annmarie Cooper, Rory A. Ding, Dan TI Estimation of Energy Expenditure for Wheelchair Users Using a Physical Activity Monitoring System SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Energy metabolism; Estimation; Exercise test; Motor activity; Rehabilitation; Smartphone; Spinal cord injuries; Wheelchairs ID SPINAL-CORD-INJURY; RANDOMIZED CONTROLLED-TRIAL; WEIGHT-LOSS; VALIDATION; ACCELEROMETER; INTERVENTION; DISABILITIES; PARAPLEGIA; PEOPLE AB Objective: To develop and evaluate energy expenditure (EE) estimation models for a physical activity monitoring system (PAMS) in manual wheelchair users with spinal cord injury (SCI). Design: Cross-sectional study. Setting: University-based laboratory environment, a semistructured environment at the National Veterans Wheelchair Games, and the participants' home environments. Participants: Volunteer sample of manual wheelchair users with SCI (N=45). Intervention: Participants were asked to perform 10 physical activities (PAs) of various intensities from a list. The PAMS consists of a gyroscope-based wheel rotation monitor (G-WRM) and an accelerometer device worn on the upper arm or on the wrist. Criterion EE using a portable metabolic cart and raw sensor data from PAMS were collected during each of these activities. Main Outcome Measures: Estimated EE using custom models for manual wheelchair users based on either the G-WRM and arm accelerometer (PAMS-Arm) or the G-WRM and wrist accelerometer (PAMS-Wrist). Results: EE estimation performance for the PAMS-Arm (average error +/- SD: -9.82%+/- 37.03%) and PAMS-Wrist (-5.65%+/- 32.61%) on the validation dataset indicated that both PAMS-Arm and PAMS-Wrist were able to estimate EE for a range of PAs with <10% error. Moderate to high intraclass correlation coefficients (ICCs) indicated that the EE estimated by PAMS-Arm (ICC3,1 = .82, P<.05) and PAMS-Wrist (ICC3,1 = .89, P<.05) are consistent with the criterion EE. Conclusions: Availability of PA monitors can assist wheelchair users to track PA levels, leading toward a healthier lifestyle. The new models we developed can estimate PA levels in manual wheelchair users with SCI in laboratory and community settings. (C) 2016 by the American Congress of Rehabilitation Medicine C1 [Hiremath, Shivayogi V.; Kelleher, Annmarie; Cooper, Rory A.; Ding, Dan] Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, US Dept Vet Affairs, Pittsburgh, PA USA. [Hiremath, Shivayogi V.; Kelleher, Annmarie; Cooper, Rory A.; Ding, Dan] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Hiremath, Shivayogi V.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Hiremath, Shivayogi V.] Temple Univ, Dept Phys Therapy, Philadelphia, PA 19140 USA. [Intille, Stephen S.] Northeastern Univ, Coll Comp & Informat Sci, Boston, MA 02115 USA. [Intille, Stephen S.] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Cooper, Rory A.; Ding, Dan] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Hiremath, SV (reprint author), Temple Univ, Dept Phys Therapy, Coll Publ Hlth, 3307 N Broad St,Jones Hall,Ste 623, Philadelphia, PA 19140 USA. EM Shiv.Hiremath@temple.edu RI Emchi, Karma/Q-1952-2016 FU Department of Defense [W81XWH-10-1-0816]; Switzer Research Fellowship [H133F110032]; National Institute on Disability and Rehabilitation Research, Department of Education; Human Engineering Research Laboratories, Veterans Affairs Pittsburgh Healthcare System FX Supported by the Department of Defense (grant no. W81XWH-10-1-0816); the Switzer Research Fellowship (grant no. H133F110032), awarded by the National Institute on Disability and Rehabilitation Research, Department of Education; and the Human Engineering Research Laboratories, Veterans Affairs Pittsburgh Healthcare System. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 30 TC 0 Z9 0 U1 2 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUL PY 2016 VL 97 IS 7 BP 1146 EP 1153 DI 10.1016/j.apmr.2016.02.016 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DQ1RZ UT WOS:000378979400014 PM 26976800 ER PT J AU Elliott, DS Newman, KJH Forward, DP Hahn, DM Ollivere, B Kojima, K Handley, R Rossiter, ND Wixted, JJ Smith, RM Moran, CG AF Elliott, D. S. Newman, K. J. H. Forward, D. P. Hahn, D. M. Ollivere, B. Kojima, K. Handley, R. Rossiter, N. D. Wixted, J. J. Smith, R. M. Moran, C. G. TI A unified theory of bone healing and nonunion SO BONE & JOINT JOURNAL LA English DT Article ID INTERNAL-FIXATION; FRACTURE; MECHANOBIOLOGY; COMPLICATIONS; STABILITY; MODEL AB This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff's law, Perren's strain theory and Frost's concept of the "mechanostat". In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture-healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. C1 [Elliott, D. S.; Newman, K. J. H.; Forward, D. P.; Hahn, D. M.; Ollivere, B.; Kojima, K.; Handley, R.; Rossiter, N. D.; Wixted, J. J.; Smith, R. M.; Moran, C. G.] Univ Nottingham Hosp, Dept Trauma & Orthopaed, Nottingham, England. [Elliott, D. S.; Newman, K. J. H.] Ashford & St Peters Hosp NHS Fdn Trust, Guildford Rd, Chertsey KT160PZ, Surrey, England. [Smith, R. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Forward, D. P.; Hahn, D. M.; Ollivere, B.] Nottingham Univ Hosp NHS Trust, Nottingham NG7 2UH, England. [Moran, C. G.] Nottingham Univ Hosp NHS Trust, Trauma, Nottingham NG7 2UH, England. [Moran, C. G.] Nottingham Univ Hosp NHS Trust, Orthopaed Trauma Surg, Nottingham NG7 2UH, England. [Kojima, K.] Univ Sao Paulo, Orthoped Trauma Grp, Rua Dr Ovidio Pires Campos 333, Sao Paulo, Brazil. [Handley, R.] John Radcliffe Hosp, Oxford OX3 9DU, England. [Rossiter, N. D.] Basingstoke & Northamptonshire Hosp, Basingstoke RG24 9NA, Hants, England. [Wixted, J. J.] Beth Israel Hosp, Boston, MA USA. RP Smith, RM (reprint author), Univ Nottingham Hosp, Dept Trauma & Orthopaed, Nottingham, England.; Smith, RM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM RMSMITH1@PARTNERS.ORG NR 39 TC 2 Z9 2 U1 5 U2 8 PU BRITISH EDITORIAL SOC BONE JOINT SURGERY PI LONDON PA 22 BUCKINGHAM STREET, LONDON WC2N 6ET, ENGLAND SN 2049-4394 J9 BONE JOINT J JI Bone Joint J. PD JUL PY 2016 VL 98B IS 7 BP 884 EP 891 DI 10.1302/0301-620X.98B7.36061 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DQ5JN UT WOS:000379241400004 PM 27365465 ER PT J AU Harshman, LC AF Harshman, Lauren C. TI Mind the gap: What is driving the survival disparity between the sexes in bladder cancer? SO CANCER LA English DT Editorial Material ID CELL CARCINOMA; UROTHELIAL CARCINOMA; CHEMOTHERAPY; EXPRESSION; RESPONSES; GENDER; NIVOLUMAB; IMMUNITY; MELANOMA; SUBTYPES AB Bladder cancer is well known to preferentially afflict men. However, women are significantly more likely to die of the disease even when corrected for stage, tumor characteristics, and age. In this issue of Cancer, Rose and colleagues highlight concerning disparities in bladder cancer treatment and outcomes between the sexes. See also pages 2012-20. C1 [Harshman, Lauren C.] Dana Farber Canc Inst, Lank Ctr Genitourinary Canc, Boston, MA 02115 USA. RP Harshman, LC (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Lank Ctr Genitourinary Canc, 450 Brookline Ave, Boston, MA 02215 USA. EM LaurenC_Harshman@dfci.harvard.edu 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 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 2016 VL 122 IS 13 BP 1966 EP 1970 DI 10.1002/cncr.30027 PG 5 WC Oncology SC Oncology GA DQ3XS UT WOS:000379137900004 PM 27224470 ER PT J AU Liao, ZW Rodrigues, MC Poynter, JN Amatruda, JF Rodriguez-Galindo, C Frazier, AL AF Liao, Zi Wei Rodrigues, Maria Clarissa Poynter, Jenny N. Amatruda, James F. Rodriguez-Galindo, Carlos Frazier, A. Lindsay TI Risk of second gonadal cancers in women and children with germ cell tumors SO CANCER LA English DT Article DE epidemiology; germ cell tumor; pediatrics; second cancer; Surveillance; Epidemiology; and End Results (SEER); testicular cancer ID LONG-TERM SURVIVORS; TESTICULAR-CANCER; MALIGNANT NEOPLASMS; UNITED-STATES; ASSOCIATIONS; PERSPECTIVE; CHILDHOOD; PROFILES; FEATURES; DISEASE AB BACKGROUNDMen with testicular cancer have an increased risk of developing cancer in the contralateral testis, but the risks of second gonadal cancers (SGCs) in women and children treated for germ cell tumors (GCTs) have not previously been quantified. METHODSThe incidence of SGCs was ascertained in patients who had survived for at least 1 year after GCT diagnosis using data from the Surveillance, Epidemiology, and End Results SEER 9 registries (1980-2012). Relative risks of SGCs were estimated separately for boys, women, and girls compared with men based on Poisson regression analysis. RESULTSThe cohort included 21,546 individuals (1116 boys, 827 women, 622 girls, and 18,981 men). A total of 25 SGCs were identified in boys, 1 in women, and 2 in girls compared with 254 in men. The risk of SGC in postpubertal boys (aged 10 years) was comparable to that of adult men (boys: standardized incidence ratio, 15.90; 95% confidence interval, 10.29-23.47; men: standardized incidence ratio, 10.88; 95% confidence interval, 9.58-12.30). However, no SGCs were observed in boys who were diagnosed with a testicular GCT before age 10 years (N = 179). An elevated risk of SGC was also not observed for women or girls. CONCLUSIONSThe apparent lack of an SGC in prepubertal boys suggests that susceptibility is either age-dependent and/or histology-dependent. The sex differences in the risk of SGC suggest differences in the etiology of ovarian versus testicular GCT. The finding that the risk of SGCs in postpubertal boys is similar to that observed in men indicates that long-term follow-up for SGC is warranted in postpubertal boys. Cancer 2016;122:2076-82. (c) 2016 American Cancer Society. Postpubertal boys and men with germ cell tumors share a similar risk of developing a second testicular cancer. However, neither prepubertal boys with testicular cancer nor females with ovarian germ cell tumors appear to have an increased risk of second gonadal cancer. C1 [Liao, Zi Wei; Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Dana Farber Canc Inst, 450 Brookline Ave,D-3127, Boston, MA 02216 USA. [Liao, Zi Wei; Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Boston Childrens Hosp, 450 Brookline Ave,D-3127, Boston, MA 02216 USA. [Liao, Zi Wei] Wellesley Coll, Interdept Program Biochem, Wellesley, MA 02181 USA. [Rodrigues, Maria Clarissa] Coll Med Sci Santa Casa Sao Paulo, Sao Paulo, Brazil. [Poynter, Jenny N.] Univ Minnesota, Dept Pediat, Div Epidemiol & Clin Res, Minneapolis, MN 55455 USA. [Poynter, Jenny N.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Amatruda, James F.] Univ Texas Southwestern Med Ctr, Dept Pediat, Dallas, TX USA. [Amatruda, James F.] Univ Texas Southwestern Med Ctr, Dept Mol Biol, Dallas, TX USA. [Amatruda, James F.] Childrens Med Ctr, Ctr Canc & Blood Disorders, Dallas, TX 75235 USA. RP Frazier, AL (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D-3127, Boston, MA 02216 USA.; Frazier, AL (reprint author), Boston Childrens Hosp, 450 Brookline Ave,D-3127, Boston, MA 02216 USA. EM lindsay_frazier@dfci.harvard.edu FU Global Engagement Internship; Department of Biological Sciences at Wellesley College FX This study was supported by the Global Engagement Internship and by the Department of Biological Sciences at Wellesley College. NR 31 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 2016 VL 122 IS 13 BP 2076 EP 2082 DI 10.1002/cncr.30014 PG 7 WC Oncology SC Oncology GA DQ3XS UT WOS:000379137900017 PM 27152727 ER PT J AU Halasz, LM Uno, H Hughes, M D'Amico, T Dexter, EU Edge, SB Hayman, JA Niland, JC Otterson, GA Pisters, KMW Theriault, R Weeks, JC Punglia, RS AF Halasz, Lia M. Uno, Hajime Hughes, Melissa D'Amico, Thomas Dexter, Elisabeth U. Edge, Stephen B. Hayman, James A. Niland, Joyce C. Otterson, Gregory A. Pisters, Katherine M. W. Theriault, Richard Weeks, Jane C. Punglia, Rinaa S. TI Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non-small cell lung cancer SO CANCER LA English DT Article DE breast neoplasms; comparative effectiveness research; neoplasm metastasis; non-small cell lung carcinoma; radiosurgery ID ONCOLOGY-GROUP; TRIALS; NCCN AB BACKGROUNDThe optimal treatment for patients with brain metastases remains controversial as the use of stereotactic radiosurgery (SRS) alone, replacing whole-brain radiation therapy (WBRT), has increased. This study determined the patterns of care at multiple institutions before 2010 and examined whether or not survival was different between patients treated with SRS and patients treated with WBRT. METHODSThis study examined the overall survival of patients treated with radiation therapy for brain metastases from non-small cell lung cancer (NSCLC; initially diagnosed in 2007-2009) or breast cancer (initially diagnosed in 1997-2009) at 5 centers. Propensity score analyses were performed to adjust for confounding factors such as the number of metastases, the extent of extracranial metastases, and the treatment center. RESULTSOverall, 27.8% of 400 NSCLC patients and 13.4% of 387 breast cancer patients underwent SRS alone for the treatment of brain metastases. Few patients with more than 3 brain metastases or lesions 4 cm in size underwent SRS. Patients with fewer than 4 brain metastases less than 4 cm in size (n = 189 for NSCLC and n = 117 for breast cancer) who were treated with SRS had longer survival (adjusted hazard ratio [HR] for NSCLC, 0.58; 95% confidence Interval [CI], 0.38-0.87; P = .01; adjusted HR for breast cancer, 0.54; 95% CI, 0.33-0.91; P = .02) than those treated with WBRT. CONCLUSIONSPatients treated for fewer than 4 brain metastases from NSCLC or breast cancer with SRS alone had longer survival than those treated with WBRT in this multi-institutional, retrospective study, even after adjustments for the propensity to undergo SRS. Cancer 2016;122:2091-100. (c) 2016 American Cancer Society. With data from a multi-institutional, longitudinal database, propensity score analyses have been performed for patients treated for brain metastases from non-small cell lung cancer or breast cancer. Patients treated initially for fewer than 4 brain metastases with stereotactic radiosurgery alone have improved survival. C1 [Halasz, Lia M.] Univ Washington, Dept Radiat Oncol, 1959 NE Pacific St, Seattle, WA 98195 USA. [Uno, Hajime; Hughes, Melissa; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [D'Amico, Thomas] Duke Canc Inst, Dept Surg, Durham, NC USA. [Dexter, Elisabeth U.; Edge, Stephen B.] Roswell Pk Canc Inst, Dept Surg, Buffalo, NY 14263 USA. [Dexter, Elisabeth U.; Edge, Stephen B.] Univ Buffalo, Buffalo, NY USA. [Hayman, James A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Niland, Joyce C.] City Hope Natl Med Ctr, Informat Sci, Duarte, CA USA. [Otterson, Gregory A.] Ohio State Univ, Ctr Comprehens Canc, Dept Med, Columbus, OH 43210 USA. [Pisters, Katherine M. W.; Theriault, Richard] Univ Texas MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX 77030 USA. [Punglia, Rinaa S.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Halasz, LM (reprint author), Univ Washington, Dept Radiat Oncol, 1959 NE Pacific St, Seattle, WA 98195 USA. EM lhalasz@uw.edu FU National Institutes of Health/National Cancer Institute [RC2CA148185]; Career Development Award from the National Institutes of Health [1K07CA118629]; National Comprehensive Cancer Network FX This study was supported by a grant from the National Institutes of Health/National Cancer Institute (Building CER Capacity: Aligning CRN, CMS, and State Resources to Map Cancer Care [RC2CA148185]) and by a Career Development Award from the National Institutes of Health (1K07CA118629 to Rinaa S. Punglia). The National Comprehensive Cancer Network provided funding for the data collection. NR 18 TC 6 Z9 6 U1 1 U2 2 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 2016 VL 122 IS 13 BP 2091 EP 2100 DI 10.1002/cncr.30009 PG 10 WC Oncology SC Oncology GA DQ3XS UT WOS:000379137900019 PM 27088755 ER PT J AU Nipp, RD El-Jawahri, A Fishbein, JN Eusebio, J Stagl, JM Gallagher, ER Park, ER Jackson, VA Pirl, WF Greer, JA Temel, JS AF Nipp, Ryan D. El-Jawahri, Areej Fishbein, Joel N. Eusebio, Justin Stagl, Jamie M. Gallagher, Emily R. Park, Elyse R. Jackson, Vicki A. Pirl, William F. Greer, Joseph A. Temel, Jennifer S. TI The relationship between coping strategies, quality of life, and mood in patients with incurable cancer SO CANCER LA English DT Article DE anxiety; coping behavior; depression; incurable cancer; palliative care; quality of life ID CELL LUNG-CANCER; RANDOMIZED CONTROLLED-TRIAL; EARLY PALLIATIVE CARE; STAGE BREAST-CANCER; NEAR-DEATH; GYNECOLOGIC CANCER; SYMPTOM BURDEN; WOMEN; PREDICTORS; ADJUSTMENT AB BACKGROUNDPatients with incurable cancer face many physical and emotional stressors, yet little is known about their coping strategies or the relationship between their coping strategies, quality of life (QOL), and mood. METHODSAs part of a randomized trial of palliative care, this study assessed baseline QOL (Functional Assessment of Cancer Therapy-General), mood (Hospital Anxiety and Depression Scale), and coping (Brief COPE) in patients within 8 weeks of a diagnosis of incurable lung or gastrointestinal cancer and before randomization. To examine associations between coping strategies, QOL, and mood, we used linear regression, adjusting for patients' age, sex, marital status, and cancer type. RESULTSThere were 350 participants (mean age, 64.9 years), and the majority were male (54.0%), were married (70.0%), and had lung cancer (54.6%). Most reported high utilization of emotional support coping (77.0%), whereas fewer reported high utilization of acceptance (44.8%), self-blame (37.9%), and denial (28.2%). Emotional support (QOL: = 2.65, P < .01; depression: = -0.56, P = .02) and acceptance (QOL: = 1.55, P < .01; depression: = -0.37, P = .01; anxiety: = -0.34, P = .02) correlated with better QOL and mood. Denial (QOL: = -1.97, P < .01; depression: = 0.36, P = .01; anxiety: = 0.61, P < .01) and self-blame (QOL: = -2.31, P < .01; depression: = 0.58, P < .01; anxiety: = 0.66, P < .01) correlated with worse QOL and mood. CONCLUSIONSPatients with newly diagnosed, incurable cancer use a variety of coping strategies. The use of emotional support and acceptance coping strategies correlated with better QOL and mood, whereas the use of denial and self-blame negatively correlated with these outcomes. Interventions to improve patients' QOL and mood should seek to cultivate the use of adaptive coping strategies. Cancer 2016;122:2110-6. (c) 2016 American Cancer Society. Patients with a new diagnosis of incurable cancer cope in a variety of unique ways. Patients' use of certain coping strategies correlate with their quality of life and mood, and this suggests that evaluating and addressing patients' coping behaviors may affect other key patient-reported outcomes. C1 [Nipp, Ryan D.; El-Jawahri, Areej; Gallagher, Emily R.; Temel, Jennifer S.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Div Hematol & Oncol, Boston, MA 02114 USA. [Nipp, Ryan D.; El-Jawahri, Areej; Fishbein, Joel N.; Eusebio, Justin; Stagl, Jamie M.; Gallagher, Emily R.; Park, Elyse R.; Jackson, Vicki A.; Pirl, William F.; Greer, Joseph A.; Temel, Jennifer S.] Harvard Med Sch, Boston, MA USA. [Fishbein, Joel N.; Eusebio, Justin; Stagl, Jamie M.; Park, Elyse R.; Pirl, William F.; Greer, Joseph A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Jackson, Vicki A.] Massachusetts Gen Hosp, Dept Med, Div Palliat Care, Boston, MA 02114 USA. RP Nipp, RD (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM rnipp@mgh.harvard.edu OI Jacobs, Jamie M./0000-0001-9740-624X FU National Institute of Nursing Research [R01 NR012735]; National Cancer Institute [K24 CA181253] FX This study was funded by the National Institute of Nursing Research (R01 NR012735 to Jennifer S. Temel) and the National Cancer Institute (K24 CA181253 to Jennifer S. Temel). NR 45 TC 3 Z9 3 U1 8 U2 11 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 2016 VL 122 IS 13 BP 2110 EP 2116 DI 10.1002/cncr.30025 PG 7 WC Oncology SC Oncology GA DQ3XS UT WOS:000379137900021 PM 27089045 ER PT J AU Gaffney, AW Verhoef, PA Hall, JB AF Gaffney, Adam W. Verhoef, Philip A. Hall, Jesse B. TI POINT: Should Pulmonary/ICU Physicians Support Single-payer Health-care Reform? Yes SO CHEST LA English DT Editorial Material ID INHALED MEDICATIONS; UNITED-STATES; INSURANCE; DISPARITIES; DISEASE; COSTS; WILL C1 [Gaffney, Adam W.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Verhoef, Philip A.; Hall, Jesse B.] Univ Chicago, Sect Pulm & Crit Care Med, Chicago, IL 60637 USA. RP Verhoef, PA (reprint author), Univ Chicago, Dept Med, Sect Pulm & Crit Care, 5841 S Maryland Ave,MC 6076, Chicago, IL 60637 USA. EM philip.verhoef@uchospitals.edu NR 19 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2016 VL 150 IS 1 BP 9 EP 11 DI 10.1016/j.chest.2016.02.660 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ5BS UT WOS:000379220000011 PM 27396772 ER PT J AU Gaffney, AW Verhoef, PA Hall, JB AF Gaffney, Adam W. Verhoef, Philip A. Hall, Jesse B. TI Rebuttal From Drs Gaffney, Verhoef, and Hall SO CHEST LA English DT Editorial Material ID CARE; INSURANCE C1 [Gaffney, Adam W.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Verhoef, Philip A.; Hall, Jesse B.] Univ Chicago, Sect Pulm & Crit Care Med, Chicago, IL 60637 USA. RP Verhoef, PA (reprint author), Univ Chicago, Dept Med, Sect Pulm & Crit Care, 5841 S Maryland Ave,MC 6076, Chicago, IL 60637 USA. EM philip.verhoef@uchospitals.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2016 VL 150 IS 1 BP 14 EP 15 DI 10.1016/j.chest.2016.02.661 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ5BS UT WOS:000379220000013 PM 27396774 ER PT J AU Bourge, RC Waxman, AB Gomberg-Maitland, M Shapiro, SM Tarver, JH Zwicke, DL Feldman, JP Chakinala, MM Frantz, RP Torres, F Cerkvenik, J Morris, M Thalin, M Peterson, L Rubin, LJ AF Bourge, Robert C. Waxman, Aaron B. Gomberg-Maitland, Mardi Shapiro, Shelley M. Tarver, James H., III Zwicke, Dianne L. Feldman, Jeremy P. Chakinala, Murali M. Frantz, Robert P. Torres, Fernando Cerkvenik, Jeffrey Morris, Marty Thalin, Melissa Peterson, Leigh Rubin, Lewis J. TI Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System Results of the DelIVery for PAH Trial SO CHEST LA English DT Article DE central venous catheters; drugs; health-related quality of life; pulmonary arterial hypertension; pulmonary hypertension; treprostinil ID QUALITY-OF-LIFE; CATHETERS; INFUSION; INFECTIONS; SAFETY AB BACKGROUND: The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. METHODS: A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. RESULTS: Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 +/- 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 +/- 1.7 hours per week preimplantation, and this time decreased to 0.6 +/- 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions. CONCLUSIONS: The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. C1 [Bourge, Robert C.] Univ Alabama Birmingham, 321k Tinsley Harrison Tower,1900 Univ Blvd, Birmingham, AL 35294 USA. [Waxman, Aaron B.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Gomberg-Maitland, Mardi] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Shapiro, Shelley M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Shapiro, Shelley M.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Tarver, James H., III] Orlando Reg Med Ctr Inc, Orlando, FL USA. [Zwicke, Dianne L.] Aurora St Lukes Med Ctr, Milwaukee, WI USA. [Feldman, Jeremy P.] Arizona Pulm Specialists Ltd, Scottsdale, AZ USA. [Chakinala, Murali M.] Washington Univ, Sch Med, St Louis, MO USA. [Frantz, Robert P.] Mayo Clin, Rochester, MN USA. [Torres, Fernando] Univ Texas Southwestern Med Ctr, Rochester, MN USA. [Cerkvenik, Jeffrey; Morris, Marty; Thalin, Melissa] Medtronic Inc, Minneapolis, MN USA. [Peterson, Leigh] United Therapeut Corp, Res Triangle Pk, NC USA. [Rubin, Lewis J.] Univ Calif San Diego, Div Pulm & Crit Care Med, La Jolla, CA USA. RP Bourge, RC (reprint author), Univ Alabama Birmingham, 321k Tinsley Harrison Tower,1900 Univ Blvd, Birmingham, AL 35294 USA. EM bbourge@uab.edu FU Medtronic, Inc; United Therapeutics Corporation FX The sponsor of this study was Medtronic, Inc, and the funding for this study came from United Therapeutics Corporation. NR 20 TC 4 Z9 5 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2016 VL 150 IS 1 BP 27 EP 34 DI 10.1016/j.chest.2015.11.005 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ5BS UT WOS:000379220000016 PM 27396777 ER PT J AU Hasegawa, K Tsugawa, Y Clark, S Eastin, CD Gabriel, S Herrera, V Bittner, JC Camargo, CA AF Hasegawa, Kohei Tsugawa, Yusuke Clark, Sunday Eastin, Carly D. Gabriel, Susan Herrera, Vivian Bittner, Jane C. Camargo, Carlos A., Jr. CA MARC-37 Investigators TI Improving Quality of Acute Asthma Care in US Hospitals Changes Between 1999-2000 and 2012-2013 SO CHEST LA English DT Article DE asthma; guideline; hospitalization; quality of care ID EMERGENCY-DEPARTMENT; UNITED-STATES; OF-CARE; HEALTH-CARE; CHILDREN; PERFORMANCE; GUIDELINES; MANAGEMENT; ADHERENCE; OUTCOMES AB BACKGROUND: Little is known about the longitudinal change in the quality of acute asthma care for hospitalized children and adults in the United States. We investigated whether the concordance of inpatient asthma care with the national guidelines improved over time, identified hospital characteristics predictive of guideline concordance, and determined whether guideline-concordant care is associated with a shorter hospital length of stay (LOS). METHODS: This study was an analysis of data from two multicenter chart review studies of hospitalized patients aged 2 to 54 years with acute asthma during two time periods: 19992000 and 2012-2013. Outcomes were guideline concordance at the patient and hospital levels, and association of patient composite concordance with hospital LOS. RESULTS: The analytic cohort for the comparison of guideline concordance comprised 1,634 patients: 834 patients from 1999-2000 vs 800 patients from 2012-2013. Over these 15 years, inpatient asthma care became more concordant at the hospital-level, with the mean composite score increasing from 74 to 82 (P < .001). However, during 2012-2013, wide variability in guideline concordance of acute asthma care remained across hospitals, with the greatest variation in provision of individualized written action plan at discharge (SD, 36). Guideline concordance was significantly lower in Midwestern and Southern hospitals compared with Northeastern hospitals. After adjusting for severity, patients who received care perfectly concordant with the guidelines had significantly shorter hospital LOS (-14% [95% CI, -23 to -4]; P = .009). CONCLUSIONS: Between 1999 and 2013, the guideline concordance of acute asthma care for hospitalized patients improved. However, interhospital variability remains substantial. Greater concordance with evidence-based guidelines was associated with a shorter hospital LOS. C1 [Hasegawa, Kohei; Bittner, Jane C.; Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Tsugawa, Yusuke] Harvard Sch Publ Hlth, Boston, MA USA. [Clark, Sunday] Weill Cornell Med Coll, Dept Emergency Med, New York, NY USA. [Eastin, Carly D.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Gabriel, Susan; Herrera, Vivian] Novartis Pharmaceut, E Hanover, NJ USA. RP Hasegawa, K (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Ste 920, Boston, MA 02114 USA. EM khasegawa1@partners.org FU University HealthSystem Consortium; Novartis Pharmaceuticals Corporation FX The 1999-2000 study was supported by the University HealthSystem Consortium; the 2012-2013 study was supported by Novartis Pharmaceuticals Corporation (Principal Investigator, Dr Camargo). NR 32 TC 1 Z9 1 U1 2 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2016 VL 150 IS 1 BP 112 EP 122 DI 10.1016/j.chest.2016.03.037 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ5BS UT WOS:000379220000024 PM 27056585 ER PT J AU Gubatan, J Staller, K Barshop, K Kuo, B AF Gubatan, John Staller, Kyle Barshop, Kenneth Kuo, Braden TI Cannabis Abuse Is Increasing and Associated with Increased Emergency Department Utilization in Gastroenterology Patients SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Medical marijuana; Cannabis; Cannabinoids; Epidemiology; Healthcare utilization; Functional GI disorders ID IRRITABLE-BOWEL-SYNDROME; HEALTH-CARE UTILIZATION; QUALITY-OF-LIFE; MEDICAL MARIJUANA; CROHNS-DISEASE; SUBSTANCE USE; SOCIOECONOMIC-STATUS; RECEPTOR AGONIST; CB2 RECEPTORS; UNITED-STATES AB The role of cannabinoids in gastrointestinal diseases is controversial and of great interest, yet their use in patients has not been critically examined. To determine the prevalence and effects of cannabis abuse on healthcare utilization, as measured by emergency department (ED) visits, in a large, tertiary gastroenterology practice. All patients seen in the gastroenterology clinic at a tertiary care center during a 27-year period (1986-2013) were included in our study to determine the overall prevalence of cannabis abuse. We matched cannabis abusers 1:2 with non-abusing controls to determine the effect of cannabis on ED utilization, our primary outcome. We used multivariate linear regression to adjust for confounders and define the independent effect of cannabis abuse on ED utilization. Our prevalence study cohort included 190,303 GI clinic patients with an overall cannabis abuse prevalence of 0.80 % (1520 patients). From 1986 to 2012, the prevalence of cannabis abuse in this clinic increased by 0.73 % (0.03 %/year) (p < 0.0001). From the 1520 cannabis abusers identified, 467 patients were randomly selected as cases and were matched to 934 controls. From this retrospective cohort, the median ED visits/year for cannabis abusers was 1.88 versus 0.89 for non-abusers (p < 0.0001). After multivariate adjustment, cannabis abuse was associated with a 1.47-fold increase (95 % CI 1.23-1.76, p < 0.0001) in median ED visits/year. Reported cannabis abuse in GI clinic patients is less prevalent than in the adult US population, but is increasing. Cannabis abuse among gastroenterology patients is associated with increased ED visits. C1 [Gubatan, John] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. [Staller, Kyle; Kuo, Braden] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA USA. [Staller, Kyle; Kuo, Braden] Massachusetts Gen Hosp, Ctr Neurointestinal Hlth, Boston, MA 02114 USA. [Barshop, Kenneth] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. RP Gubatan, J (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM jgubatan@bidmc.harvard.edu OI Staller, Kyle/0000-0003-4925-4290; Gubatan, John Mark/0000-0001-6037-2883 FU Vibrant FX J. Gubatan, K. Staller, and K. Barshop declare no conflict of interest; B. Kuo receives clinical trial support from Vibrant. NR 47 TC 1 Z9 1 U1 4 U2 5 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 2016 VL 61 IS 7 BP 1844 EP 1852 DI 10.1007/s10620-016-4090-9 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DQ2EA UT WOS:000379013300013 PM 26935430 ER PT J AU Cadoni, S Falt, P Sanna, S Argiolas, M Fanari, V Gallittu, P Liggi, M Mura, D Porcedda, ML Smajstrla, V Erriu, M Leung, FW AF Cadoni, Sergio Falt, Premysl Sanna, Stefano Argiolas, Mariangela Fanari, Viviana Gallittu, Paolo Liggi, Mauro Mura, Donatella Porcedda, Maria L. Smajstrla, Vit Erriu, Matteo Leung, Felix W. TI Impact of Colonoscopy Insertion Techniques on Adenoma Detection SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Bowel cleanliness; Colon lesion detection; Interval cancer; Small adenomas; Water-aided colonoscopy ID INTERVAL COLORECTAL CANCERS; BOWEL PREPARATION QUALITY; WATER EXCHANGE; NEGATIVE COLONOSCOPY; MISS RATE; RISK; IMMERSION; POLYPS; RATES; METAANALYSIS AB Low adenoma detection rate (ADR) predicts development of interval cancers, found mainly in the right (cecum-ascending) colon, where poor bowel preparation is an associated factor. Single-site studies reported increased detection of adenomas in the proximal colon segments by water exchange (WE). Data about colon cleansing revealed that WE had the greatest impact in the right colon. To test the hypothesis that WE had the greatest impact on ADR in colon segments with the most favorable bowel cleanliness scores, namely the right colon. We pooled right colon and overall ADR data of three similarly designed colonoscopy trials that compared WE, water immersion (WI) and insufflation of air or carbon dioxide (AICD) in a mixed gender European population. In this study, 1200 (704 males) subjects and were included. 288 were screening cases. Demographic and procedural data were comparable. Water exchange achieved significantly higher right colon < 10 mm ADR (11.9 %, vs WI 6.9 %, p = 0.016; vs AICD 7.2 %, p = 0.025). Water exchange achieved the lowest proportions of poor bowel preparation and the highest right colon and overall Boston bowel preparation scale scores (p range 0.003, < 0.0005). In patients with right colon excellent bowel cleanliness, water exchange was the only method significantly associated with right colon adenoma detection. One of the limitations is unblinded colonoscopists. In a mixed gender European population, water exchange is confirmed to be a superior insertion technique showing a significant increase in < 10 mm right colon adenoma detection, achieving the cleanest colon and lowest proportions of poor bowel preparation requiring repeat procedures. NCT01781650, 01954862, 01780818. C1 [Cadoni, Sergio; Gallittu, Paolo; Liggi, Mauro; Mura, Donatella] St Barbara Hosp, Digest Endoscopy Unit, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. [Falt, Premysl; Smajstrla, Vit] Vitkovice Hosp, Ctr Digest Dis, Zaluzanskeho 1192-15, Ostrava 70384, Czech Republic. [Sanna, Stefano; Argiolas, Mariangela; Fanari, Viviana; Porcedda, Maria L.] NS Bonaria Hosp, Digest Endoscopy Unit, I-09037 San Gavino Monreale, VS, Italy. [Erriu, Matteo] Univ Cagliari, Dept Surg Sci, I-09121 Cagliari, Italy. [Leung, Felix W.] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA 91343 USA. [Leung, Felix W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Cadoni, S (reprint author), St Barbara Hosp, Digest Endoscopy Unit, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. EM cadonisergio@gmail.com; faltprem@centrum.cz; endo.sangav@tiscali.it; Margiolas2003@tiscali.it; mavivi@tiscali.it; paologallittu@gmail.com; liggim@gmail.com; muradonatella@live.it; toniolaura@tiscali.it; bormed1@volny.cz; matteoerr@gmail.com; felixleung@socal.rr.com NR 44 TC 2 Z9 2 U1 1 U2 2 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 2016 VL 61 IS 7 BP 2068 EP 2075 DI 10.1007/s10620-016-4053-1 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DQ2EA UT WOS:000379013300037 PM 26846118 ER PT J AU Corey, KE Klebanoff, MJ Tramontano, AC Chung, RT Hur, C AF Corey, Kathleen E. Klebanoff, Matthew J. Tramontano, Angela C. Chung, Raymond T. Hur, Chin TI Screening for Nonalcoholic Steatohepatitis in Individuals with Type 2 Diabetes: A Cost-Effectiveness Analysis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Nonalcoholic steatohepatitis; Fibrosis; Cirrhosis; Screening ID FATTY LIVER-DISEASE; PLACEBO-CONTROLLED TRIAL; UNITED-STATES; HEPATOCELLULAR-CARCINOMA; VITAMIN-E; PIOGLITAZONE; PREVALENCE; MELLITUS; OUTCOMES; BIOPSY AB Individuals with type 2 diabetes are at heightened risk for nonalcoholic fatty liver disease, which gives rise to nonalcoholic steatohepatitis (NASH) and cirrhosis. Yet, current guidelines do not recommend screening for NASH among these high-risk patients. Using a simulation model, we assessed the effectiveness and cost-effectiveness of screening diabetic patients for NASH. A Markov model was constructed to compare two management strategies for 50-year-olds with diabetes. In the No Screening strategy, patients do not undergo screening, although NASH may be diagnosed incidentally over their lifetime. In the NASH Screening strategy, all patients receive a one-time screening ultrasound. Individuals with fatty infiltration on ultrasound then have a liver biopsy, and those found to have NASH receive medical therapy, which decreases progression to cirrhosis. Endpoints evaluated included quality-adjusted life years (QALYs) gained, costs, and incremental cost-effectiveness ratios (ICERs). Screening for NASH decreased the number of individuals who developed cirrhosis by 12.9 % and resulted in an 11.9 % decrease in liver-related deaths. However, screening resulted in 0.02 fewer QALYs, due to the disutility associated with treatment, and was therefore dominated by the No Screening strategy. When the model excluded this quality-of-life decrement, screening became cost-effective, at an ICER of $42,134 per QALY. Screening for NASH may improve liver-related outcomes, but is not cost-effective at present, due to side effects of therapy. As better tolerated treatments for NASH become available, even with modest efficacy, screening for NASH will become cost-effective. C1 [Corey, Kathleen E.; Klebanoff, Matthew J.; Chung, Raymond T.; Hur, Chin] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Corey, Kathleen E.; Chung, Raymond T.; Hur, Chin] Harvard Med Sch, Boston, MA 02115 USA. [Klebanoff, Matthew J.; Tramontano, Angela C.; Hur, Chin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Corey, KE (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.; Corey, KE (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM kcorey@partners.org; mklebanoff@mgh.harvard.edu; angela@mgh-ita.org; rtchung@mgh.harvard.edu; chur@mgh.harvard.edu OI Hur, Chin/0000-0002-2819-7576 FU NIH [K23 DK099422, K24 DK078772] FX Kathleen E. Corey and Raymond T. Chung received grant support from NIH K23 DK099422 and K24 DK078772, respectively. NR 48 TC 1 Z9 1 U1 0 U2 0 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 2016 VL 61 IS 7 BP 2108 EP 2117 DI 10.1007/s10620-016-4044-2 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DQ2EA UT WOS:000379013300042 PM 26825843 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Reduction of LDL-cholesterol: important at all ages SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID RISK-FACTORS; CAROTID PLAQUE; METAANALYSIS; INFARCTION; MORTALITY; SMOKING; DISEASE; SEX C1 [Braunwald, Eugene] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Med Sch, Dept Med, Boston, MA USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, 350 Longwood Ave, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 13 TC 1 Z9 1 U1 1 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 JUL 1 PY 2016 VL 37 IS 25 BP 1982 EP 1984 DI 10.1093/eurheartj/ehw100 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ3TN UT WOS:000379126000012 PM 26984858 ER PT J AU Griffith, M Griffith, OL Krysiak, K Skidmore, ZL Christopher, MJ Klco, JM Ramu, A Lamprecht, TL Wagner, AH Campbell, KM Lesurf, R Hundal, J Zhang, J Spies, NC Ainscough, BJ Larson, DE Heath, SE Fronick, C O'Laughlin, S Fulton, RS Magrini, V McGrath, S Smith, SM Miller, CA Maher, CA Payton, JE Walker, JR Eldred, JM Walter, MJ Link, DC Graubert, TA Westervelt, P Kulkarni, S DiPersio, JF Mardis, ER Wilson, RK Ley, TJ AF Griffith, Malachi Griffith, Obi L. Krysiak, Kilannin Skidmore, Zachary L. Christopher, Matthew J. Klco, Jeffery M. Ramu, Avinash Lamprecht, Tamara L. Wagner, Alex H. Campbell, Katie M. Lesurf, Robert Hundal, Jasreet Zhang, Jin Spies, Nicholas C. Ainscough, Benjamin J. Larson, David E. Heath, Sharon E. Fronick, Catrina O'Laughlin, Shelly Fulton, Robert S. Magrini, Vincent McGrath, Sean Smith, Scott M. Miller, Christopher A. Maher, Christopher A. Payton, Jacqueline E. Walker, Jason R. Eldred, James M. Walter, Matthew J. Link, Daniel C. Graubert, Timothy A. Westervelt, Peter Kulkarni, Shashikant DiPersio, John F. Mardis, Elaine R. Wilson, Richard K. Ley, Timothy J. TI Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID GENE-EXPRESSION; YOUNG-ADULTS; RISK; MUTATIONS; PAX5; SUSCEPTIBILITY; ADOLESCENTS; INHIBITION; DIAGNOSIS; INFANT AB The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. Although the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched-unrelated donor stem cell transplantation. The patient remains in complete remission more than 4 years later. Analysis of this patient's relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate a novel therapeutic intervention that could alter outcome. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. C1 [Griffith, Malachi; Griffith, Obi L.; Krysiak, Kilannin; Skidmore, Zachary L.; Ramu, Avinash; Wagner, Alex H.; Campbell, Katie M.; Lesurf, Robert; Hundal, Jasreet; Zhang, Jin; Spies, Nicholas C.; Ainscough, Benjamin J.; Larson, David E.; Fronick, Catrina; O'Laughlin, Shelly; Fulton, Robert S.; Magrini, Vincent; McGrath, Sean; Smith, Scott M.; Miller, Christopher A.; Maher, Christopher A.; Walker, Jason R.; Eldred, James M.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.] Washington Univ, McDonnell Genome Inst, St Louis, MO USA. [Griffith, Malachi; Griffith, Obi L.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.] Washington Univ, Dept Genet, St Louis, MO 63108 USA. [Griffith, Malachi; Griffith, Obi L.; Ainscough, Benjamin J.; Maher, Christopher A.; Payton, Jacqueline E.; Walter, Matthew J.; Link, Daniel C.; Westervelt, Peter; DiPersio, John F.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.] Washington Univ, Siteman Canc Ctr, St Louis, MO USA. [Griffith, Obi L.; Christopher, Matthew J.; Heath, Sharon E.; Miller, Christopher A.; Maher, Christopher A.; Payton, Jacqueline E.; Walter, Matthew J.; Link, Daniel C.; Westervelt, Peter; DiPersio, John F.; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.] Washington Univ, Dept Med, St Louis, MO 63108 USA. [Klco, Jeffery M.; Lamprecht, Tamara L.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Maher, Christopher A.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Payton, Jacqueline E.; Kulkarni, Shashikant] Washington Univ, Dept Pathol, St Louis, MO 63130 USA. [Graubert, Timothy A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Griffith, M (reprint author), Washington Univ, Dept Genet, St Louis, MO 63108 USA.; Ley, TJ (reprint author), Washington Univ, Dept Med, St Louis, MO 63108 USA. EM mgriffit@wustl.edu OI Krysiak, Kilannin/0000-0002-6299-9230; Ainscough, Benjamin/0000-0001-8340-514X; Campbell, Katie/0000-0001-6491-4432; Klco, Jeffery/0000-0003-2961-6960 FU National Institutes of Health (NIH) National Cancer Institute (NCI) [P01 CA101937, P30 CA91842]; NIH National Human Genome Research Institute (NHGRI) [U54 HG003079]; NIH NHGRI [K99 HG007940]; NIH NCI [K22 CA188163, R21 CA185983, R00 CA149182] FX This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute (NCI) (P01 CA101937, P30 CA91842) with support for analysis from NIH National Human Genome Research Institute (NHGRI) (U54 HG003079). MG was supported by NIH NHGRI grant K99 HG007940. OLG was supported by NIH NCI grant K22 CA188163. CAM was supported by NIH NCI grants R21 CA185983 and R00 CA149182. NR 36 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2016 VL 44 IS 7 BP 603 EP 613 DI 10.1016/j.exphem.2016.04.011 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DP7DS UT WOS:000378660000011 PM 27181063 ER PT J AU Sung, YJ Winkler, TW Manning, AK Aschard, H Gudnason, V Harris, TB Smith, AV Boerwinkle, E Brown, MR Morrison, AC Fornage, M Lin, LA Richard, M Bartz, TM Psaty, BM Hayward, C Polasek, O Marten, J Rudan, I Feitosa, MF Kraja, AT Province, MA Deng, X Fisher, VA Zhou, Y Bielak, LF Smith, J Huffman, JE Padmanabhan, S Smith, BH Ding, J Liu, Y Lohman, K Bouchard, C Rankinen, T Rice, TK Arnett, D Schwander, K Guo, X Palmas, W Rotter, JI Alfred, T Bottinger, EP Loos, RJF Amin, N Franco, OH van Duijn, CM Vojinovic, D Chasman, DI Ridker, PM Rose, LM Kardia, S Zhu, X Rice, K Borecki, IB Rao, DC Gauderman, WJ Cupples, LA AF Sung, Yun Ju Winkler, Thomas W. Manning, Alisa K. Aschard, Hugues Gudnason, Vilmundur Harris, Tamara B. Smith, Albert V. Boerwinkle, Eric Brown, Michael R. Morrison, Alanna C. Fornage, Myriam Lin, Li-An Richard, Melissa Bartz, Traci M. Psaty, Bruce M. Hayward, Caroline Polasek, Ozren Marten, Jonathan Rudan, Igor Feitosa, Mary F. Kraja, Aldi T. Province, Michael A. Deng, Xuan Fisher, Virginia A. Zhou, Yanhua Bielak, Lawrence F. Smith, Jennifer Huffman, Jennifer E. Padmanabhan, Sandosh Smith, Blair H. Ding, Jingzhong Liu, Yongmei Lohman, Kurt Bouchard, Claude Rankinen, Tuomo Rice, Treva K. Arnett, Donna Schwander, Karen Guo, Xiuqing Palmas, Walter Rotter, Jerome I. Alfred, Tamuno Bottinger, Erwin P. Loos, Ruth J. F. Amin, Najaf Franco, Oscar H. van Duijn, Cornelia M. Vojinovic, Dina Chasman, Daniel I. Ridker, Paul M. Rose, Lynda M. Kardia, Sharon Zhu, Xiaofeng Rice, Kenneth Borecki, Ingrid B. Rao, Dabeeru C. Gauderman, W. James Cupples, L. Adrienne TI An Empirical Comparison of Joint and Stratified Frameworks for Studying G x E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group SO GENETIC EPIDEMIOLOGY LA English DT Article DE gene-environment interaction; meta-analysis; low-frequency variants ID GENOME-WIDE ASSOCIATION; GENERALIZED ESTIMATING EQUATIONS; ENVIRONMENT INTERACTION; GENOTYPE IMPUTATION; QUANTITATIVE TRAITS; METAANALYSIS; VARIANTS; DISEASES; PACKAGE AB Studying gene-environment (G x E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G x E interactions uses a single regression model that includes both the genetic main and G x E interaction effects (the joint framework). The alternative stratified framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts. C1 [Sung, Yun Ju; Rice, Treva K.; Schwander, Karen; Rao, Dabeeru C.] Washington Univ, Div Biostat, St Louis, MO USA. [Winkler, Thomas W.] Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Manning, Alisa K.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Manning, Alisa K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Aschard, Hugues; Chasman, Daniel I.; Ridker, Paul M.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Gudnason, Vilmundur; Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur; Smith, Albert V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Boerwinkle, Eric; Brown, Michael R.; Morrison, Alanna C.; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Fornage, Myriam; Lin, Li-An; Richard, Melissa] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA. [Bartz, Traci M.; Psaty, Bruce M.; Rice, Kenneth] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bartz, Traci M.; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hayward, Caroline; Marten, Jonathan; Huffman, Jennifer E.] Univ Edinburgh, MRC Human Genet Unit, IGMM, Edinburgh, Midlothian, Scotland. [Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Polasek, Ozren; Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Feitosa, Mary F.; Kraja, Aldi T.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Deng, Xuan; Fisher, Virginia A.; Zhou, Yanhua; Cupples, L. Adrienne] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Bielak, Lawrence F.; Smith, Jennifer; Kardia, Sharon] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Padmanabhan, Sandosh] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Padmanabhan, Sandosh; Smith, Blair H.] Univ Edinburgh, Generat Scotland, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Smith, Blair H.] Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland. [Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Lohman, Kurt] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Bouchard, Claude; Rankinen, Tuomo] Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Arnett, Donna] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, LABioMed, Torrance, CA 90509 USA. [Palmas, Walter] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Alfred, Tamuno; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Amin, Najaf; van Duijn, Cornelia M.; Vojinovic, Dina] Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands. [Franco, Oscar H.] Erasmus MC, Cardiovasc Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands. [Chasman, Daniel I.; Ridker, Paul M.; Rose, Lynda M.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Gauderman, W. James] Univ Southern Calif, Dept Prevent Med, Los Angeles, CA USA. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Sung, YJ (reprint author), Washington Univ, Sch Med, Div Biostat, 660 South Euclid Ave,Campus Box 8067, St Louis, MO 63110 USA. EM yunju@wubios.wustl.edu RI Padmanabhan, Sandosh/S-3963-2016; Lin, LiAn/C-5819-2017; Bouchard, Claude/A-7637-2009; Polasek, Ozren/B-6002-2011; Feitosa, Mary/K-8044-2012 OI Lin, LiAn/0000-0003-2731-1346; Polasek, Ozren/0000-0002-5765-1862; Feitosa, Mary/0000-0002-0933-2410 FU Chief Scientist Office [CZD/16/6/4]; Medical Research Council [MC_PC_U127561128]; NCATS NIH HHS [UL1 TR000124]; NHLBI NIH HHS [K25 HL121091, R01 HL118305]; NIDDK NIH HHS [P30 DK063491] NR 38 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2016 VL 40 IS 5 BP 404 EP 415 DI 10.1002/gepi.21978 PG 12 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DQ2ZU UT WOS:000379073200005 PM 27230302 ER PT J AU Marabelli, M Cheng, SC Parmigiani, G AF Marabelli, Monica Cheng, Su-Chun Parmigiani, Giovanni TI Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk SO GENETIC EPIDEMIOLOGY LA English DT Article DE ataxia-telangiectasia mutated (ATM) gene; hereditary breast cancer; penetrance; genetic predisposition ID ATAXIA-TELANGIECTASIA; EARLY-ONSET; SUSCEPTIBILITY; MISSENSE; PREDISPOSITION; VARIANTS; CARRIERS; FAMILY AB The gene responsible for ataxia-telangiectasia syndrome, ATM, is also an intermediate-risk breast cancer (BC) susceptibility gene. Numerous studies have been carried out to determine the contribution of ATM gene mutations to BC risk. Epidemiological cohorts, segregation analyses, and case-control studies reported BC risk in different forms, including penetrance, relative risk, standardized incidence ratio, and odds ratio. Because the reported estimates vary both qualitatively and quantitatively, we developed a general model allowing the integration of the different types of cancer risk available in the literature. We performed a comprehensive meta-analysis identifying 19 studies, and used our model to obtain a consensus estimate of BC penetrance. We estimated the cumulative risk of BC in heterozygous ATM mutation carriers to be 6.02% by 50 years of age (95% credible interval: 4.58-7.42%) and 32.83% by 80 years of age (95% credible interval: 24.55-40.43%). An accurate assessment of cancer penetrance is crucial to help mutation carriers make medical and lifestyle decisions that can reduce their chances of developing the disease. C1 [Marabelli, Monica] Univ Pavia, Dept Biol & Biotechnol, Via Ferrata 1, I-27100 Pavia, Italy. [Cheng, Su-Chun; Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cheng, Su-Chun; Parmigiani, Giovanni] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Marabelli, M (reprint author), Univ Pavia, Dept Biol & Biotechnol, Via Ferrata 1, I-27100 Pavia, Italy. EM monica.marabelli01@ateneopv.it FU NCI NIH HHS [R21 CA177233] NR 29 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2016 VL 40 IS 5 BP 425 EP 431 DI 10.1002/gepi.21971 PG 7 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DQ2ZU UT WOS:000379073200007 PM 27112364 ER PT J AU Rauh-Hain, JA Gonzalez, R Bregar, AJ Clemmer, J Hernandez-Blanquisett, A Clark, RM Schorge, JO del Carmen, MG AF Rauh-Hain, J. Alejandro Gonzalez, Rafael Bregar, Amy J. Clemmer, Joel Hernandez-Blanquisett, Abraham Clark, Rachel M. Schorge, John O. del Carmen, Marcela G. TI Patterns of care, predictors and outcomes of chemotherapy for ovarian carcinosarcoma: A National Cancer Database analysis SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Carcinosarcoma; Chemotherapy ID UTERINE; ADENOCARCINOMA; SURVIVAL; TRENDS; HER2 AB Objective. The aim of this study is to determine if outcomes of patients with ovarian carcinosarcoma (OCS) differ from those of women with high-grade papillary serous ovarian carcinoma (HG-PSOC) when compared by stage and treatment modalities. Methods. The National Cancer Database was queried to identify patients with OCS and HG-PSOC diagnosed between 2003 and 2011. Demographic and clinical data were compared, and the impact of tumor histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Results. The final study group consisted of 45,153 women. 2886 (6.39%) had OCS and 42,267 (93.61%) had HG-PSOC. The mean age at diagnosis was 65.43 (+/- 12.21) years for women with OCS and 61.52 (+/- 12.6) years for HG-PSOC (P < 0.001). African-American women had higher rate of OCS relative to white non-hispanic women (7.84% vs. 6.37%; P = 0.002). Overall, women with OCS had a worse five-year survival rate, 26.63% [95% Confidence Interval (CI) = 24.86%-28.53%] vs. 43.61% (95% CI = 43.07%-44.17%). This difference persisted for each FIGO disease stage I-IV, with five-year survival consistently worse for women with OCS compared to those with HG-PSOC. Over the entire study period and after adjusting for histology, age, period of diagnosis, SEER registry, marital status, stage, surgery, radiotherapy, and lymph node dissection, carcinosarcoma histology was associated with decreased survival. Conclusion. OCS is associated with a poor prognosis compared to HG-PSOC. This difference was noted across all FIGO stages. (C) 2016 Elsevier Inc. All rights reserved. C1 [Rauh-Hain, J. Alejandro; Gonzalez, Rafael; Bregar, Amy J.; Clemmer, Joel; Hernandez-Blanquisett, Abraham; Clark, Rachel M.; Schorge, John O.; del Carmen, Marcela G.] Harvard Med Sch, Massachusetts Gen Hosp, 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 This work was supported by The Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital. NR 26 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2016 VL 142 IS 1 BP 38 EP 43 DI 10.1016/j.ygyno.2016.04.025 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DQ3KB UT WOS:000379100100009 PM 27107722 ER PT J AU del Campo, JM Birrer, M Davis, C Fujiwara, K Gollerkeri, A Gore, M Houk, B Lau, S Poveda, A Gonzalez-Martin, A Muller, C Muro, K Pierce, K Suzuki, M Vermette, J Oza, A AF Maria del Campo, Josep Birrer, Michael Davis, Craig Fujiwara, Keiichi Gollerkeri, Ashwin Gore, Martin Houk, Brett Lau, Susie Poveda, Andres Gonzalez-Martin, Antonio Muller, Carolyn Muro, Kei Pierce, Kristen Suzuki, Mie Vermette, Jennifer Oza, Amit TI A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; Gedatolisib; mTOR; PI3K; Stathmin ID DUAL INHIBITOR; SMALL-MOLECULE; BREAST-CANCER; MTOR; CARCINOMA; PI3K; PNEUMONITIS; CISPLATIN; KINASES; PATHWAY AB Objective. PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for 16 weeks) following treatment with PF-04691502 or gedatolisib. Methods. The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort. Results. In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population. Conclusions. Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. (C) 2016 Published by Elsevier Inc. C1 [Maria del Campo, Josep] VHIO, Pg Vall dHebron 119-129, Barcelona 08035, Spain. [Birrer, Michael] Massachusetts Gen Hosp, 55 Fruit St 410, Boston, MA 02114 USA. [Davis, Craig; Houk, Brett] Pfizer Oncol, 10646 Sci Ctr Dr, La Jolla, CA 92121 USA. [Fujiwara, Keiichi] Saitama Med Univ, Int Med Ctr, 1397-1 Yamane, Hidaka, Saitama 3501298, Japan. [Gollerkeri, Ashwin] Pfizer Worldwide Res & Dev, 35 Cambridge Pk Dr, Cambridge, MA 02140 USA. [Gore, Martin] Royal Marsden Hosp, 203 Fullham Rd, London SW3 6JJ, England. [Lau, Susie] McGill Univ, Jewish Gen Hosp, 3755 Chemin Cote Ste Catherine, Montreal, PQ H3R 1E2, Canada. [Poveda, Andres] Fdn Inst Valenciano Oncol, C Gregorio Gea 31, Valencia 46009, Spain. [Gonzalez-Martin, Antonio] MD Anderson Canc Ctr, Serv Oncol Med, C Arturo Soria 270, Madrid 28033, Spain. [Muller, Carolyn] Univ New Mexico, Hlth Sci Ctr, MSC07 4025 1201 Camino Salud NE, Albuquerque, NM 87131 USA. [Muro, Kei] Aichi Canc Ctr Hosp, Chikusa Ku, 1-1 Kanododen, Nagoya, Aichi 4648681, Japan. [Pierce, Kristen] Pfizer Oncol, 558 Eastern Point Rd, Groton, CT 06340 USA. [Suzuki, Mie] Pfizer Japan, Shibuya Ku, 3-22-7 Yoyogi, Tokyo 1518589, Japan. [Vermette, Jennifer] Pfizer Oncol, 300 Technol Sq,Suite 302, Cambridge, MA 02139 USA. [Oza, Amit] Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. RP del Campo, JM (reprint author), Vall dHebron Univ Hosp, VHIO, Pg Vall dHebron 119-129, Barcelona 08035, Spain. EM jmcampof2@seom.org; mbirrer@mgh.harvard.edu; craig.davis@pfizer.com; fujiwara@saitama-med.ac.jp; ashwingollerkeri@gmail.com; Martin.Gore@rmh.nhs.uk; susie.lau@mcgill.ca; apoveda@fivo.org; agonzalezm@seom.org; cmuller@salud.unm.edu; kmuro@aichi-cc.jp; kristen.j.pierce@pfizer.com; mie.suzuki@pfizer.com; jennifer.vermette@pfizer.com; Amit.Oza@uhn.ca FU Pfizer FX This study was supported by Pfizer. NR 22 TC 0 Z9 0 U1 1 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 2016 VL 142 IS 1 BP 62 EP 69 DI 10.1016/j.ygyno.2016.04.019 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DQ3KB UT WOS:000379100100013 PM 27103175 ER PT J AU Brown, JR Harb, WA Hill, BT Gabrilove, J Sharman, JP Schreeder, MT Barr, PM Foran, JM Miller, TP Burger, JA Kelly, KR Mahadevan, D Ma, S Li, Y Pierce, DW Barnett, E Marine, J Miranda, M Azaryan, A Yu, XJ Nava-Parada, P Mei, J Kipps, TJ AF Brown, Jennifer R. Harb, Wael A. Hill, Brian T. Gabrilove, Janice Sharman, Jeff P. Schreeder, Marshall T. Barr, Paul M. Foran, James M. Miller, Thomas P. Burger, Jan A. Kelly, Kevin R. Mahadevan, Daruka Ma, Shuo Li, Yan Pierce, Daniel W. Barnett, Evelyn Marine, Jeffrey Miranda, Monika Azaryan, Ada Yu, Xujie Nava-Parada, Pilar Mei, Jay Kipps, Thomas J. TI Phase I study of single-agent CC-292, a highly selective Bruton's tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia SO HAEMATOLOGICA LA English DT Letter DE CC-292; single-agent; chronic lymphocytic leukemia; small lymphocytic lymphoma; relapsed; refractory; BTK inhibitors ID B-CELL RECEPTOR; TARGETING BTK; IBRUTINIB; LYMPHOMA C1 [Brown, Jennifer R.] Dana Farber Canc Inst, Boston, MA USA. [Harb, Wael A.] Horizon Oncol Ctr, Lafayette, IN USA. [Hill, Brian T.] Cleveland Clin, Taussig Canc Inst, Dept Hematol & Med Oncol, Cleveland, OH 44195 USA. [Gabrilove, Janice] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Sharman, Jeff P.] US Oncol Res, Willamette Valley Canc Inst & Res Ctr, Eugene, OR USA. [Schreeder, Marshall T.] Clearview Canc Inst, Huntsville, AL USA. [Barr, Paul M.] Univ Rochester, Med Ctr, Hematol Oncol, Rochester, NY 14642 USA. [Foran, James M.] Mayo Clin, Hematol & Oncol, Jacksonville, FL USA. [Miller, Thomas P.] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Burger, Jan A.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Kelly, Kevin R.] Univ Texas Hlth Sci Ctr San Antonio, CTRC Inst Drug Dev, San Antonio, TX 78229 USA. [Mahadevan, Daruka] Univ Tennessee, Ctr Hlth Sci, ACORN Res LLC, West Clin, Memphis, TN 38163 USA. [Ma, Shuo] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Li, Yan; Pierce, Daniel W.] Celgene Corp, Dept Translat Med, San Francisco, CA USA. [Barnett, Evelyn; Marine, Jeffrey; Miranda, Monika; Nava-Parada, Pilar; Mei, Jay] Celgene Corp, Summit, NJ USA. [Azaryan, Ada; Yu, Xujie] Celgene Corp, Berkeley Hts, NJ USA. [Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Brown, JR (reprint author), Dana Farber Canc Inst, Boston, MA USA. EM jennifer_brown@dfci.harvard.edu FU NCI NIH HHS [P30 CA016672] NR 13 TC 2 Z9 2 U1 2 U2 7 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUL PY 2016 VL 101 IS 7 BP 295 EP 298 DI 10.3324/haematol.2015.140806 PG 4 WC Hematology SC Hematology GA DQ8SN UT WOS:000379481500007 PM 27151992 ER PT J AU Simon, TG Bonilla, H Yan, P Chung, RT Butt, AA AF Simon, Tracey G. Bonilla, Hector Yan, Peng Chung, Raymond T. Butt, Adeel A. TI Atorvastatin and Fluvastatin Are Associated With Dose-Dependent Reductions in Cirrhosis and Hepatocellular Carcinoma, Among Patients With Hepatitis C Virus: Results From ERCHIVES SO HEPATOLOGY LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; LOVASTATIN-INDUCED APOPTOSIS; FIBROSIS PROGRESSION; METABOLIC SYNDROME; LIVER-CIRRHOSIS; STELLATE CELLS; UNITED-STATES; RISK-FACTOR; STATINS; CANCER AB Statins are associated with delayed fibrosis progression and a reduced risk of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV). Limited data exist regarding the most effective type and dose of statin in this population. We sought to determine the impact of statin type and dose upon fibrosis progression and HCC in patients with HCV. Using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, we identified all subjects initiated on HCV antibody (anti-HCV) therapy from 2001 to 2014, and all incident cases of cirrhosis and HCC. Statin use was measured using cumulative defined daily dose (cDDD). Multivariable Cox's proportional hazard regression models were used to examine the relationship between statin use and development of cirrhosis and HCC. Among 9,135 eligible subjects, 1,649 developed cirrhosis and 239 developed incident HCC. Statin use was associated with a 44% reduction in development of cirrhosis (adjusted hazard ratio [HR]: 0.6; 95% confidence interval [CI]: 0.53, 0.68). The adjusted HRs (95% CI) of fibrosis progression with statin cDDD 28-89, 89-180, and >180 were 0.74 (0.59, 0.93), 0.71 (0.59, 0.88), and 0.6 (0.53, 0.68), respectively. Mean change in FIB-4 score with atorvastatin (n = 944) and fluvastatin (n = 34) was -0.17 and -0.13, respectively (P = 0.04), after adjustment for baseline FIB-4 score and established predictors of cirrhosis. Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed. Conclusion: In patients with chronic HCV, statin use was associated with a dose-dependent reduction in incident cirrhosis and HCC. Atorvastatin and fluvastatin were associated with the most significant antifibrotic effects, compared with other statins. C1 [Simon, Tracey G.; Chung, Raymond T.] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Div, Ctr Liver, Boston, MA 02114 USA. [Simon, Tracey G.; Chung, Raymond T.] Harvard Med Sch, Boston, MA USA. [Bonilla, Hector] Diablo Infect Dis, Castro Valley, CA USA. [Yan, Peng; Butt, Adeel A.] Weill Cornell Med Coll, Doha, Qatar. [Yan, Peng; Butt, Adeel A.] Weill Cornell Med Coll, New York, NY USA. [Yan, Peng; Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Ctr Liver, 55 Fruit St Warren 1007, Boston, MA 02114 USA.; Chung, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, 55 Fruit St Warren 1007, Boston, MA 02114 USA. EM rtchung@partners.org FU NIH [K24 DK078772] FX Supported by NIH K24 DK078772 (to R.T.C.). NR 52 TC 7 Z9 7 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2016 VL 64 IS 1 BP 47 EP 57 DI 10.1002/hep.28506 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DQ5GP UT WOS:000379233400011 PM 26891205 ER PT J AU Swiderska-Syn, M Xie, GH Michelotti, GA Jewell, ML Premont, RT Syn, WK Diehl, AM AF Swiderska-Syn, Marzena Xie, Guanhua Michelotti, Gregory A. Jewell, Mark L. Premont, Richard T. Syn, Wing-Kin Diehl, Anna Mae TI Hedgehog Regulates Yes-Associated Protein 1 in Regenerating Mouse Liver SO HEPATOLOGY LA English DT Article ID HEPATIC-FIBROSIS; HEPATOCYTE DIFFERENTIATION; TRANSCRIPTION FACTOR; PARTIAL-HEPATECTOMY; ACTIVATION; PATHWAY; CELLS; YAP; TUMORIGENESIS; CANCER AB Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1- and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. Conclusions: Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post-PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. C1 [Swiderska-Syn, Marzena; Xie, Guanhua; Michelotti, Gregory A.; Jewell, Mark L.; Premont, Richard T.; Diehl, Anna Mae] Duke Univ, Med Ctr, Dept Med, Div Gastroenterol, Durham, NC USA. [Syn, Wing-Kin] Fdn Liver Res, Inst Hepatol, Regenerat & Repair, London, England. [Syn, Wing-Kin] Med Univ South Carolina, Dept Med, Div Gastroenterol & Hepatol, Charleston, SC USA. [Syn, Wing-Kin] Ralph H Johnson VAMC, Gastroenterol Sect, Charleston, SC USA. RP Diehl, AM (reprint author), Duke Univ, Med Ctr, Div Gastroenterol, 595 LaSalle St,Snyderman Bldg,Suite 1073, Durham, NC 27710 USA. EM diehl004@mc.duke.edu FU National Institute of Health (NIH) - NIDDK [R37 AA010154, R56 DK106633, R01 DK077794] FX This work was supported by the following grants: National Institute of Health (NIH) - NIDDK, R37 AA010154, R56 DK106633, and R01 DK077794 (to A.M.D.). NR 31 TC 3 Z9 3 U1 4 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2016 VL 64 IS 1 BP 232 EP 244 DI 10.1002/hep.28542 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DQ5GP UT WOS:000379233400027 PM 26970079 ER PT J AU Fitzpatrick, MA Suda, KJ Safdar, N Goldstein, B Jones, MM Poggensee, L Ramanathan, S LeWan, R Evans, CT AF Fitzpatrick, Margaret A. Suda, Katie J. Safdar, Nasia Goldstein, Barry Jones, Makoto M. Poggensee, Linda Ramanathan, Swetha LeWan, Ryan Evans, Charlesnika T. TI Unique Risks and Clinical Outcomes Associated With Extended-Spectrum beta-Lactamase Enterobacteriaceae in Veterans With Spinal Cord Injury or Disorder: A Case-Case-Control Study SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI BACTEREMIA; ACUTE REHABILITATION UNIT; NOSOCOMIAL INFECTIONS; URINARY-TRACT; ADMINISTRATIVE DATA; IMPACT; PREVALENCE; ORGANISMS; SUSCEPTIBILITY AB OBJECTIVES. To describe the burden of extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae in veterans with spinal cord injury or disorder (SCI/D), to identify risk factors for ESBL acquisition, and to assess impact on clinical outcomes DESIGN. Retrospective case-case-control study PATIENTS AND SETTING. Veterans with SCI/D and utilization at a Veterans' Affairs medical center from January 1, 2012, to December 31, 2013. METHODS. Patients with a positive culture for ESBL Klebsiella pneumoniae, Escherichia coli, or Proteus mirabilis were matched with patients with non-ESBL organisms by organism, facility, and level of care and to uninfected controls by facility and level of care. Inpatients were also matched by time at risk. Univariate and multivariate matched models were assessed for differences in risk factors and outcomes. RESULTS. A total of 492 cases (62.6% outpatients) were matched 1:1 with each comparison group. Recent prior use of fluoroquinolones and prior use of third- and fourth-generation cephalosporins were independently associated with ESBL compared to the non-ESBL group (adjusted odds ratio [aOR], 2.61; 95% confidence interval [CI], 1.77-3.84; P < .001 for fluoroquinolones and aOR, 3.86; 95% CI, 2.06-7.25; P < .001 for third- and fourth-generation cephalosporins) and the control group (aOR, 2.10; 95% CI, 1.29-3.43; P = .003 for fluoroquinolones; and aOR, 3.31; 95% CI, 1.56-7.06; P = .002 for third- and fourth-generation cephalosporins). Although there were no differences in mortality rate, the ESBL group had a longer post-culture length of stay (LOS) than the non-ESBL group (incidence rate ratio, 1.36; 95% CI, 1.13-1.63; P = .001). CONCLUSIONS. All SCI/D patients with ESBL were more likely to have had recent exposure to fluoroquinolones or third- and fourth generation cephalosporins, and hospitalized patients were more likely to have increased post-culture LOS. Programs targeted toward reduced antibiotic use in SCI/D patients may prevent subsequent ESBL acquisition. C1 [Fitzpatrick, Margaret A.; Suda, Katie J.; Poggensee, Linda; Ramanathan, Swetha; LeWan, Ryan; Evans, Charlesnika T.] Dept Vet Affairs, Ctr Innovat Complex Chron Healthcare, Hines, IL USA. [Fitzpatrick, Margaret A.; Suda, Katie J.; Poggensee, Linda; Ramanathan, Swetha; LeWan, Ryan; Evans, Charlesnika T.] Edward Hines Jr VA Hosp, Spinal Cord Injury Qual Enhancement Res Initiat, Hines, IL USA. [Fitzpatrick, Margaret A.] Loyola Univ, Stritch Sch Med, Dept Med, Div Infect Dis, Maywood, IL 60153 USA. [Suda, Katie J.] Univ Illinois, Coll Pharm, Dept Pharm Syst Outcomes & Policy, Chicago, IL USA. [Safdar, Nasia] Dept Vet Affairs, William S Middleton VA Med Ctr, Madison, WI USA. [Safdar, Nasia] Univ Wisconsin, Dept Med, Div Infect Dis, Madison, WI USA. [Goldstein, Barry] VA Puget Sound Healthcare Syst, Dept Vet Affairs, Off Spinal Cord Injury & Disorders Serv, Seattle, WA USA. [Goldstein, Barry] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Jones, Makoto M.] VA Salt Lake City Healthcare Syst, Dept Vet Affairs, Salt Lake City, UT USA. [Jones, Makoto M.] Univ Utah, Dept Med, Div Epidemiol, Salt Lake City, UT 84112 USA. [Ramanathan, Swetha] Edward Hines Jr VA Hosp, Dept Vet Affairs, Dept Pharm, Hines, IL USA. [Evans, Charlesnika T.] Northwestern Univ, Ctr Healthcare Studies, Feinberg Sch Med, Chicago, IL 60611 USA. [Evans, Charlesnika T.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Inst Publ Hlth & Med, Chicago, IL 60611 USA. RP Fitzpatrick, MA (reprint author), 5000 S 5th Ave, Hines, IL 60141 USA. EM Margaret.fitzpatrick@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service Merit Review Award [B-1583-P]; Health Services Research and Development Service Post-Doctoral Fellowship Award [TPR 42-005]; Spinal Cord Injury Quality Enhancement Research Initiative [SCI-98-001]; VA FX We would like to thank Scott Miskevics for his assistance with programming and data analysis. This work was supported by The Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service Merit Review Award (grant no. B-1583-P), Health Services Research and Development Service Post-Doctoral Fellowship Award (grant no. TPR 42-005), and the Spinal Cord Injury Quality Enhancement Research Initiative (grant no. SCI-98-001). Dr. Nasia Safdar is additionally supported by a VA-funded Patient Safety Center of Inquiry. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. NR 37 TC 0 Z9 0 U1 1 U2 1 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 2016 VL 37 IS 7 BP 768 EP 776 DI 10.1017/ice.2016.60 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DQ3KL UT WOS:000379101100004 PM 27025908 ER PT J AU Shenoy, ES Lee, H Hou, TG Ware, W Ryan, EE Hooper, DC Walensky, RP AF Shenoy, Erica S. Lee, Hang Hou, Taige Ware, Winston Ryan, Erin E. Hooper, David C. Walensky, Rochelle P. TI The Impact of Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus (VRE) Flags on Hospital Operations SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID HEALTH-CARE SETTINGS; CONTACT PRECAUTIONS; PROLONGED CARRIAGE; NATURAL-HISTORY; RISK-FACTORS; COLONIZATION; DURATION; DELAYS; ROOMS; PREVALENCE AB OBJECTIVE. To determine the impact of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (MRSA/VRE) designations, or flags, on selected hospital operational outcomes. DESIGN. Retrospective cohort study of inpatients admitted to the Massachusetts General Hospital during 2010-2011. METHODS. Operational outcomes were time to bed arrival, acuity-unrelated within-hospital transfers, and length of stay. Covariates considered included demographic and clinical characteristics: age, gender, severity of illness on admission, admit day of week, residence prior to admission, hospitalization within the prior 30 days, clinical service, and discharge destination. RESULTS. Overall, 81,288 admissions were included. After adjusting for covariates, patients with a MRSA/VRE flag at the time of admission experienced a mean delay in time to bed arrival of 1.03 hours (9.63 hours [95% CI, 9.39-9.88] vs 8.60 hours [95% CI, 8.47-8.73]). These patients had 1.19 times the odds of experiencing an acuity-unrelated within-hospital transfer [95% CI, 1.13-1.26] and a mean length of stay 1.76 days longer (7.03 days [95% CI, 6.82-7.24] vs 5.27 days [95% CI, 5.15-5.38]) than patients with no MRSA/VRE flag. CONCLUSIONS. MRSA/VRE designation was associated with delays in time to bed arrival, increased likelihood of acuity-unrelated within hospital transfers and extended length of stay. Efforts to identify patients who have cleared MRSA/VRE colonization are critically important to mitigate inefficient use of resources and to improve inpatient flow. C1 [Shenoy, Erica S.; Hooper, David C.] Massachusetts Gen Hosp, Infect Control Unit, 55 Fruit St,Bulfinch 334, Boston, MA 02114 USA. [Shenoy, Erica S.; Hooper, David C.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Shenoy, Erica S.; Hou, Taige; Ryan, Erin E.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Shenoy, Erica S.; Hooper, David C.; Walensky, Rochelle P.] Harvard Med Sch, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Ware, Winston] Massachusetts Gen Hosp, Clin Care Management Unit, Boston, MA 02114 USA. RP Shenoy, ES (reprint author), Massachusetts Gen Hosp, Infect Control Unit, 55 Fruit St,Bulfinch 334, Boston, MA 02114 USA. EM eshenoy@partners.org FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [K01AI110524]; 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 Award) [ULI TR001102]; Harvard University FX This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant no. K01AI110524 to E.S.S.). This work was conducted with support from Harvard Catalyst/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 ULI 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 33 TC 0 Z9 0 U1 3 U2 3 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 2016 VL 37 IS 7 BP 782 EP 790 DI 10.1017/ice.2016.54 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DQ3KL UT WOS:000379101100006 PM 27019995 ER PT J AU Kim, J Saitou, K Matuszak, MM Balter, JM AF Kim, Jihun Saitou, Kazuhiro Matuszak, Martha M. Balter, James M. TI A finite element head and neck model as a supportive tool for deformable image registration SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article DE Finite element method; Image registration; Head and neck; Deformation; Radiation therapy ID CONE-BEAM CT; RADIATION-THERAPY; CERVICAL-SPINE; ACCURACY; RADIOTHERAPY; CANCER; UNCERTAINTIES AB A finite element (FE) head and neck model was developed as a tool to aid investigations and development of deformable image registration and patient modeling in radiation oncology. Useful aspects of a FE model for these purposes include ability to produce realistic deformations (similar to those seen in patients over the course of treatment) and a rational means of generating new configurations, e.g., via the application of force and/or displacement boundary conditions. The model was constructed based on a cone-beam computed tomography image of a head and neck cancer patient. The three-node triangular surface meshes created for the bony elements (skull, mandible, and cervical spine) and joint elements were integrated into a skeletal system and combined with the exterior surface. Nodes were additionally created inside the surface structures which were composed of the three-node triangular surface meshes, so that four-node tetrahedral FE elements were created over the whole region of the model. The bony elements were modeled as a homogeneous linear elastic material connected by intervertebral disks. The surrounding tissues were modeled as a homogeneous linear elastic material. Under force or displacement boundary conditions, FE analysis on the model calculates approximate solutions of the displacement vector field. A FE head and neck model was constructed that skull, mandible, and cervical vertebrae were mechanically connected by disks. The developed FE model is capable of generating realistic deformations that are strain-free for the bony elements and of creating new configurations of the skeletal system with the surrounding tissues reasonably deformed. The FE model can generate realistic deformations for skeletal elements. In addition, the model provides a way of evaluating the accuracy of image alignment methods by producing a ground truth deformation and correspondingly simulated images. The ability to combine force and displacement conditions provides flexibility for simulating realistic anatomic configurations. C1 [Kim, Jihun] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Saitou, Kazuhiro] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Matuszak, Martha M.; Balter, James M.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. RP Kim, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jkim115@mgh.harvard.edu OI Kim, Jihun/0000-0003-4856-6305 FU [NIHP01CA59827] FX This work was supported by NIHP01CA59827. NR 18 TC 0 Z9 0 U1 5 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD JUL PY 2016 VL 11 IS 7 BP 1311 EP 1317 DI 10.1007/s11548-015-1335-6 PG 7 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DQ2KW UT WOS:000379032200007 PM 26704371 ER PT J AU Llerena, K Wynn, JK Hajcak, G Green, MF Horan, WP AF Llerena, Katiah Wynn, Jonathan K. Hajcak, Greg Green, Michael F. Horan, William P. TI Patterns and reliability of EEG during error monitoring for internal versus external feedback in schizophrenia SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Event related potentials; Schizophrenia; Principal component analysis; Reward; Electroencephalography; Performance monitoring ID EVENT-RELATED POTENTIALS; TIME-ESTIMATION TASK; BRAIN ACTIVITY; HEALTHY-VOLUNTEERS; ANTISACCADE TASK; REWARD MAGNITUDE; NEURAL SYSTEM; NEGATIVITY; ERP; STATE AB Background: Accurately monitoring one's performance on daily life tasks, and integrating internal and external performance feedback are necessary for guiding productive behavior. Although internal feedback processing, as indexed by the error-related negativity (ERN), is consistently impaired in schizophrenia, initial findings suggest that external performance feedback processing, as indexed by the feedback negativity (FN), may actually be intact. The current study evaluated internal and external feedback processing task performance and test-retest reliability in schizophrenia. Methods: 92 schizophrenia outpatients and 63 healthy controls completed a flanker task (ERN) and a time estimation task (FN). Analyses examined the Delta ERN and Delta FN defined as difference waves between correct/positive versus error/negative feedback conditions. A temporal principal component analysis was conducted to distinguish the Delta ERN and Delta FN from overlapping neural responses. We also assessed test-retest reliability of Delta ERN and Delta FN in patients over a 4-week interval. Results: Patients showed reduced Delta ERN accompanied by intact Delta FN. In patients, test-retest reliability for both Delta ERN and Delta FN over a four-week period was fair to good. Conclusion: Individuals with schizophrenia show a pattern of impaired internal, but intact external, feedback processing. This pattern has implications for understanding the nature and neural correlates of impaired feedback processing in schizophrenia. Published by Elsevier B.V. C1 [Llerena, Katiah; Wynn, Jonathan K.; Green, Michael F.; Horan, William P.] VISN 22 Mental Illness Res Educ & Clin Ctr, Dept Vet Affairs, 11301 Wilshire Blvd,Bldg 210, Los Angeles, CA 90073 USA. [Llerena, Katiah; Wynn, Jonathan K.; Green, Michael F.; Horan, William P.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Llerena, K (reprint author), VA Greater Los Angeles, Healthcare Syst, MIRECC, Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM kllerena@ucla.edu FU AbbVie; DSP; Forum; Mnemosyne (scientific board); Takeda; Roche; Amgen FX Dr. Green reports having received consulting fees from AbbVie, DSP, Forum, Mnemosyne (scientific board), Takeda, Roche. He has received grant funding from Amgen and Forum. The rest of the authors report no biomedical financial interests or potential conflicts of interest. NR 59 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD JUL PY 2016 VL 105 BP 39 EP 46 DI 10.1016/j.ijpsycho.2016.04.012 PG 8 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DQ3MQ UT WOS:000379106800006 PM 27166742 ER PT J AU McCurry, SM Guthrie, KA Morin, C Woods, NF Landis, CA Ensrud, KE Larson, JC Joffe, H Cohen, LS Hunt, JR Newton, KM Otte, JL Reed, SD Sternfeld, B Tinker, LF LaCroix, AZ AF McCurry, Susan M. Guthrie, Katherine A. Morin, CharlesM. Woods, Nancy F. Landis, Carol A. Ensrud, Kristine E. Larson, Joseph C. Joffe, Hadine Cohen, Lee S. Hunt, Julie R. Newton, Katherine M. Otte, Julie L. Reed, Susan D. Sternfeld, Barbara Tinker, Lesley F. LaCroix, Andrea Z. TI Telephone-Based Cognitive Behavioral Therapy for Insomnia in Perimenopausal and Postmenopausal Women With Vasomotor Symptoms A MsFLASH Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID SLEEP DISTURBANCE; MENOPAUSAL SYMPTOMS; BREAST-CANCER; HOT FLASHES; METAANALYSIS; QUALITY; HEALTH; MEDICATION; TRANSITION; DISORDERS AB IMPORTANCE Effective, practical, nonpharmacologic therapies are needed to treat menopause-related insomnia symptoms in primary and women's specialty care settings. OBJECTIVE To evaluate the efficacy of telephone-based cognitive behavioral therapy for insomnia (CBT-I) vs menopause education control (MEC). DESIGN, SETTING, AND PARTICIPANTS A single-site, randomized clinical trial was conducted from September 1, 2013, to August 31, 2015, in western Washington State among 106 perimenopausal or postmenopausal women aged 40 to 65 years with moderate insomnia symptoms (Insomnia Severity Index [ISI] score, >= 12) and 2 or more daily hot flashes. Blinded assessments were conducted at baseline, 8, and 24 weeks postrandomization. An intent-to-treat analysis was conducted. INTERVENTIONS Six CBT-I or MEC telephone sessions in 8 weeks. Participants submitted weekly electronic sleep diaries and received group-specific written educational materials. The CBT-I sessions included sleep restriction, stimulus control, sleep hygiene education, cognitive restructuring, and behavioral homework; MEC sessions provided information about menopause and women's health. MAIN OUTCOMES AND MEASURES Primary outcome was scores on the ISI (score range, 0-28; scores >= 15 indicate moderate to severe insomnia). Secondary outcome was scores on the Pittsburgh Sleep Quality Index (score range, 0-21; higher scores indicate worse sleep quality). Additional outcomes included sleep and hot flash diary variables and hot flash interference. RESULTS At 8 weeks, ISI scores had decreased 9.9 points among 53 women receiving CBT-I (mean [SD] age, 55.0 [3.5] years) and 4.7 points among 53 women receiving MEC (age, 54.7 [4.7] years), a mean between-group difference of 5.2 points (95% CI, -6.1 to -3.3; P < .001). Pittsburgh Sleep Quality Index scores decreased 4.0 points in women receiving CBT-I and 1.4 points in women receiving MEC, a mean between-group difference of 2.7 points (95% CI, -3.9 to -1.5; P < .001). Significant group differences were sustained at 24 weeks. At 8 and 24 weeks, 33 of 47 women (70%) and 37 of 44 (84%) in the CBT-I group, respectively, had ISI scores in the no-insomnia range compared with 10 of 41 (24%) and 16 of 37 (43%) in the MEC group, respectively. The CBT-I group also had greater improvements in diary-reported sleep latency, wake time, and sleep efficiency. There were no between-group differences in frequency of daily hot flashes, but hot flash interference was significantly decreased at 8 weeks for the CBT-I group (-15.7; 95% CI, -20.4 to -11.0) compared with the MEC group (-7.1; 95% CI, -14.6 to 0.4) (P = .03), differences that were maintained at 24 weeks for the CBT-I group (-22.8; 95% CI, -28.6 to -16.9) and MEC group (-11.6; 95% CI, -19.4 to -3.8) (P = .003). CONCLUSIONS AND RELEVANCE Telephone-based CBT-I improved sleep in perimenopausal and postmenopausal women with insomnia and hot flashes. Results support further development and testing of centralized CBT-I programs for treating menopausal insomnia. C1 [McCurry, Susan M.] Univ Washington, Dept Psychosocial & Community Hlth, 6200 NE 74th St,Ste 42, Seattle, WA 98115 USA. [Guthrie, Katherine A.; Larson, Joseph C.; Hunt, Julie R.; Tinker, Lesley F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Washington, DC USA. [Morin, CharlesM.] Univ Laval, Dept Psychol, Quebec City, PQ, Canada. [Woods, Nancy F.; Landis, Carol A.] Univ Washington, Biobehav Nursing & Hlth Syst, Seattle, WA 98115 USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Med, Div Epidemiol & Community Hlth, Box 736 UMHC, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Minneapolis VA Hlth Care Syst, Ctr Chron Dis Outcomes Res, Minneapolis, MN USA. [Joffe, Hadine] Harvard Med Sch, Brigham & Womens Hosp, Div Womens Mental Hlth, Dept Psychiat, Boston, MA USA. [Joffe, Hadine] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Cohen, Lee S.] Harvard Med Sch, Ctr Womens Mental Hlth, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Newton, Katherine M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Otte, Julie L.] Indiana Univ, Dept Sci Nursing Care, Indianapolis, IN 46204 USA. [Reed, Susan D.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98115 USA. [Sternfeld, Barbara] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [LaCroix, Andrea Z.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. RP McCurry, SM (reprint author), Univ Washington, Dept Psychosocial & Community Hlth, 6200 NE 74th St,Ste 42, Seattle, WA 98115 USA. EM smccurry@uw.edu FU National Institute on Aging; Eunice Kennedy Shriver National Institute of Child Health and Development; National Center for Complementary and Alternative Medicine; Office of Research on Women's Health; National Institute on Aging, National Institutes of Health [U01AG032699] FX The Menopause Strategies Finding Lasting Answers for Symptoms and Health research network was established under a National Institutes of Health cooperative agreement to conduct studies of the efficacy of treatments for the management of menopausal hot flashes. The studies were sponsored by the National Institute on Aging in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, the National Center for Complementary and Alternative Medicine, and the Office of Research on Women's Health. This study was supported by grant U01AG032699 from the National Institute on Aging, National Institutes of Health. NR 50 TC 1 Z9 1 U1 6 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 913 EP 920 DI 10.1001/jamainternmed.2016.1795 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700012 PM 27213646 ER PT J AU Percac-Lima, S Ashburner, J Zai, AH Chang, YC Oo, SA Guimaraes, E Atlas, SJ AF Percac-Lima, Sanja Ashburner, JeffreyM. Zai, Adrian H. Chang, Yuchiao Oo, Sarah A. Guimaraes, Erica Atlas, Steven J. TI Patient Navigation for Comprehensive Cancer Screening in High-Risk Patients Using a Population-Based Health Information Technology System A Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID FORCE RECOMMENDATION STATEMENT; PRIMARY-CARE; MANAGEMENT-SYSTEM; WOMEN; DISPARITIES; BARRIERS; QUALITY; EQUITY AB IMPORTANCE Patient navigation (PN) to improve cancer screening in low-income and racial/ethnic minority populations usually focuses on navigating for single cancers in community health center settings. OBJECTIVE We evaluated PN for breast, cervical, and colorectal cancer screening using a population-based information technology (IT) system within a primary care network. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted from April 2014 to December 2014 in 18 practices in an academic primary care network. All patients eligible and overdue for cancer screening were identified and managed using a population-based IT system. Those at high risk for nonadherence with completing screening were identified using an electronic algorithm (language spoken, number of overdue tests, no-show visit history), and randomized to a PN intervention (n = 792) or usual care (n = 820). Navigators used the IT system to track patients, contact them, and provide intense outreach to help them complete cancer screening. MAIN OUTCOMES AND MEASURES Mean cancer screening test completion rate over 8-month trial for each eligible patient, with all overdue cancer screening tests combined using linear regression models. Secondary outcomes included the proportion of patients completing any and each overdue cancer screening test. RESULTS Among 1612 patients (673 men and 975 women; median age, 57 years), baseline patient characteristics were similar among randomized groups. Of 792 intervention patients, patient navigators were unable to reach 151 (19%), deferred 246 (38%) (eg, patient declined, competing comorbidity), and navigated 202 (32%). The mean proportion of patients who were up to date with screening among all overdue screening examinations was higher in the intervention vs the control group for all cancers combined (10.2% vs 6.8%; 95% CI [for the difference], 1.5%-5.2%; P < .001), and for breast (14.7% vs 11.0%; 95% CI, 0.2%-7.3%; P = .04), cervical (11.1% vs 5.7%; 95% CI, 0.8%-5.2%; P = .002), and colon (7.6% vs 4.6%; 95% CI, 0.8%-5.2%; P = .01) cancer compared with control. The proportion of overdue patients who completed any cancer screening during follow-up was higher in the intervention group (25.5% vs 17.0%; 95% CI, 4.7%-12.7%; P < .001). The intervention group had more patients completing screening for breast (23.4% vs 16.6%; 95% CI, 1.8%-12.0%; P = .009), cervical (14.4% vs 8.6%; 95% CI, 1.6%-10.5%; P = .007), and colorectal (13.7% vs 7.0%; 95% CI, 3.2%-10.4%; P < .001) cancer. CONCLUSIONS AND RELEVANCE Patient navigation as part of a population-based IT system significantly increased screening rates for breast, cervical, and colorectal cancer in patients at high risk for nonadherence with testing. Integrating patient navigation into population health management activities for low-income and racial/ethnic minority patients might improve equity of cancer care. C1 [Percac-Lima, Sanja; Ashburner, JeffreyM.; Chang, Yuchiao; Atlas, Steven J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Percac-Lima, Sanja; Oo, Sarah A.; Guimaraes, Erica] Massachusetts Gen Hosp, Chelsea HealthCare Ctr, Chelsea, MA USA. [Percac-Lima, Sanja; Ashburner, JeffreyM.; Zai, Adrian H.; Chang, Yuchiao; Atlas, Steven J.] Harvard Med Sch, Boston, MA USA. [Zai, Adrian H.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. RP Percac-Lima, S (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA. EM spercaclima@mgh.harvard.edu FU American Cancer Society: Cancer Control Career Development Award for Primary Care Physicians [CCCDAA-14-012-01-CCCDA]; Lazarex Cancer Foundation; Harvard Medical School Center for Primary Care Innovation Fellowship FX This work was supported by American Cancer Society: Cancer Control Career Development Award for Primary Care Physicians, CCCDAA-14-012-01-CCCDA, Lazarex Cancer Foundation, and the Harvard Medical School Center for Primary Care Innovation Fellowship. NR 30 TC 5 Z9 5 U1 5 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 930 EP 937 DI 10.1001/jamainternmed.2016.0841 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700015 PM 27273602 ER PT J AU Jena, AB Goldman, D Karaca-Mandic, P AF Jena, Anupam B. Goldman, Dana Karaca-Mandic, Pinar TI Hospital Prescribing of Opioids to Medicare Beneficiaries SO JAMA INTERNAL MEDICINE LA English DT Article ID PAIN MANAGEMENT; UNITED-STATES; OLDER-ADULTS; RISK-FACTORS; ANALGESICS; COHORT; CARE; FRACTURES; ARTHRITIS; OVERDOSE AB IMPORTANCE Use of opioids during and shortly after an acute hospitalization is warranted in some clinical settings. However, given the potential of opioids for short-term adverse events and long-term physiologic tolerance, it is important to understand the frequency of opioid prescribing at hospital discharge, hospital variation, and patient and hospital factors associated with opioid prescribing, which is currently unknown in the United States. OBJECTIVE To estimate the frequency of opioid prescribing at hospital discharge among Medicare beneficiaries without an opioid prescription claim 60 days prior to hospitalization; to document hospital variation in prescribing; and to analyze patient and hospital factors associated with prescribing, including hospital average performance on pain-related Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) measures. DESIGN, SETTING, AND PARTICIPANTS Analysis of pharmacy claims of a 20% random sample of Medicare beneficiaries hospitalized in 2011 without an opioid prescription claim in the 60 days before hospitalization. MAIN OUTCOMES AND MEASURES Our main outcome was a new opioid claim within 7 days of hospital discharge. We estimated a multivariable linear probability model of patient factors associated with new opioid use and described hospital variation in adjusted rates of new opioid use. In multivariable linear regression analysis, we also analyzed hospital factors associated with average adjusted new opioid use at the hospital level, including the percentage of each hospital's patients who reported that their pain during hospitalization was always well controlled in the 2011 HCAHPS surveys. RESULTS Among 623 957 hospitalizations, 92 882 (14.9%) were associated with a new opioid claim. Among those hospitalizations with an associated opioid claim within 7 days of hospital discharge, 32 731 (42.5%) of 77 092 were associated with an opioid claim after 90 days postdischarge. Across 2512 hospitals, the average adjusted rate of new opioid use within 7 days of hospitalization was 15.1% (interquartile range, 12.3%-17.4%; interdecile range, 10.5%-20.0%). A hospital's adjusted rate of new opioid use was modestly positively associated with the percentage of its inpatients reporting that their pain was always well managed (increase from 25th to the 75th percentile in the HCAHPS measure was associated with an absolute increase in new opioid use of 0.89 percentage points or a relative increase of 6.0%; P < .001). CONCLUSIONS AND RELEVANCE New opioid use after hospitalization is common among Medicare beneficiaries, with substantial variation across hospitals and a large proportion of patients using a prescription opioid 90 days after hospitalization. The degree to which observed hospital variation in short-and longer-term opioid use reflects variation in inappropriate prescribing at hospital discharge is unknown. C1 [Jena, Anupam B.] Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Goldman, Dana] Univ So Calif, Leonard D Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA USA. [Goldman, Dana] RAND Corp, Santa Monica, CA USA. [Karaca-Mandic, Pinar] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. RP Jena, AB (reprint author), Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu FU Office of the Director, National Institutes of Health [1DP50D017897-01]; National Institute on Aging [5P01AG033559, 5K01AG036740]; University of Minnesota Academic Health Center Faculty Development Grant FX The authors report funding from the Office of the Director, National Institutes of Health (Early Independence Award, grant 1DP50D017897-01 [Dr Jena]), National Institute on Aging (grants 5P01AG033559 [Dr Goldman] and 5K01AG036740 [Dr Karaca-Mandic]), and a University of Minnesota Academic Health Center Faculty Development Grant (Dr Karaca-Mandic). NR 21 TC 3 Z9 3 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 990 EP 997 DI 10.1001/jamainternmed.2016.2737 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700025 PM 27294595 ER PT J AU Kirkpatrick, JN Hauptman, PJ Swetz, KM Blume, ED Gauvreau, K Maurer, M Goodlin, SJ AF Kirkpatrick, James N. Hauptman, Paul J. Swetz, Keith M. Blume, Elizabeth D. Gauvreau, Kimberlee Maurer, Mathew Goodlin, Sarah J. TI Palliative Care for Patients With End-Stage Cardiovascular Disease and Devices: A Report From the Palliative Care Working Group of the Geriatrics Section of the American College of Cardiology SO JAMA INTERNAL MEDICINE LA English DT Letter ID VENTRICULAR ASSIST DEVICES C1 [Kirkpatrick, James N.] Univ Washington, Div Cardiol, Eth Consultat Serv, 1959 NE Pacific St, Seattle, WA 98125 USA. [Hauptman, Paul J.] St Louis Univ, Div Cardiol, Dept Med, St Louis, MO 63103 USA. [Swetz, Keith M.] Univ Alabama Birmingham, Ctr Palliat & Support Care, Birmingham, AL USA. [Swetz, Keith M.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Blume, Elizabeth D.; Gauvreau, Kimberlee] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Maurer, Mathew] Columbia Univ, Med Ctr, New York Presbyterian Hosp, New York, NY USA. [Goodlin, Sarah J.] Portland VA Med Ctr, Portland, OR USA. [Goodlin, Sarah J.] Patient Ctr Educ & Res, Portland, OR USA. RP Kirkpatrick, JN (reprint author), Univ Washington, Div Cardiol, Eth Consultat Serv, 1959 NE Pacific St, Seattle, WA 98125 USA. EM kirkpatj@uw.edu NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 1017 EP 1019 DI 10.1001/jamainternmed.2016.2096 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700032 PM 27214624 ER PT J AU Munshi, MN Slyne, C Segal, AR Saul, N Lyons, C Weinger, K AF Munshi, Medha N. Slyne, Christine Segal, Alissa R. Saul, Nora Lyons, Courtney Weinger, Katie TI Simplification of Insulin Regimen in Older Adults and Risk of Hypoglycemia SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Munshi, Medha N.; Slyne, Christine; Segal, Alissa R.; Saul, Nora; Lyons, Courtney; Weinger, Katie] Joslin Diabet Ctr, Boston, MA 02215 USA. [Munshi, Medha N.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Munshi, Medha N.; Weinger, Katie] Harvard Med Sch, Dept Med, Boston, MA USA. [Segal, Alissa R.] MCPHS Univ, Sch Pharm, Boston, MA USA. RP Munshi, MN (reprint author), 110,Francis St,LMOB 1B, Boston, MA 02215 USA. EM mmunshi@bidmc.harvard.edu NR 7 TC 3 Z9 3 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 1023 EP 1025 DI 10.1001/jamainternmed.2016.2288 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700035 PM 27273335 ER PT J AU Talebreza, S Widera, E AF Talebreza, Shaida Widera, Eric TI A Perspective on Hospice Reform and Additional Caregiver Support Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Talebreza, Shaida] Univ Utah, Div Geriatr, Sch Med, Salt Lake City, UT USA. [Talebreza, Shaida] Home Based Primary Care, Salt Lake City, UT USA. [Talebreza, Shaida] George E Wahlen Salt Lake City Vet Affairs Med Ct, Salt Lake City, UT USA. [Talebreza, Shaida] Inspirat Hosp, Salt Lake City, UT USA. [Widera, Eric] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Widera, Eric] San Francisco VA Med Ctr, Hosp & Palliat Care, 4150 Clement St, San Francisco, CA 94121 USA. RP Widera, E (reprint author), San Francisco VA Med Ctr, Hosp & Palliat Care, 4150 Clement St, San Francisco, CA 94121 USA.; Widera, E (reprint author), UCSF, Div Geriatr & Geriatr Med Fellowship, San Francisco, CA 94121 USA. EM eric.widera@ucsf.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 1032 EP 1033 DI 10.1001/jamainternmed.2016.2742 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700041 PM 27379480 ER PT J AU Majmudar, MD Aungst, TD AF Majmudar, Maulik D. Aungst, Timothy Dy TI Telemedicine in Heart Failure-Ineffective or Just Ill Used? SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Majmudar, Maulik D.] Massachusetts Gen Hosp, Healthcare Transformat Lab, 60 Staniford St, Boston, MA 02114 USA. [Majmudar, Maulik D.] Harvard Med Sch, Boston, MA USA. [Aungst, Timothy Dy] Massachusetts Coll Pharm & Hlth Sci Univ, Worcester, MA USA. RP Majmudar, MD (reprint author), Massachusetts Gen Hosp, Healthcare Transformat Lab, 60 Staniford St, Boston, MA 02114 USA. EM mmajmudar@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 1035 EP 1035 DI 10.1001/jamainternmed.2016.2857 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700045 PM 27379484 ER PT J AU Ong, MK Romano, PS Fonarow, GC AF Ong, Michael K. Romano, Patrick S. Fonarow, Gregg C. TI Telemedicine in Heart Failure-Ineffective or Just Ill Used? Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Ong, Michael K.; Fonarow, Gregg C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, 10940 Wilshire Blvd,Ste 700, Los Angeles, CA 90024 USA. [Ong, Michael K.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Romano, Patrick S.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Romano, Patrick S.] Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. RP Ong, MK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, 10940 Wilshire Blvd,Ste 700, Los Angeles, CA 90024 USA. EM michael.ong@ucla.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2016 VL 176 IS 7 BP 1035 EP 1036 DI 10.1001/jamainternmed.2016.2860 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2NR UT WOS:000379039700046 PM 27379485 ER PT J AU Faraone, SV Biederman, J AF Faraone, Stephen V. Biederman, Joseph TI Can Attention-Deficit/Hyperactivity Disorder Onset Occur in Adulthood? SO JAMA PSYCHIATRY LA English DT Editorial Material ID DEFICIT HYPERACTIVITY DISORDER; FOLLOW-UP; TWIN C1 [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. [Faraone, Stephen V.] Univ Bergen, Dept Biomed, KG Jebsen Ctr Neuropsychiat Disorders, Bergen, Norway. [Biederman, Joseph] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. EM sfaraone@childpsychresearch.org FU Shire; Alcobra; Otsuka; McNeil; Janssen; Novartis; Pfizer; Eli Lilly; K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; European Union's Seventh Framework Programme for research, technological development; National Institute of Mental Health; AACAP; APSARD; ElMindA; Forest Research Institute; Ironshore; Lundbeck; Magceutics Inc; Merck; National Institutes of Health; Neurocentria Inc; PamLab; Shire Pharmaceuticals Inc; SPRITES; Sunovion; US Department of Defense; US Food & Drug Administration; Vaya Pharma/Enzymotec; Ingenix; Prophase; Bracket Global; Theravance; Department of Psychiatry at MGH FX In the past year, Dr Faraone received income, potential income, travel expenses, and/or research support from Rhodes, Arbor, Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, and NeuroLifeSciences. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of attention-deficit/hyperactivity disorder (ADHD). In previous years, he received income or research support from Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. Dr Faraone receives royalties from books. Dr Faraone is also supported by the K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union's Seventh Framework Programme for research, technological development, and the National Institute of Mental Health. Dr Biederman reported receiving research support from the AACAP, Alcobra, APSARD, ElMindA, Forest Research Institute, Ironshore, Lundbeck, Magceutics Inc, McNeil, Merck, the National Institutes of Health, Neurocentria Inc, PamLab, Pfizer, Shire Pharmaceuticals Inc, SPRITES, Sunovion, the US Department of Defense, the US Food & Drug Administration, and Vaya Pharma/Enzymotec; honoraria from the Massachusetts General Hospital (MGH) Psychiatry Academy for tuition-funded continuing medical education (CME) courses and Alcobra and American Academy of Child and Adolescent Psychiatry; and departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Dr Biederman also has a US patent application pending (provisional No. 61/233,686) through MGH corporate licensing on a method to prevent stimulant abuse. No other disclosures were reported. NR 10 TC 7 Z9 7 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2016 VL 73 IS 7 BP 655 EP 656 DI 10.1001/jamapsychiatry.2016.0400 PG 2 WC Psychiatry SC Psychiatry GA DQ2OT UT WOS:000379042700005 PM 27191055 ER PT J AU Shear, MK Reynolds, CF Simon, NM Zisook, S Wang, YJ Mauro, C Duan, NH Lebowitz, B Skritskaya, N AF Shear, M. Katherine Reynolds, Charles F., III Simon, Naomi M. Zisook, Sidney Wang, Yuanjia Mauro, Christine Duan, Naihua Lebowitz, Barry Skritskaya, Natalia TI Optimizing Treatment of Complicated Grief A Randomized Clinical Trial SO JAMA PSYCHIATRY LA English DT Article ID PROLONGED GRIEF; MISSING DATA; BEREAVEMENT; DEPRESSION; DISORDER; SCALE; INTERVENTION; SUICIDALITY; INVENTORY; VALIDITY AB IMPORTANCE To our knowledge, this is the first placebo-controlled randomized clinical trial to evaluate the efficacy of antidepressant pharmacotherapy, with and without complicated grief psychotherapy, in the treatment of complicated grief. OBJECTIVE To confirm the efficacy of a targeted complicated grief treatment (CGT), determine whether citalopram (CIT) enhances CGT outcome, and examine CIT efficacy without CGT. DESIGN, SETTING, AND PARTICIPANTS Included in the study were 395 bereaved adults who met criteria for CG recruited from March 2010 to September 2014 from academic medical centers in Boston, Massachusetts; New York, New York; Pittsburgh, Pennsylvania; and San Diego, California. Co-occurring substance abuse, psychosis, mania, and cognitive impairment were exclusionary. Study participants were randomized using site-specific permuted blocks stratified by major depression into groups prescribed CIT (n = 101), placebo (PLA; n = 99), CGT with CIT (n = 99), and CGT with PLA (n = 96). Independent evaluators conducted monthly assessments for 20 weeks. Response rates were compared under the intention-to-treat principle, including all randomized participants in a logistic regression with inverse probability weighting. INTERVENTIONS All participants received protocolized pharmacotherapy optimized by flexible dosing, psychoeducation, grief monitoring, and encouragement to engage in activities. Half were also randomized to receive manualized CGT in 16 concurrent weekly sessions. MAIN OUTCOMES AND MEASURES Complicated grief-anchored Clinical Global Impression scale measurments every 4 weeks. Response was measured as a rating of "much improved" or "very much improved." RESULTS Of the 395 study participants, 308 (78.0%) were female and 325 (82.3%) were white. Participants' response to CGT with PLA vs PLA (82.5% vs 54.8%; relative risk [RR], 1.51; 95% CI, 1.16-1.95; P = .002; number needed to treat [NNT], 3.6) suggested the efficacy of CGT, and the addition of CIT did not significantly improve CGT outcome (CGT with CIT vs CGT with PLA: 83.7% vs 82.5%; RR, 1.01; 95% CI, 0.88-1.17; P = .84; NNT, 84). However, depressive symptoms decreased significantly more when CIT was added to treatment (CGT with CIT vs CGT with PLA: model-based adjusted mean [standard error] difference, -2.06 [1.00]; 95% CI, -4.02 to -0.11; P = .04). By contrast, adding CGT improved CIT outcome (CIT vs CGT with CIT: 69.3% vs 83.7%; RR, 1.21; 95% CI, 1.00-1.46; P = .05; NNT, 6.9). Last, participant response to CIT was not significantly different from PLA at week 12 (45.9% vs 37.9%; RR, 1.21; 95% CI, 0.82-1.81; P = .35; NNT, 12.4) or at week 20 (69.3% vs 54.8%; RR, 1.26; 95% CI, 0.95-1.68; P = .11; NNT, 6.9). Rates of suicidal ideation diminished to a substantially greater extent among participants receiving CGT than among those who did not. CONCLUSIONS AND RELEVANCE Complicated grief treatment is the treatment of choice for CG, and the addition of CIT optimizes the treatment of co-occurring depressive symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01179568 C1 [Shear, M. Katherine; Skritskaya, Natalia] Columbia Univ Coll Phys & Surg, Columbia Sch Social Work, 1255 Amsterdam Ave, New York, NY 10027 USA. [Shear, M. Katherine] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. [Reynolds, Charles F., III] Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Sch Med, Pittsburgh, PA 15213 USA. [Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi M.] Harvard Med Sch, Boston, MA USA. [Zisook, Sidney; Lebowitz, Barry] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Zisook, Sidney] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA. [Zisook, Sidney] Vet Med & Res Fdn, La Jolla, CA USA. [Wang, Yuanjia; Mauro, Christine] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Duan, Naihua] Columbia Univ Coll Phys & Surg, Dept Psychiat, Div Biostat, New York, NY 10027 USA. RP Shear, MK (reprint author), Columbia Univ Coll Phys & Surg, Columbia Sch Social Work, 1255 Amsterdam Ave, New York, NY 10027 USA. EM ks2394@columbia.edu FU National Institutes of Health [R01MH60783, R01MH085297, R01MH085288, R01MH085308, P30 MH90333]; American Foundation for Suicide Prevention [LSRG-S-172-12] FX This work was supported by grants R01MH60783, R01MH085297, R01MH085288, R01MH085308, and P30 MH90333 from the National Institutes of Health and by grant LSRG-S-172-12 from the American Foundation for Suicide Prevention. NR 37 TC 3 Z9 3 U1 10 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2016 VL 73 IS 7 BP 685 EP 694 DI 10.1001/jamapsychiatry.2016.0892 PG 10 WC Psychiatry SC Psychiatry GA DQ2OT UT WOS:000379042700009 PM 27276373 ER PT J AU Stein, MB Chen, CY Ursano, RJ Cai, TX Gelernter, J Heeringa, SG Jain, S Jensen, KP Maihofer, AX Mitchell, C Nievergelt, CM Nock, MK Neale, BM Polimanti, R Ripke, S Sun, XY Thomas, ML Wang, Q Ware, EB Borja, S Kessler, RC Smoller, J AF Stein, Murray B. Chen, Chia-Yen Ursano, Robert J. Cai, Tianxi Gelernter, Joel Heeringa, Steven G. Jain, Sonia Jensen, Kevin P. Maihofer, Adam X. Mitchell, Colter Nievergelt, Caroline M. Nock, Matthew K. Neale, Benjamin M. Polimanti, Renato Ripke, Stephan Sun, Xiaoying Thomas, Michael L. Wang, Qian Ware, Erin B. Borja, Susan Kessler, Ronald C. Smoller, JordanW. CA Army Study Assess Risk Resilience TI Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers SO JAMA PSYCHIATRY LA English DT Article ID COMBAT-RELATED PTSD; C-REACTIVE PROTEIN; OF-THE-LITERATURE; ASSESS RISK; RHEUMATOID-ARTHRITIS; MAJOR DEPRESSION; PSYCHIATRIC-DISORDERS; SUSCEPTIBILITY LOCI; MENTAL-DISORDERS; TRAUMA EXPOSURE AB IMPORTANCE Posttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological foundation of vulnerability and comorbidity. OBJECTIVE To discover genetic loci associated with the lifetime risk for PTSD in 2 cohorts from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). DESIGN, SETTING, AND PARTICIPANTS Two coordinated genome-wide association studies of mental health in the US military contributed participants. The New Soldier Study (NSS) included 3167 unique participants with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique participants with PTSD and 4969 trauma-exposed controls. The NSS data were collected from February 1, 2011, to November 30, 2012; the PDDS data, from January 9 to April 30, 2012. The primary analysis compared lifetime DSM-IV PTSD cases with trauma-exposed controls without lifetime PTSD. Data were analyzed from March 18 to December 27, 2015. MAIN OUTCOMES AND MEASURES Association analyses for PTSD used logistic regression models within each of 3 ancestral groups (European, African, and Latino American) by study, followed by meta-analysis. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated. RESULTS The NSS population was 80.7% male (6277 of 7774 participants; mean [SD] age, 20.9 [3.3] years); the PPDS population, 94.4% male (5583 of 5916 participants; mean [SD] age, 26.5 [6.0] years). A genome-wide significant locus was found in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR], 1.62; 95% CI, 1.37-1.92; P = 2.34 x 10(-8)) and persisted after adjustment for cumulative trauma exposure (adjusted OR, 1.64; 95% CI, 1.39-1.95; P = 1.18 x 10(-8)) in the African American samples from the NSS. A genome-wide significant locus was also found in or near ZNF626 on chromosome 19 (rs11085374; OR, 0.77; 95% CI, 0.70-0.85; P = 4.59 x 10(-8)) in the European American samples from the NSS. Similar results were not found for either single-nucleotide polymorphism in the corresponding ancestry group from the PPDS sample, in other ancestral groups, or in transancestral meta-analyses. Single-nucleotide polymorphism-based heritability was nonsignificant, and no significant genetic correlations were observed between PTSD and 6 mental disorders or 9 immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis. CONCLUSIONS AND RELEVANCE In the largest genome-wide association study of PTSD to date, involving a US military sample, limited evidence of association for specific loci was found. Further efforts are needed to replicate the genome-wide significant association with ANKRD55-associated in prior research with several autoimmune and inflammatory disorders-and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis. C1 [Stein, Murray B.; Maihofer, Adam X.; Nievergelt, Caroline M.; Thomas, Michael L.] Univ Calif San Diego, Dept Psychiat, Mail Code 0855,9500 Gilman Dr, La Jolla, CA 92093 USA. [Stein, Murray B.; Jain, Sonia; Sun, Xiaoying] UCSD, Dept Family Med & Publ Hlth, La Jolla, CA USA. [Stein, Murray B.] Vet Affairs San Diego Healthcare Syst, Psychiat Serv, San Diego, CA USA. [Chen, Chia-Yen; Smoller, JordanW.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Chen, Chia-Yen; Smoller, JordanW.] Harvard Med Sch, Boston, MA USA. [Chen, Chia-Yen; Neale, Benjamin M.; Ripke, Stephan; Smoller, JordanW.] Broad Inst Massachusetts Inst Technol & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. [Cai, Tianxi] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Gelernter, Joel; Jensen, Kevin P.; Polimanti, Renato; Wang, Qian] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Gelernter, Joel; Polimanti, Renato; Wang, Qian] Yale Univ, Dept Genet, New Haven, CT USA. [Gelernter, Joel; Polimanti, Renato; Wang, Qian] Yale Univ, Dept Neurobiol, New Haven, CT USA. [Heeringa, Steven G.; Mitchell, Colter; Ware, Erin B.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Wang, Qian] Yale Univ, Grad Sch Arts & Sci, Dept Computat Biol & Bioinformat, New Haven, CT USA. [Borja, Susan] NIMH, NIH, Bethesda, MD 20892 USA. [Kessler, Ronald C.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. RP Stein, MB (reprint author), Univ Calif San Diego, Dept Psychiat, Mail Code 0855,9500 Gilman Dr, La Jolla, CA 92093 USA. EM mstein@ucsd.edu RI Wang, Qian/Q-4664-2016; OI Wang, Qian/0000-0002-5615-4506; Ware, Erin/0000-0003-4731-8158 FU Department of the Army; US Department of Health and Human Services [U01MH087981]; National Institute of Drug Abuse [R01 DA12690]; National Institutes of Health, National Institute of Mental Health (NIMH) FX This study was sponsored by the Department of the Army and supported by cooperative agreement U01MH087981 from the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIMH) (Drs Stein and Ursano). The GPA analyses were supported by grant R01 DA12690 from the National Institute of Drug Abuse (Dr Gelemter). NR 89 TC 6 Z9 6 U1 5 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2016 VL 73 IS 7 BP 695 EP 704 DI 10.1001/jamapsychiatry.2016.0350 PG 10 WC Psychiatry SC Psychiatry GA DQ2OT UT WOS:000379042700010 PM 27167565 ER PT J AU Hoge, CW Yehuda, R Castro, CA McFarlane, AC Vermetten, E Jetly, R Koenen, KC Greenberg, N Shalev, AY Rauch, SAM Marmar, CR Rothbaum, BO AF Hoge, Charles W. Yehuda, Rachel Castro, Carl A. McFarlane, Alexander C. Vermetten, Eric Jetly, Rakesh Koenen, Karestan C. Greenberg, Neil Shalev, Arieh Y. Rauch, Sheila A. M. Marmar, Charles R. Rothbaum, Barbara O. TI Unintended Consequences of Changing the Definition of Posttraumatic Stress Disorder in DSM-5 Critique and Call for Action SO JAMA PSYCHIATRY LA English DT Article ID IV-TR; PTSD; CRITERIA; PREVALENCE; ICD-11; CHECKLIST; SYMPTOMS; VETERANS; IMPACT; TRIALS C1 [Hoge, Charles W.] US Army Med Res & Mat Command, Walter Reed Army Inst Res, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. [Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Yehuda, Rachel] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Castro, Carl A.] Univ So Calif, Sch Social Work, Los Angeles, CA 90089 USA. [McFarlane, Alexander C.] Univ Adelaide, Ctr Traumat Stress Studies, Adelaide, SA, Australia. [Vermetten, Eric] Minist Def, Mil Mental Hlth Res Ctr, Utrecht, Netherlands. [Vermetten, Eric] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Vermetten, Eric] Arq Psychotrauma Expert Grp, Diemen, Netherlands. [Jetly, Rakesh] Directorate Mental Hlth, Canadian Forces Hlth Serv Grp Headquarters, Ottawa, ON, Canada. [Koenen, Karestan C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Koenen, Karestan C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Greenberg, Neil] Kings Coll London, Kings Ctr Military Hlth Res, London, England. [Shalev, Arieh Y.] NYU Langone Med Ctr, Dept Psychiat, New York, NY USA. [Shalev, Arieh Y.] Hadassah & Hebrew Univ, Sch Med, Jerusalem, Israel. [Rauch, Sheila A. M.; Rothbaum, Barbara O.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Rauch, Sheila A. M.] Atlanta Vet Affairs Med Ctr, Mental Hlth Serv, Atlanta, GA USA. [Marmar, Charles R.] NYU Langone Med Ctr, Dept Psychiat, Steven & Alexandra Cohen Vet Ctr Posttraumat Stre, New York, NY USA. RP Hoge, CW (reprint author), US Army Med Res & Mat Command, Walter Reed Army Inst Res, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM charles.w.hoge.civ@mail.mil OI Shalev, Arieh/0000-0001-9425-050X NR 34 TC 12 Z9 12 U1 11 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2016 VL 73 IS 7 BP 750 EP 752 DI 10.1001/jamapsychiatry.2016.0647 PG 3 WC Psychiatry SC Psychiatry GA DQ2OT UT WOS:000379042700016 PM 27224895 ER PT J AU Kudler, H Day, K Schnurr, PP AF Kudler, Harold Day, Kristine Schnurr, Paula P. TI Treatment Options for Veterans With Posttraumatic Stress Disorder SO JAMA PSYCHIATRY LA English DT Letter C1 [Kudler, Harold] US Dept Vet Affairs, Mental Hlth Serv, Washington, DC 20420 USA. [Day, Kristine] US Dept Vet Affairs, Natl Evidence Based Psychotherapy Program, Washington, DC 20420 USA. [Schnurr, Paula P.] US Dept Vet Affairs, Natl Ctr PTSD, Washington, DC 20420 USA. RP Kudler, H (reprint author), US Dept Vet Affairs, 810 Vermont Ave NW, Washington, DC 20420 USA. EM harold.kudler@va.gov NR 4 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 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2016 VL 73 IS 7 BP 756 EP 757 DI 10.1001/jamapsychiatry.2016.0746 PG 2 WC Psychiatry SC Psychiatry GA DQ2OT UT WOS:000379042700019 PM 27191547 ER PT J AU Yehuda, R Hoge, CW AF Yehuda, Rachel Hoge, Charles W. TI Treatment Options for Veterans With Posttraumatic Stress Disorder Reply SO JAMA PSYCHIATRY LA English DT Letter ID MENTAL-HEALTH-CARE; PSYCHOTHERAPY; SOLDIERS; DROPOUT; PTSD; IRAQ C1 [Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Yehuda, Rachel] Icahn Sch Med Mt Sinai, 1 Gustave L Levy Pl, New York, NY 10029 USA. [Hoge, Charles W.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Yehuda, R (reprint author), Icahn Sch Med Mt Sinai, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM rachel.yehuda@mssm.edu NR 6 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 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2016 VL 73 IS 7 BP 758 EP 758 DI 10.1001/jamapsychiatry.2016.0572 PG 1 WC Psychiatry SC Psychiatry GA DQ2OT UT WOS:000379042700021 PM 27191824 ER PT J AU Nathan, DG Nathan, DM AF Nathan, David G. Nathan, David M. TI Eulogy for the clinical research center SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID HORMONE-RELEASING HORMONE; LONG-ACTING ANALOG; PRECOCIOUS PUBERTY; DIABETES-MELLITUS; TERM TREATMENT; COMPLICATIONS AB The extramural General Clinical Research Center (GCRC) program has been funded for more than 50 years, first by the National Center for Research Resources, NIH, and more recently as part of the Clinical Translational Science Award (CTSA) program through the newly formed National Center for Advancing Translation Sciences (NCATS). The GCRCs represent the federally funded laboratories that employ a highly trained cadre of research nurses, dietitians, and other support staff and in which generations of clinical investigators trained and performed groundbreaking human studies that advanced medical science and improved clinical care. Without the opportunity for adequate discussion, NCATS has now stopped funding these Research Centers. In this "eulogy," we review the origins and history of the GCRCs, their contributions to the advancement of medicine, and the recent events that have essentially defunded them. We mourn their loss. C1 [Nathan, David G.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Nathan, David M.] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Diabet, Boston, MA USA. [Nathan, David M.] Massachusetts Gen Hosp, Harvard Med Sch, Clin Res Ctr, Boston, MA USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, Dana 1644,450 Brookline Ave, Boston, MA 02215 USA. EM david_nathan@dfci.harvard.edu NR 19 TC 2 Z9 2 U1 2 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2016 VL 126 IS 7 BP 2388 EP 2391 DI 10.1172/JCI88381 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DQ3IA UT WOS:000379094800002 PM 27270173 ER PT J AU Souma, T Tompson, SW Thomson, BR Siggs, OM Kizhatil, K Yamaguchi, S Feng, L Limviphuvadh, V Whisenhunt, KN Maurer-Stroh, S Yanovitch, TL Kalaydjieva, L Azmanov, DN Finzi, S Mauri, L Javadiyan, S Souzeau, E Zhou, T Hewitt, AW Kloss, B Burdon, KP MacKey, DA Allen, KF Ruddle, JB Lim, SH Rozen, S Tran-Viet, KN Liu, XR John, S Wiggs, JL Pasutto, F Craig, JE Jin, J Quaggin, SE Young, TL AF Souma, Tomokazu Tompson, Stuart W. Thomson, Benjamin R. Siggs, Owen M. Kizhatil, Krishnakumar Yamaguchi, Shinji Feng, Liang Limviphuvadh, Vachiranee Whisenhunt, Kristina N. Maurer-Stroh, Sebastian Yanovitch, Tammy L. Kalaydjieva, Luba Azmanov, Dimitar N. Finzi, Simone Mauri, Lucia Javadiyan, Shahrbanou Souzeau, Emmanuelle Zhou, Tiger Hewitt, Alex W. Kloss, Bethany Burdon, Kathryn P. MacKey, David A. Allen, Keri F. Ruddle, Jonathan B. Lim, Sing-Hui Rozen, Steve Tran-Viet, Khanh-Nhat Liu, Xiaorong John, Simon Wiggs, Janey L. Pasutto, Francesca Craig, Jamie E. Jin, Jing Quaggin, Susan E. Young, Terri L. TI Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID OPEN-ANGLE GLAUCOMA; AQUEOUS-HUMOR DYNAMICS; CELL-CELL CONTACTS; MOLECULAR-GENETICS; CYTOCHROME P4501B1; CRYSTAL-STRUCTURES; TYROSINE KINASES; WEB SERVER; TIE2; CYP1B1 AB Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity. C1 [Souma, Tomokazu; Thomson, Benjamin R.; Yamaguchi, Shinji; Jin, Jing; Quaggin, Susan E.] Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA. [Souma, Tomokazu; Thomson, Benjamin R.; Yamaguchi, Shinji; Jin, Jing; Quaggin, Susan E.] Northwestern Univ, Feinberg Sch Med, Div Nephrol Hypertens, Chicago, IL 60611 USA. [Tompson, Stuart W.; Whisenhunt, Kristina N.; Kloss, Bethany; Young, Terri L.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, 2828 Marshall Ct,Ste 200, Madison, WI 53705 USA. [Siggs, Owen M.; Javadiyan, Shahrbanou; Souzeau, Emmanuelle; Zhou, Tiger; Burdon, Kathryn P.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Kizhatil, Krishnakumar; John, Simon] Howard Hughes Med Inst, Jackson Lab, Bar Harbor, ME USA. [Feng, Liang; Liu, Xiaorong] Northwestern Univ, Feinberg Sch Med, Dept Ophthalmol, Chicago, IL 60611 USA. [Limviphuvadh, Vachiranee; Maurer-Stroh, Sebastian] Agcy Sci Technol & Res, Bioinformat Inst, Singapore, Singapore. [Maurer-Stroh, Sebastian] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. [Yanovitch, Tammy L.] Univ Oklahoma, Dean McGee Eye Inst, Dept Ophthalmol, Oklahoma City, OK USA. [Kalaydjieva, Luba; Azmanov, Dimitar N.] Univ Western Australia, Harry Perkins Inst Med Res, Perth, WA 6009, Australia. [Kalaydjieva, Luba; Azmanov, Dimitar N.] Univ Western Australia, Med Res Ctr, Perth, WA 6009, Australia. [Azmanov, Dimitar N.] PathWest, QEII Med Ctr, Dept Diagnost Gen, Perth, WA, Australia. [Finzi, Simone] Univ Sao Paulo, Hosp Clin, Dept Ophthalmol, Sao Paulo, Brazil. [Mauri, Lucia] Osped Niguarda Ca Granda, Milan, Italy. [Hewitt, Alex W.; Ruddle, Jonathan B.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Hewitt, Alex W.; MacKey, David A.] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Lions Eye Inst, Perth, WA 6009, Australia. [Hewitt, Alex W.; Burdon, Kathryn P.; MacKey, David A.] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia. [Allen, Keri F.; Wiggs, Janey L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Lim, Sing-Hui; Rozen, Steve; Young, Terri L.] Duke Nat Univ Singapore, Grad Sch Med, Singapore, Singapore. [Tran-Viet, Khanh-Nhat] Calif State Univ Sacramento, Med Ctr, Sacramento, CA 95819 USA. [John, Simon] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [John, Simon] Tufts Univ, Sch Med, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Pasutto, Francesca] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. RP Young, TL (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, 2828 Marshall Ct,Ste 200, Madison, WI 53705 USA.; Quaggin, SE (reprint author), Northwestern Univ, Feinberg Cardiovasc Res Inst, 303 E Super St,Suite 10-105, Chicago, IL 60611 USA.; Quaggin, SE (reprint author), Northwestern Univ, Div Nephrol Hypertens, 303 E Super St,Suite 10-105, Chicago, IL 60611 USA. EM quaggin@northwestern.edu; tyoung6@wisc.edu RI Mackey, David/H-5340-2014 OI Mackey, David/0000-0001-7914-4709 FU NIH [R01 HL124120, R01 EY014685, 1K23EY020554]; Research to Prevent Blindness Inc.; Duke National University of Singapore; University of Wisconsin; March of Dimes Foundation; Howard Hughes Medical Center; Ophthalmic Research Institute of Australia; Channel Seven Children's Research Foundation; Department of Innovation, Industry, Science and Research; National Health and Medical Research Council of Australia (NHMRC); Japan Society for the Promotion of Science; Mallinckrodt Pharmaceuticals; Canadian Institute of Health Research; NHMRC; NCI CCSG [P30 CA060553]; University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences [NEI P30EY016665]; [EY 11721] FX We thank the patient subjects for participating in this study. We also thank John Pater, Joanna Black, Jane Kelly, Sharon Freedman, Ivailo Tourney, and Sylvia Cherninkova for clinical input and Richard Smith for assessment of murine eye phenotypes; Daniel Berner for sequencing assistance; and Andrew Wei and Anna Woo for technical assistance. This study was funded by NIH R01 HL124120 (S.E. Quaggin); NIH R01 EY014685, the Research to Prevent Blindness Inc. Lew R. Wasserman Award, the Duke National University of Singapore Core Grant, and the University of Wisconsin Centennial Scholars Award (T.L. Young); and NIH Career Development Award K12, 1K23EY020554 (T.L. Yanovitch). This work was also supported by grants from the March of Dimes Foundation (J.L. Wiggs), Howard Hughes Medical Center and EY 11721 (S. John and K. Kizhatil), the Ophthalmic Research Institute of Australia, the Channel Seven Children's Research Foundation, Department of Innovation, Industry, Science and Research, and the National Health and Medical Research Council of Australia (NHMRC). T. Souma is supported by fellowship grants from the Japan Society for the Promotion of Science and Mallinckrodt Pharmaceuticals. B.R. Thomson is supported by the Canadian Institute of Health Research. K.P. Burdon, J.E. Craig, and D.N. Azmanov are supported by fellowships from the NHMRC. Imaging was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We also acknowledge support from Vision Core Grant NEI P30EY016665 of the University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences. Proteomics analyses were supported by the Northwestern University Proteomics Core. We thank Dhaval Nanavati (Northwestern University, Proteomics Core) for technical support and helpful discussions. NR 65 TC 1 Z9 1 U1 2 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2016 VL 126 IS 7 BP 2575 EP 2587 DI 10.1172/JCI85830 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DQ3IA UT WOS:000379094800021 PM 27270174 ER PT J AU Won, OJ Zhang, L Wang, JH Su, QT Feng, Q Zhang, XHF Mani, SA Paulter, R Creighton, CJ Ittmann, MM Xin, L AF Won, Oh-Joon Zhang, Li Wang, Jianghua Su, Qingtai Feng, Qin Zhang, Xiang H. F. Mani, Sendurai A. Paulter, Robia Creighton, Chad J. Ittmann, Michael M. Xin, Li TI Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TO-MESENCHYMAL TRANSITION; CELL-GROWTH INHIBITION; CANCER-CELLS; DOWN-REGULATION; ANDROGEN RECEPTOR; SEMINAL-VESICLE; BREAST-CANCER; SIGNALING PATHWAYS; ORGANOID CULTURES; EPITHELIAL-CELLS AB Although Notch signaling is deregulated in prostate cancer, the role of this pathway in disease development and progression is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression. However, augmentation of Notch activity in this model promoted both proliferation and apoptosis of prostate epithelial cells, which collectively reduced the primary tumor burden. The increase in cellular apoptosis was linked to DNA damage-induced p53 activation. Despite a reduced primary tumor burden, Notch activation in Pten-null mice promoted epithelial-mesenchymal transition and FOXC2-dependent tumor metastases but did not confer resistance to androgen deprivation. Notch activation also resulted in transformation of seminal vesicle epithelial cells in Pten-null mice. Our study highlights a multifaceted role for Notch signaling in distinct aspects of prostate cancer biology and supports Notch as a potential therapeutic target for metastatic prostate cancer. C1 [Won, Oh-Joon; Zhang, Li; Su, Qingtai; Feng, Qin; Zhang, Xiang H. F.; Xin, Li] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Wang, Jianghua; Ittmann, Michael M.; Xin, Li] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Zhang, Xiang H. F.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Zhang, Xiang H. F.; Creighton, Chad J.; Ittmann, Michael M.; Xin, Li] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Mani, Sendurai A.] Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Dept Translat Mol Pathol, Houston, TX 77030 USA. [Paulter, Robia] Baylor Coll Med, Dept Mol Physiol, Houston, TX 77030 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Ittmann, Michael M.] Baylor Coll Med, Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Xin, L (reprint author), Baylor Coll Med, M533 DeBakey Bldg,BCM MS130,One Baylor Plaza, Houston, TX 77030 USA. EM xin@bcm.edu RI Mani, Sendurai/A-7244-2009 OI Mani, Sendurai/0000-0002-5918-4276 FU NIH [P30-AI036211, P30-CA125123, S10-RR024574, R01-CA190378, R21-CA196570, U01-CA141497] FX We thank Joseph Valdez for initiating some early studies, Boyu Zhang for technical help, Yiqun Zhang for analyzing expression microarray analyses, the Small Animal Imaging Facilities at Baylor College of Medicine and Texas Children's Hospital, the Cytometry and Cell Sorting Core at Baylor College of Medicine for technical support with funding from the NIH (P30-AI036211, P30-CA125123, and S10-RR024574), and Joel M. Sederstrom for expert assistance. This work is supported by NIH R01-CA190378 and R21-CA196570 (to L. Xin), NIH U01-CA141497 (to M.M. Ittmann), and NIH P30-CA125123 (the Cancer Center Shared Resources Grant). NR 63 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2016 VL 126 IS 7 BP 2626 EP 2641 DI 10.1172/JCI84637 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DQ3IA UT WOS:000379094800026 ER PT J AU Saha, A O'Connor, RS Thangavelu, G Lovitch, SB Dandamudi, DB Wilson, CB Vincent, BG Tkachev, V Pawlicki, JM Furlan, SN Kean, LS Aoyama, K Taylor, PA Panoskaltsis-Mortari, A Foncea, R Ranganathan, P Devine, SM Burrill, JS Guo, LL Sacristan, C Snyder, NW Blair, IA Milone, MC Dustin, ML Riley, JL Bernlohr, DA Murphy, WJ Fife, BT Munn, DH Miller, JS Serody, JS Freeman, GJ Sharpe, AH Turka, LA Blazer, BR AF Saha, Asim O'Connor, Roddy S. Thangavelu, Govindarajan Lovitch, Scott B. Dandamudi, Durga Bhavani Wilson, Caleph B. Vincent, Benjamin G. Tkachev, Victor Pawlicki, Jan M. Furlan, Scott N. Kean, Leslie S. Aoyama, Kazutoshi Taylor, Patricia A. Panoskaltsis-Mortari, Angela Foncea, Rocio Ranganathan, Parvathi Devine, Steven M. Burrill, Joel S. Guo, Lili Sacristan, Catarina Snyder, Nathaniel W. Blair, Ian A. Milone, Michael C. Dustin, Michael L. Riley, James L. Bernlohr, David A. Murphy, William J. Fife, Brian T. Munn, David H. Miller, Jeffrey S. Serody, Jonathan S. Freeman, Gordon J. Sharpe, Arlene H. Turka, Laurence A. Blazer, Bruce R. TI Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BONE-MARROW-TRANSPLANTATION; IMMUNE REGULATORY CELLS; FATTY-ACID-METABOLISM; FALSE DISCOVERY RATE; RNA-SEQ DATA; LYMPHOCYTE-ACTIVATION; DIFFERENTIAL EXPRESSION; SIGNALING PATHWAY; EFFECTOR FUNCTION; VIRAL-INFECTION AB Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1(-/-) donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1(-/-) donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD. C1 [Saha, Asim; Thangavelu, Govindarajan; Aoyama, Kazutoshi; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazer, Bruce R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Saha, Asim; Thangavelu, Govindarajan; Aoyama, Kazutoshi; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazer, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [O'Connor, Roddy S.; Milone, Michael C.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Lovitch, Scott B.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Lovitch, Scott B.; Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Dandamudi, Durga Bhavani] NYU, Sch Med, Sackler Grad Program, New York, NY USA. [Wilson, Caleph B.; Pawlicki, Jan M.; Riley, James L.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Vincent, Benjamin G.; Serody, Jonathan S.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Tkachev, Victor; Furlan, Scott N.; Kean, Leslie S.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Foncea, Rocio; Bernlohr, David A.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA. [Ranganathan, Parvathi; Devine, Steven M.] Ohio State Univ, Ctr Comprehens Canc, Dept Med, Columbus, OH 43210 USA. [Guo, Lili; Snyder, Nathaniel W.; Blair, Ian A.] Univ Penn, Penn SRP Ctr, Dept Syst Pharmacol Translat Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sacristan, Catarina; Dustin, Michael L.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Snyder, Nathaniel W.] Drexel Univ, AJ Drexel Autism Inst, Philadelphia, PA 19104 USA. [Dustin, Michael L.] Univ Oxford, Nuffield Dept Orthoped Rheumatol & Musculoskeleta, S Parks Rd, Oxford, England. [Murphy, William J.] UCD, Dept Dermatol & Internal Med, Sacramento, CA USA. [Fife, Brian T.] Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Fife, Brian T.] Univ Minnesota, Ctr Immunol, Minneapolis, MN USA. [Munn, David H.] Georgia Regents Univ, Dept Pediat, Augusta, GA USA. [Miller, Jeffrey S.] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Box 736 UMHC, Minneapolis, MN 55455 USA. [Serody, Jonathan S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Turka, Laurence A.] Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA. [Turka, Laurence A.] Harvard Univ, Sch Med, Boston, MA USA. [Blazer, Bruce R.] Univ Minnesota, Dept Pediat, MMC 109,420 Delaware St SE, Minneapolis, MN 55455 USA. RP Blazer, BR (reprint author), Univ Minnesota, Dept Pediat, MMC 109,420 Delaware St SE, Minneapolis, MN 55455 USA. EM blaza001@umn.edu OI Lovitch, Scott/0000-0001-9013-0105; Fife, Brian/0000-0001-9826-5637; Dustin, Michael/0000-0003-4983-6389 FU NIH [HL056067, AI034495, AI056299, AI043542]; Wellcome Trust FX We thank Christopher Lees and colleagues of B.R. Blazar's laboratory for technical assistance, S. Davis (University of Oxford, Oxford, UK) for human PD-L1, and S. Garrett and S. Almo (Einstein School of Medicine, New York, NY) for data on interspecies interactions. This study was supported in part by NIH grants HL056067 (to B.R. Blazar), AI034495 (to B.R. Blazar), AI056299 (to B.R. Blazar), and AI043542 (to M.L. Dustin), and the Wellcome Trust (to M.L. Dustin). NR 92 TC 4 Z9 5 U1 1 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2016 VL 126 IS 7 BP 2642 EP 2660 DI 10.1172/JCI85796 PG 19 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DQ3IA UT WOS:000379094800027 PM 27294527 ER PT J AU Xie, Q Wu, QL Kim, L Miller, TE Liau, BB Mack, SC Yang, KL Factor, DC Fang, XG Huang, Z Zhou, WC Alazem, K Wang, XX Bernstein, BE Bao, SD Rich, JN AF Xie, Qi Wu, Qiulian Kim, Leo Miller, Tyler E. Liau, Brian B. Mack, Stephen C. Yang, Kailin Factor, Daniel C. Fang, Xiaoguang Huang, Zhi Zhou, Wenchao Alazem, Kareem Wang, Xiuxing Bernstein, Bradley E. Bao, Shideng Rich, Jeremy N. TI RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BET BROMODOMAIN INHIBITION; GLIOMA STEM-CELLS; FACTOR COMPLEX; PAUSE RELEASE; C-MYC; GLIOBLASTOMA; SURVIVAL; TEMOZOLOMIDE; ADDICTION; PROMOTES AB Glioblastomas co-opt stem cell regulatory pathways to maintain brain tumor-initiating cells (BTICs), also known as cancer stem cells. NOTCH signaling has been a molecular target in BTICs, but NOTCH antagonists have demonstrated limited efficacy in clinical trials. Recombining binding protein suppressor of hairless (RBPJ) is considered a central transcriptional mediator of NOTCH activity. Here, we report that pharmacologic NOTCH inhibitors were less effective than targeting RBPJ in suppressing tumor growth. While NOTCH inhibitors decreased canonical NOTCH gene expression, RBPJ regulated a distinct profile of genes critical to BTIC sternness and cell cycle progression. RBPJ was preferentially expressed by BTICs and required for BTIC self-renewal and tumor growth. MYC, a key BTIC regulator, bound the RBPJ promoter and treatment with a bromodomain and extraterminal domain (BET) family bromodomain inhibitor decreased MYC and RBPJ expression. Proteomic studies demonstrated that RBPJ binds CDK9, a component of positive transcription elongation factor b (P-TEFb), to target gene promoters, enhancing transcriptional elongation. Collectively, RBPJ links MYC and transcriptional control through CDK9, providing potential nodes of fragility for therapeutic intervention, potentially distinct from NOTCH. C1 [Xie, Qi; Wu, Qiulian; Kim, Leo; Mack, Stephen C.; Yang, Kailin; Fang, Xiaoguang; Huang, Zhi; Zhou, Wenchao; Alazem, Kareem; Wang, Xiuxing; Bao, Shideng; Rich, Jeremy N.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Stem Cell Biol & Regenerat Med,Lerner Res In, Cleveland, OH 44106 USA. [Kim, Leo; Miller, Tyler E.; Yang, Kailin; Bao, Shideng; Rich, Jeremy N.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Mol Med, Cleveland, OH 44106 USA. [Liau, Brian B.; Bernstein, Bradley E.] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Liau, Brian B.; Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Liau, Brian B.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Liau, Brian B.; Bernstein, Bradley E.] Harvard Med Sch, Boston, MA USA. [Liau, Brian B.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Liau, Brian B.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Factor, Daniel C.] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. RP Rich, JN (reprint author), Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA. EM drjeremyrich@gmail.com OI Yang, Kailin/0000-0001-5968-6738; Miller, Tyler E/0000-0002-1269-1895 FU NIH [CA197718, CA154130, CA171652, CA169117, CA198892, NS087913, NS089272, NS070315, HG006991]; Research Programs Committees of Cleveland Clinic; James S. McDonnell Foundation; Howard Hughes Medical Institute FX We appreciate the kind provision of the 4XRBPJ-Luc reporter plasmid from Takahiro Maeda (Harvard University) and the tk-renilla reporter plasmid from Zengqiang Yuan (Institute of Biophysics, Chinese Academy of Sciences). Mary McGraw and the Cleveland Clinic Foundation Tissue Procurement Service provided primary brain tumor tissues. We would like to thank the Cleveland Clinic Lerner Research Institute imaging core and proteomics core for technical assistance and the members of the Rich and Bao laboratories for critical reading of the manuscript and helpful discussions. Finally, we would like to thank our funding sources: The NIH (grants CA197718, CA154130, CA171652, CA169117, CA198892, NS087913, NS089272 [to J.N. Rich], NS070315 [to S. Bao], and HG006991 [to B.E. Bernstein]), Research Programs Committees of Cleveland Clinic (to J.N. Rich), James S. McDonnell Foundation (to J.N. Rich), and the Howard Hughes Medical Institute (to B.E. Bernstein). NR 35 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2016 VL 126 IS 7 BP 2757 EP 2772 DI 10.1172/JCI86114 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DQ3IA UT WOS:000379094800035 PM 27322055 ER PT J AU Silver, JK Binder, DS Zubcevik, N Zafonte, RD AF Silver, Julie K. Binder, David S. Zubcevik, Nevena Zafonte, Ross D. TI Healthcare Hackathons Provide Educational and Innovation Opportunities: A Case Study and Best Practice Recommendations SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Hackathon; Interdisciplinary; Healthcare training; Education; Rehabilitation; Innovation ID MEDICINE AB Physicians and other healthcare professionals are often the end users of medical innovation; however, they are rarely involved in the beginning design stages. This often results in ineffective healthcare solutions with poor adoption rates. At the early design stage, innovation would benefit from input from healthcare professionals. This report describes the first-ever rehabilitation hackathon-an interdisciplinary and competitive team event aimed at accelerating and improving healthcare solutions and providing an educational experience for participants. Hackathons are gaining traction as a way to accelerate innovation by bringing together a diverse group of interdisciplinary professionals from different industries who work collaboratively in teams and learn from each other, focus on a specific problem ("pain point"), develop a solution using design thinking techniques, pitch the solution to participants, gather fast feedback and quickly alter the prototype design ("pivoting"). 102 hackers including 19 (18.6 %) physicians and other professionals participated, and over the course of 2 days worked in teams, pitched ideas and developed design prototypes. Three awards were given for prototypes that may improve function in persons with disabilities. 43 hackers were women (42.2 %) and 59 men (57.8 %); they ranged in age from 16 to 79 years old; and, of the 75 hackers who reported their age, 63 (84 %) were less than 40 years old and 12 (16 %) were 40 years or older. This report contributes to the emerging literature on healthcare hackathons as a means of providing interdisciplinary education and training and supporting innovation. C1 [Silver, Julie K.; Binder, David S.; Zubcevik, Nevena; Zafonte, Ross D.] Harvard Med Sch, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, 300 1st Ave, Charlestown, MA 02139 USA. [Silver, Julie K.; Binder, David S.; Zubcevik, Nevena; Zafonte, Ross D.] Massachusetts Gen Hosp, Phys Med & Rehabil, Boston, MA 02114 USA. [Silver, Julie K.; Zafonte, Ross D.] Brigham & Womens Hosp, Phys Med & Rehabil, 75 Francis St, Boston, MA 02115 USA. RP Silver, JK (reprint author), Harvard Med Sch, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, 300 1st Ave, Charlestown, MA 02139 USA.; Silver, JK (reprint author), Massachusetts Gen Hosp, Phys Med & Rehabil, Boston, MA 02114 USA.; Silver, JK (reprint author), Brigham & Womens Hosp, Phys Med & Rehabil, 75 Francis St, Boston, MA 02115 USA. EM julie_silver@hms.harvard.edu FU Microsoft; HeartWare; Eastham Capital; RAWZ Foundation; Ekso Bionics; Goodwin Procter; MadPowAmy Cueva; Cambridge Innovation Center FX Massachusetts Institute of Technology (MIT) Hacking Medicine Team assisted with logistical support and planning as well as some recruitment of attendees. Financial support was provided by Microsoft, HeartWare, Eastham Capital, RAWZ Foundation, Ekso Bionics, Goodwin Procter, MadPowAmy Cueva, and an anonymous donor. Physical space was subsidized by the Cambridge Innovation Center. Promotional support was provided by the American Academy of Physical Medicine and Rehabilitation. NR 13 TC 0 Z9 0 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 EI 1573-689X J9 J MED SYST JI J. Med. Syst. PD JUL PY 2016 VL 40 IS 7 AR 177 DI 10.1007/s10916-016-0532-3 PG 7 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DQ0NH UT WOS:000378895600019 PM 27277278 ER PT J AU Rosenberg, L Thomas, JD AF Rosenberg, Leah Thomas, Jane deLima TI Pharmacologic Management of Depression in Advanced Illness #309 SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Editorial Material ID CANCER-PATIENTS; TRIAL; PAIN C1 [Rosenberg, Leah] Massachusetts Gen Hosp, Palliat Care Dept, 55 Fruit St,Founders 602, Boston, MA 02114 USA. RP Rosenberg, L (reprint author), Massachusetts Gen Hosp, Palliat Care Dept, 55 Fruit St,Founders 602, Boston, MA 02114 USA. EM leah_rosenberg@dfci.harvard.edu NR 16 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 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD JUL PY 2016 VL 19 IS 7 BP 783 EP 784 DI 10.1089/jpm.2016.0075 PG 2 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DP7CC UT WOS:000378655600019 PM 27286475 ER PT J AU Hill, ID Fasano, A Guandalini, S Hoffenberg, E Levy, J Reilly, N Verma, R AF Hill, Ivor D. Fasano, Alessio Guandalini, Stefano Hoffenberg, Edward Levy, Joseph Reilly, Norelle Verma, Ritu TI NASPGHAN Clinical Report on the Diagnosis and Treatment of Gluten-related Disorders SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE celiac disease; celiac disease serological tests; gluten-free diet; IgE-specific antibodies; nonceliac gluten sensitivity; wheat allergy ID ANTITISSUE TRANSGLUTAMINASE ANTIBODIES; PEDIATRIC CELIAC-DISEASE; QUALITY-OF-LIFE; INFLAMMATORY-BOWEL-DISEASE; POPULATION-BASED COHORT; FREE DIET; FOLLOW-UP; FOOD ALLERGY; GASTROINTESTINAL SYMPTOMS; CHANGING PATTERN AB Dietary exclusion of gluten-containing products has become increasingly popular in the general population, and currently similar to 30% of people in the United States are limiting gluten ingestion. Although celiac disease (CD), wheat allergy (WA), and nonceliac gluten sensitivity (NCGS) constitute a spectrum of gluten-related disorders that require exclusion of gluten from the diet, together these account for a relatively small percentage of those following a gluten-free diet, and the vast majority has no medical necessity for doing so. Differentiating between CD, WA, and NCGS has important prognostic and therapeutic implications. Because of the protean manifestations of gluten-related disorders, it is not possible to differentiate between them on clinical grounds alone. This clinical report will compare and contrast the manifestations of gluten-related disorders, emphasize the importance of differentiating between these conditions, discuss initial and subsequent tests needed to confirm the diagnosis, and provide recommendations on treatment and follow-up for each condition. C1 [Hill, Ivor D.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Fasano, Alessio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Celiac Res,Children & Celiac Program, Boston, MA USA. [Guandalini, Stefano] Univ Chicago, Sect Pediat Gastroenterol Hepatol & Nutr, Celiac Dis Ctr, Chicago, IL 60637 USA. [Hoffenberg, Edward] Univ Colorado, Ctr Celiac Dis, Digest Hlth Inst, Childrens Hosp Colorado,Sch Med, Aurora, CO USA. [Levy, Joseph] NYU, Sch Med, Special Projects Div Pediat Gastroenterol, Langone Med Ctr, New York, NY USA. [Reilly, Norelle] Columbia Univ, Med Ctr, Div Pediat Gastroenterol, New York, NY USA. [Reilly, Norelle] Columbia Univ, Med Ctr, Celiac Dis Ctr, New York, NY USA. [Verma, Ritu] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Hill, ID (reprint author), Nationwide Childrens Hosp, Div Gastroenterol, 700 Childrens Dr, Columbus, OH 43205 USA. EM Ivor.Hill@nationwidechildrens.org NR 76 TC 1 Z9 1 U1 5 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JUL PY 2016 VL 63 IS 1 BP 156 EP 165 DI 10.1097/MPG.0000000000001216 PG 10 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA DP7PX UT WOS:000378692400037 PM 27035374 ER PT J AU Raymond, SB Gee, MS Anupindi, SA Shailam, R Kaplan, JL Nimkin, K AF Raymond, Scott B. Gee, Michael S. Anupindi, Sudha A. Shailam, Randheer Kaplan, Jess L. Nimkin, Katherine TI CT and MRI of Rare Extraintestinal Manifestations of Inflammatory Bowel Disease in Children and Adolescents SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Review DE Crohn disease; imaging; pediatric ID RECURRENT MULTIFOCAL OSTEOMYELITIS; PRIMARY SCLEROSING CHOLANGITIS; ANTI-TNF THERAPY; CROHNS-DISEASE; AUTOIMMUNE PANCREATITIS; PEDIATRIC-PATIENTS; LIVER-ABSCESS; PULMONARY MANIFESTATIONS; ULCERATIVE-COLITIS; VENOUS THROMBOSIS AB Inflammatory bowel disease (IBD) is associated with a spectrum of extraintestinal manifestations (EIMs) affecting many organ systems. EIMs can occur in more than 40% of patients with IBD and are associated with significant morbidity. They occur at any time point in the course of disease, often during an active phase of bowel inflammation, but sometimes preceding bowel disease. Prompt recognition of EIMs enables timely and more effective therapy. Physicians who image patients with IBD should be aware of the myriad extraintestinal conditions that may be detected on imaging studies, both within and outside of the abdomen, as they may predate the diagnosis of IBD. Cross-sectional imaging of unusual conditions associated with IBD will be presented, including pathology in the hepatobiliary, pancreatic, genitourinary, musculoskeletal, mucocutaneous, vascular, neurologic, and pulmonary systems. C1 [Raymond, Scott B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gee, Michael S.; Shailam, Randheer; Nimkin, Katherine] Massachusetts Gen Hosp, Dept Radiol, Div Pediat Radiol, 55 Fruit St,Ellison 237, Boston, MA 02114 USA. [Anupindi, Sudha A.] Childrens Hosp Philadelphia, Dept Radiol, Philadelphia, PA 19104 USA. [Kaplan, Jess L.] MassGen Hosp Children, Dept Pediat, Div Pediat Gastroenterol, Boston, MA USA. RP Nimkin, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Pediat Radiol, 55 Fruit St,Ellison 237, Boston, MA 02114 USA. EM knimkin@partners.org NR 78 TC 0 Z9 0 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JUL PY 2016 VL 63 IS 1 BP E1 EP E9 DI 10.1097/MPG.0000000000001225 PG 9 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA DP7PX UT WOS:000378692400001 PM 27050046 ER PT J AU Raciborska, A Bilska, K Rychlowska-Pruszynska, M Duczkowski, M Duczkowska, A Drabko, K Chaber, R Sobol, G Wyrobek, E Michalak, E Rodriguez-Galindo, C Wozniak, W AF Raciborska, Anna Bilska, Katarzyna Rychlowska-Pruszynska, Magdalena Duczkowski, Marek Duczkowska, Agnieszka Drabko, Katarzyna Chaber, Radoslaw Sobol, Grazyna Wyrobek, Elzbieta Michalak, Elzbieta Rodriguez-Galindo, Carlos Wozniak, Wojciech TI Management and follow-up of Ewing sarcoma patients with isolated lung metastases SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Ewing sarcoma; Lung metastases; Thoracotomy; Radiation; Survival ID CHILDRENS ONCOLOGY GROUP; PULMONARY METASTASES; PROGNOSTIC-FACTORS; FAMILY TUMORS; IRRADIATION; RESECTION; SURVIVAL; THERAPY; CHEMOTHERAPY; BONE AB Background: Ewing sarcoma (ES) is the second most common pediatric malignant bone tumor with a wide spectrum of clinical presentations. Although metastatic disease to the lungs is often the cause of death, isolated lung metastases at diagnosis are not frequent. The specific role of chemotherapy, surgery, and lung radiation has not been clearly defined. We investigated prognostic factors and the impact of the different treatment modalities in a cohort of patients with ES with isolated lung metastases. Materials and methods: Thirty-eight patients with ES and isolated lung metastases were treated using modern multimodal therapy during the period 2000-2014. According to the imaging characteristics of lung nodules patients were allocated into one of four treatment groups: "0" without nodules, "1" one solitary nodule of <0.5 cm or several nodules of <0.3 cm, "2" solitary nodule of 0.5-1 cm or multiple nodules of 0.3-0.5 cm, "3" one pulmonary/pleural nodule of >1 cm, or more than one nodule of >0.5 cm. Factors predictive of outcome were analyzed. Overall survival was estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. Results: Treatment of the lung metastases was performed in 23 cases (60.5%): twenty patients underwent lung surgery, 6 of them received additional postoperative whole lung radiation; three patients received lung radiation only. Malignant cells were found in all lung nodules of patients from group " 3", in 5 (62.5%) patients from group " 2", and none of the group "1". There was a correlation between histological response of the primary tumor and outcome. Three-year estimates of EFS and OS were 45.19% and 60.7%, respectively. Patients with good response measured by chest CT had significantly better EFS than patients with poor response (81% vs. 27.66%, respectively, p=0.006). Conclusions: Metastatectomy may have a role in the treatment of highly selected patients with ES and isolated lung metastases depending on the histologic response to therapy. Further studies are needed to better define the use of surgery and the response-adapted criteria in the upfront management of this population. (C) 2016 Elsevier Inc. All rights reserved. C1 [Raciborska, Anna; Bilska, Katarzyna; Rychlowska-Pruszynska, Magdalena; Wozniak, Wojciech] Inst Mother & Child Hlth, Dept Surg Oncol Children & Youth, Kasprzaka 17A Str, PL-01211 Warsaw, Poland. [Duczkowski, Marek; Duczkowska, Agnieszka] Inst Mother & Child Hlth, Dept Radiol, Kasprzaka 17A Str, PL-01211 Warsaw, Poland. [Drabko, Katarzyna] Med Univ Lublin, Dept Pediat Hematol Oncol & Bone Marrow Transplan, A Gebali 6 Str, PL-20093 Lublin, Poland. [Chaber, Radoslaw] Wroclaw Med Univ, Dept & Clin Pediat Oncol Hematol & Bone Marrow Tr, Bujwida 44 Str, PL-50368 Wroclaw, Poland. [Sobol, Grazyna] Med Univ Silesia, Unit Pediat Oncol Hematol & Chemotherapy, Medykow 16 Str, PL-40752 Katowice, Poland. [Wyrobek, Elzbieta] Univ Childrens Hosp Cracow, Dept Hematol & Oncol, Krakow, Poland. [Michalak, Elzbieta] Inst Mother & Child Hlth, Dept Pathol, Kasprzaka 17A Str, PL-01211 Warsaw, Poland. [Rodriguez-Galindo, Carlos] Harvard Med Sch, Dana Farber Canc Inst, Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Rodriguez-Galindo, Carlos] Harvard Med Sch, Childrens Hosp, 450 Brookline Ave, Boston, MA 02215 USA. RP Raciborska, A (reprint author), Inst Mother & Child Hlth, Dept Surg Oncol Children & Youth, Ul Kasprzaka 17A, PL-01211 Warsaw, Poland. EM anna.raciborska@hoga.pl NR 25 TC 2 Z9 2 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 EI 1531-5037 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD JUL PY 2016 VL 51 IS 7 BP 1067 EP 1071 DI 10.1016/j.jpedsurg.2015.11.012 PG 5 WC Pediatrics; Surgery SC Pediatrics; Surgery GA DQ0SR UT WOS:000378910700002 PM 26707423 ER PT J AU Jackson, PR AF Jackson, Peter R. TI The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness, 2nd edition SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Jackson, Peter R.] Massachusetts Gen Hosp, McLean Hosp, Boston, MA USA. [Jackson, Peter R.] Harvard Med Sch, Boston, MA USA. RP Jackson, PR (reprint author), Massachusetts Gen Hosp, McLean Hosp, Boston, MA USA.; Jackson, PR (reprint author), Harvard Med Sch, Boston, MA USA. EM prjackson@partners.org NR 3 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 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2016 VL 55 IS 7 BP 632 EP 633 DI 10.1016/j.jaac.2016.06.001 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DQ1UF UT WOS:000378985200017 ER PT J AU Setia, N Agoston, AT Han, HS Mullen, JT Duda, DG Clark, JW Deshpande, V Mino-Kenudson, M Srivastava, A Lennerz, JK Hong, TS Kwak, EL Lauwers, GY AF Setia, Namrata Agoston, Agoston T. Han, Hye S. Mullen, John T. Duda, Dan G. Clark, Jeffrey W. Deshpande, Vikram Mino-Kenudson, Mari Srivastava, Amitabh Lennerz, Jochen K. Hong, Theodore S. Kwak, Eunice L. Lauwers, Gregory Y. TI A protein and mRNA expression-based classification of gastric cancer SO MODERN PATHOLOGY LA English DT Article ID EPSTEIN-BARR-VIRUS; E-CADHERIN EXPRESSION; LYMPHOEPITHELIOMA-LIKE CARCINOMA; MICROSATELLITE INSTABILITY; CLINICOPATHOLOGICAL FEATURES; P53 PROTEIN; MOLECULAR CHARACTERIZATION; PROMOTER HYPERMETHYLATION; SIGNALING PATHWAY; SURVIVAL AB The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. C1 [Setia, Namrata; Han, Hye S.; Deshpande, Vikram; Mino-Kenudson, Mari; Lennerz, Jochen K.; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Agoston, Agoston T.; Srivastava, Amitabh] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Han, Hye S.] Konkuk Univ, Sch Med, Seoul, South Korea. [Mullen, John T.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Duda, Dan G.; Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Clark, Jeffrey W.; Kwak, Eunice L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Lauwers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM glauwers@partners.org NR 62 TC 3 Z9 3 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JUL PY 2016 VL 29 IS 7 BP 772 EP 784 DI 10.1038/modpathol.2016.55 PG 13 WC Pathology SC Pathology GA DQ1AR UT WOS:000378933500012 PM 27032689 ER PT J AU Parikh, S Karaa, A Goldstein, A Ng, YS Gorman, G Feigenbaum, A Christodoulou, J Haas, R Tarnopolsky, M Cohen, BK Dimmock, D Feyma, T Koenig, MK Mundy, H Niyazov, D Saneto, RP Wainwright, MS Wusthoff, C McFarland, R Scaglia, F AF Parikh, Sumit Karaa, Amel Goldstein, Amy Ng, Yi S. Gorman, Grainne Feigenbaum, Annette Christodoulou, John Haas, Richard Tarnopolsky, Mark Cohen, Bruce K. Dimmock, David Feyma, Tim Koenig, Mary K. Mundy, Helen Niyazov, David Saneto, Russell P. Wainwright, Mark S. Wusthoff, Courtney McFarland, Robert Scaglia, Fernando TI Solid organ transplantation in primary mitochondrial disease: Proceed with caution SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Mitochondrial disease; Solid organ transplant; Heart transplant; Kidney transplant; Liver transplant ID DEOXYGUANOSINE KINASE-DEFICIENCY; KEARNS-SAYRE SYNDROME; LIVER-TRANSPLANTATION; CARDIAC TRANSPLANTATION; PRIMARY-CARE; CARDIOMYOPATHY; EXPERIENCE; MUTATIONS; CHILDREN; OUTCOMES AB Solid organ transplants are rarely performed in both adult and pediatric patients with primary mitochondrial disease. Poor outcomes have been described in case reports and small case series. It is unclear whether the underlying genetic disease has a significant impact on post-transplant morbidity and mortality. Data were obtained for 35 patients from 17 Mitochondrial Disease Centers across North America, the United Kingdom and Australia. Patient outcomes were noted after liver, kidney or heart transplantation. Excluding patients with POLG-related disease, post-transplant survival approached or met outcomes seen in non-mitochondrial disease transplant patients. The majority of mitochondrial disease patients did not have worsening of their mitochondrial disease within 90-days post-transplant. Post-transplant complications, including organ rejection, were not a common occurrence and were generally treatable. Many patients did not have a mitochondrial disease considered or diagnosed prior to transplantation. In conclusion, patients with mitochondrial disease in this cohort generally tolerated solid-organ transplantation. Such patients may not need to be excluded from transplant solely for their mitochondrial diagnosis; additional caution may be needed for patients with POLG-related disease. Transplant teams should be aware of mitochondrial disease as an etiology for organ-failure and consider appropriate consultation in patients without a known cause of their symptoms. (C) 2016 Elsevier Inc. All rights reserved. C1 [Parikh, Sumit] Cleveland Clin, Ctr Pediat Neurol, Neurogenet & Mitochondrial Dis, Cleveland, OH 44106 USA. [Karaa, Amel] Massachusetts Gen Hosp, Dept Med Genet, Boston, MA 02114 USA. [Goldstein, Amy] Childrens Hosp Pittsburgh, Ctr Pediat Neurol, Pittsburgh, PA 15213 USA. [Ng, Yi S.; Gorman, Grainne; McFarland, Robert] Newcastle Univ, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England. [Feigenbaum, Annette] Rady Childrens Hosp, Dept Med Genet, San Diego, CA USA. [Christodoulou, John] Childrens Hosp Westmead, Western Sydney Genet Program, Sydney, NSW, Australia. [Christodoulou, John] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW, Australia. [Christodoulou, John] Univ Sydney, Discipline Genet Med, Sydney, NSW, Australia. [Haas, Richard] Rady Childrens Hosp, Dept Pediat Neurol, San Diego, CA USA. [Tarnopolsky, Mark] McMaster Univ, Div Neuromuscular & Neurometab Dis, Dept Pediat, Hamilton, ON, Canada. [Cohen, Bruce K.] Akron Childrens Hosp, Dept Pediat Neurol, Akron, OH USA. [Dimmock, David] Med Coll Wisconsin, Dept Med Genet, Milwaukee, WI 53226 USA. [Feyma, Tim] Gillette Childrens Specialty Healthcare, Dept Pediat Neurol, St Paul, MN USA. [Koenig, Mary K.] Univ Texas Houston, Sch Med, Dept Pediat, Div Child & Adolescent Neurol, Houston, TX USA. [Mundy, Helen] Evelina London Childrens Healthcare, Pediat Metab, London, England. [Niyazov, David] Ochsner Clin Fdn, Dept Pediat, Div Med Genet, New Orleans, LA USA. [Saneto, Russell P.] Seattle Childrens Hosp, Dept Pediat Neurol, Seattle, WA USA. [Wainwright, Mark S.] Lurie Childrens Hosp, Dept Pediat, Div Neurol, Chicago, IL USA. [Wusthoff, Courtney] Lucile Packard Childrens Hosp, Dept Pediat Neurol, Palo Alto, CA USA. [Scaglia, Fernando] Baylor Coll Med, Dept Mol & Human Genet, Baylor, TX USA. RP Parikh, S (reprint author), 9500 Euclid Ave,S60, Cleveland, OH 44195 USA. EM parikhs@ccf.org OI Christodoulou, John/0000-0002-8431-0641 FU Genzyme/Sanofi; Shire; Biomarin; Alexion FX Dr Dimmock has consulting agreements with, BioMarin Pharmaceutical Inc. Audentes Therapeutics, Demeter Therapeutics LLC and Complete Genomics. He has had previous consulting agreements with Illumina. He has or currently receives support for clinical trials from Genzyme/Sanofi, Shire, Biomarin, Alexion. He is employed by the Medical College of Wisconsin which is a not for profit academic organization that offers fee for service testing and clinical evaluation and care of children and adults with mitochondrial disease. In the authors opinion none of these agreements constitute a conflict of interest with the data presented within this paper. NR 26 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 2016 VL 118 IS 3 BP 178 EP 184 DI 10.1016/j.ymgme.2016.04.009 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DQ1SX UT WOS:000378981800008 PM 27312126 ER PT J AU Paiardini, M Lichterfeld, M AF Paiardini, Mirko Lichterfeld, Mathias TI Follicular T helper cells: hotspots for HIV-1 persistence SO NATURE MEDICINE LA English DT Editorial Material ID REPLICATION; RESERVOIR AB Reservoirs of virally infected cells that are resistant to standard antiretroviral therapy make HIV-1 infection an incurable disease. A new study shows that follicular T helper cells in lymph node germinal centers are prime niches for HIV-1 persistence during antiviral therapy. C1 [Paiardini, Mirko] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Paiardini, Mirko] Yerkes Natl Primate Res Ctr, Atlanta, GA USA. [Lichterfeld, Mathias] Harvard Med Sch, Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Lichterfeld, Mathias] MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lichterfeld, Mathias] Harvard Univ, Cambridge, MA 02138 USA. RP Lichterfeld, M (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA.; Lichterfeld, M (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Lichterfeld, M (reprint author), Harvard Univ, Cambridge, MA 02138 USA. EM mlichterfeld@partners.org FU NIAID NIH HHS [R21 AI106468] NR 9 TC 2 Z9 2 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2016 VL 22 IS 7 BP 711 EP 712 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DQ7DK UT WOS:000379366900008 PM 27387885 ER PT J AU Ni, J Ramkissoon, SH Xie, SZ Goel, S Stover, DG Guo, HB Luu, V Marco, E Ramkissoon, LA Kang, YJ Hayashi, M Nguyen, QD Ligon, AH Du, R Claus, EB Alexander, BM Yuan, GC Wang, ZGC Iglehart, JD Krop, IE Roberts, TM Winer, EP Lin, NU Ligon, KL Zhao, JJ AF Ni, Jing Ramkissoon, Shakti H. Xie, Shaozhen Goel, Shom Stover, Daniel G. Guo, Hanbing Luu, Victor Marco, Eugenio Ramkissoon, Lori A. Kang, Yun Jee Hayashi, Marika Quang-De Nguyen Ligon, Azra H. Du, Rose Claus, Elizabeth B. Alexander, Brian M. Yuan, Guo-Cheng Wang, Zhigang C. Iglehart, J. Dirk Krop, Ian E. Roberts, Thomas M. Winer, Eric P. Lin, Nancy U. Ligon, Keith L. Zhao, Jean J. TI Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases SO NATURE MEDICINE LA English DT Article ID PTEN LOSS; EVEROLIMUS AB Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM. C1 [Ni, Jing; Xie, Shaozhen; Goel, Shom; Guo, Hanbing; Luu, Victor; Wang, Zhigang C.; Iglehart, J. Dirk; Roberts, Thomas M.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ni, Jing; Xie, Shaozhen; Guo, Hanbing; Luu, Victor; Roberts, Thomas M.; Zhao, Jean J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ramkissoon, Shakti H.; Goel, Shom; Stover, Daniel G.; Ramkissoon, Lori A.; Kang, Yun Jee; Hayashi, Marika; Wang, Zhigang C.; Iglehart, J. Dirk; Krop, Ian E.; Winer, Eric P.; Lin, Nancy U.; Ligon, Keith L.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ramkissoon, Shakti H.; Ligon, Azra H.; Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Marco, Eugenio; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Quang-De Nguyen] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Du, Rose; Claus, Elizabeth B.] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. [Claus, Elizabeth B.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Alexander, Brian M.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Alexander, Brian M.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Zhao, JJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Zhao, JJ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Lin, NU; Ligon, KL (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Ligon, KL (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM nancy_lin@dfci.harvard.edu; keith_ligon@dfci.harvard.edu; jean_zhao@dfci.harvard.edu OI Stover, Daniel/0000-0001-9003-8165; Du, Rose/0000-0003-2641-6496 FU Breast Cancer Research Foundation; Aid for Cancer Research; Breast Cancer Alliance; Komen scholar grant; US National Institutes of Health (NIH) [R01 CA187918, CA172461, 1K08NS087118, P50 CA165962, P01 CA142536, 1P50CA168504] FX We thank D. Livingston for reading the manuscript. We thank R. Modiste and G. Dai at the Dana-Farber Lurie Family Image Center for MRI imaging. We thank R. Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histoplathology Core for histopathological analyses. We thank F. Pan, D. Light and R. Qi (Life Technologies, Thermo Fisher) for assistance with WES and transcriptome analyses with the Ion Torrent sequencing system. We thank J. Ruan and M. Ruan (VigeneTech) for quantification of pS6RP and p4EBP IHC data by the Cellvigene data-analysis program. This work was supported by the Breast Cancer Research Foundation (N.U.L., E.P.W., Z.W. and J.J.Z.); Aid for Cancer Research (E.P.W. and J.J.Z.); Breast Cancer Alliance (J.J.Z.); Komen scholar grant (E.P.W.); and US National Institutes of Health (NIH) grants R01 CA187918 (T.M.R. and J.J.Z.), CA172461 (J.J.Z.), 1K08NS087118 (S.H.R.), P50 CA165962 (T.M.R., K.L.L. and J.J.Z.), P01 CA142536 (J.J.Z.) and 1P50CA168504 (T.M.R., I.E.K., E.P.W., N.U.L., and J.J.Z.). NR 13 TC 6 Z9 6 U1 7 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2016 VL 22 IS 7 BP 723 EP 726 DI 10.1038/nm.4120 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DQ7DK UT WOS:000379366900010 PM 27270588 ER PT J AU Vaccari, M Gordon, SN Fourati, S Schifanella, L Liyanage, NPM Cameron, M Keele, BF Shen, XY Tomaras, GD Billings, E Rao, M Chung, AW Dowell, KG Bailey-Kellogg, C Brown, EP Ackerman, ME Vargas-Inchaustegui, DA Whitney, S Doster, MN Binello, N Pegu, P Montefiori, DC Foulds, K Quinn, DS Donaldson, M Liang, F Lore, K Roederer, M Koup, RA McDermott, A Ma, ZM Miller, CJ Phan, TB Forthal, DN Blackburn, M Caccuri, F Bissa, M Ferrari, G Kalyanaraman, V Ferrari, MG Thompson, D Robert-Guroff, M Ratto-Kim, S Kim, JH Michael, NL Phogat, S Barnett, SW Tartaglia, J Venzon, D Stablein, DM Alter, G Sekaly, RP Franchini, G AF Vaccari, Monica Gordon, Shari N. Fourati, Slim Schifanella, Luca Liyanage, Namal P. M. Cameron, Mark Keele, Brandon F. Shen, Xiaoying Tomaras, Georgia D. Billings, Erik Rao, Mangala Chung, Amy W. Dowell, Karen G. Bailey-Kellogg, Chris Brown, Eric P. Ackerman, Margaret E. Vargas-Inchaustegui, Diego A. Whitney, Stephen Doster, Melvin N. Binello, Nicolo Pegu, Poonam Montefiori, David C. Foulds, Kathryn Quinn, David S. Donaldson, Mitzi Liang, Frank Lore, Karin Roederer, Mario Koup, Richard A. McDermott, Adrian Ma, Zhong-Min Miller, Christopher J. Phan, Tran B. Forthal, Donald N. Blackburn, Matthew Caccuri, Francesca Bissa, Massinilliano Ferrari, Guido Kalyanaraman, Vaniambadi Ferrari, Maria G. Thompson, DeVon Robert-Guroff, Marjorie Ratto-Kim, Silvia Kim, Jerome H. Michael, Nelson L. Phogat, Sanjay Barnett, Susan W. Tartaglia, Jim Venzon, David Stablein, Donald M. Alter, Galit Sekaly, Rafick-Pierre Franchini, Genoveffa TI Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition SO NATURE MEDICINE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; HIV-1 VACCINE EFFICACY; NK CELLS; NITRIC-OXIDE; ACTIVATION; INFECTION; PROTECTION; ANTIBODIES; TRIAL; IMMUNOGENICITY AB A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum. decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution, of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies. C1 [Vaccari, Monica; Gordon, Shari N.; Schifanella, Luca; Liyanage, Namal P. M.; Doster, Melvin N.; Binello, Nicolo; Pegu, Poonam; Blackburn, Matthew; Caccuri, Francesca; Bissa, Massinilliano; Franchini, Genoveffa] NCI, Anim Models & Vaccine Sect, Bethesda, MD 20892 USA. [Fourati, Slim; Sekaly, Rafick-Pierre] Case Wetern Reserve, Dept Pathol, Cleveland, OH USA. [Schifanella, Luca] Univ Milan, L Sacco Hosp, Dept Biomed & Clin Sci, Milan, Italy. [Cameron, Mark] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH USA. [Keele, Brandon F.] Leidos Biomed Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD USA. [Shen, Xiaoying; Tomaras, Georgia D.; Ferrari, Guido] Duke Human Vaccine Inst, Durham, NC USA. [Billings, Erik; Rao, Mangala; Ratto-Kim, Silvia; Kim, Jerome H.; Michael, Nelson L.] Walter Red Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Chung, Amy W.; Alter, Galit] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Dowell, Karen G.; Bailey-Kellogg, Chris] Darthmouth Coll, Dept Comp Sci, Hanover, NH USA. [Brown, Eric P.; Ackerman, Margaret E.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Vargas-Inchaustegui, Diego A.; Robert-Guroff, Marjorie] NCI, Immune Biol Retrovial Infect Sect, Bethesda, MD USA. [Whitney, Stephen; Kalyanaraman, Vaniambadi; Ferrari, Maria G.; Thompson, DeVon] Adv Biosci Labs, Rockville, MD USA. [Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC USA. [Foulds, Kathryn; Quinn, David S.; Donaldson, Mitzi; Roederer, Mario; Koup, Richard A.; McDermott, Adrian] US Natl Inst Hlth, Vaccine Res Ctr, Bethesda, MD USA. [Liang, Frank; Lore, Karin] Karolinska Inst, Stockholm, Sweden. [Ma, Zhong-Min; Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA USA. [Phan, Tran B.; Forthal, Donald N.] Univ Calif Irvine, Irvine Sch Med, Irvine, CA USA. [Phogat, Sanjay; Tartaglia, Jim] Sanofi Pasteur, Swiftwater, PA USA. [Barnett, Susan W.] Novartis Vaccines & Diagonst Inc, Cambridge, MA USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD USA. [Stablein, Donald M.] EMMES Corp, Rockville, MD USA. [Barnett, Susan W.] GSK Vaccines, Cambridge, MA USA. [Kim, Jerome H.] Int Vaccine Inst, Seoul, South Korea. RP Franchini, G (reprint author), NCI, Anim Models & Vaccine Sect, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov OI Chung, Amy/0000-0003-0020-9704; Fourati, Slim/0000-0001-6609-7587 FU Simian Vaccine Evaluation Unit (SVEU) [HHSN266200600005C]; intramural US National Cancer Institute (NCI) program; extramural US National Institute of Allergy and Infectious Diseases (NIAID) program; US Army Medical Research and Material Command (USAMRMC) [W81XWH-07-2-0067]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.; US Department of Defense; Collaboration for AIDS Vaccine Discovery (CAVD) grants from the Bill and Melinda Gates Foundation [OPP1032325, OPP1032817]; NCI; US National Institutes of Health (NIH) [HHSN261200800001E]; NIH [HHSN27201100016C]; Center for AIDS Research [AI064518]; Bill and Melinda Gates' Foundation [OPP111572]; NIH/NIAID [5R01AI102691]; Intramural Research Program of the Vaccine Research Center, NIAID, NIH; CAVD from the Bill and Melinda Gates Foundation [OPP1032325, R01 AI118581, R01 AI102715] FX We would like to thank T. Nolan and D. Abram for their editorial assistance, N. Miller and A. Shultz for their help in the study design, and J. Warren for support with systems biology and several antibody assays under Simian Vaccine Evaluation Unit (SVEU) contract number HHSN266200600005C, awarded to Advanced BioScience Laboratories, Inc. (ABL). This work was supported by the intramural US National Cancer Institute (NCI) program and the extramural US National Institute of Allergy and Infectious Diseases (NIAID) program, together with the US Army Medical Research and Material Command (USAMRMC) (W81XWH-07-2-0067), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the US Department of Defense, the Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1032325 and OPP1032817 from the Bill and Melinda Gates Foundation, and in part, with federal funds from the NCI, US National Institutes of Health (NIH), under contract no. HHSN261200800001E (to the whole team). We would like to acknowledge the following institutions for the grants supporting the authors: NIH primate grant HHSN27201100016C (D.M.); Center for AIDS Research grant AI064518 (G.F.); Bill and Melinda Gates' Foundation grant OPP111572 (M.E.A., C.B.K., E.F.B., K.G.D.); NIH/NIAID grant 5R01AI102691 (M.E.A, E.F.B.); Intramural Research Program of the Vaccine Research Center, NIAID, NIH, and CAVD from the Bill and Melinda Gates Foundation grants OPP1032325 (R.A.K.), R01 AI118581 and R01 AI102715 (D.F.). The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense or the Department of Health and Human Services. Mention of trade names, commercial products, or organizations do not imply endorsement by the US Government. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: CEM.NKR CCR5+ by P. Creswell. The anti-alpha 4 beta 7 in APC was kindly provided by A. A. Ansari (cat. #11718, 1:50 dilution) through the NIH AIDS Reagent Program, Division of AIDS, NIAID. NR 31 TC 16 Z9 16 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2016 VL 22 IS 7 BP 762 EP 770 DI 10.1038/nm.4105 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DQ7DK UT WOS:000379366900015 PM 27239761 ER PT J AU Li, S Garrett-Bakelman, FE Chung, SS Sanders, MA Hricik, T Rapaport, F Patel, J Dillon, R Vijay, P Brown, AL Perl, AE Cannon, J Bullinger, L Luger, S Becker, M Lewis, ID To, LB Delwel, R Lowenberg, B Dohner, H Guzman, ML Hassane, DC Roboz, GJ Grimwade, D Valk, PJM D'Andrea, RJ Carroll, M Park, CY Neuberg, D Levine, R Melnick, AM Mason, CE AF Li, Sheng Garrett-Bakelman, Francine E. Chung, Stephen S. Sanders, Mathijs A. Hricik, Todd Rapaport, Franck Patel, Jay Dillon, Richard Vijay, Priyanka Brown, Anna L. Perl, Alexander E. Cannon, Joy Bullinger, Lars Luger, Selina Becker, Michael Lewis, Ian D. To, Luen Bik Delwel, Ruud Lowenberg, Bob Doehner, Hartmut Guzman, Monica L. Hassane, Duane C. Roboz, Gail J. Grimwade, David Valk, Peter J. M. D'Andrea, Richard J. Carroll, Martin Park, Christopher Y. Neuberg, Donna Levine, Ross Melnick, Ari M. Mason, Christopher E. TI Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia SO NATURE MEDICINE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CLONAL EVOLUTION; DNA METHYLATION; MUTATIONS RESULT; TET2 FUNCTION; CANCER; DIFFERENTIATION; CHEMOTHERAPY; MALIGNANCIES; PROGRESSION AB Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diveisity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors. C1 [Li, Sheng; Mason, Christopher E.] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA. [Li, Sheng; Mason, Christopher E.] Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al Sa, New York, NY 10065 USA. [Garrett-Bakelman, Francine E.; Guzman, Monica L.; Hassane, Duane C.; Roboz, Gail J.; Melnick, Ari M.] Weill Cornell Med, Div Hematol Med Oncol, Dept Med, New York, NY 10065 USA. [Chung, Stephen S.; Hricik, Todd; Rapaport, Franck; Patel, Jay; Levine, Ross] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Sanders, Mathijs A.; Delwel, Ruud; Lowenberg, Bob; Valk, Peter J. M.] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. [Dillon, Richard; Grimwade, David] Kings Coll London, Dept Med & Mol Genet, Fac Life Sci & Med, London, England. [Vijay, Priyanka] Weill Cornell Med, Triinst Training Program Computat Biol & Med, New York, NY USA. [Brown, Anna L.; Lewis, Ian D.; D'Andrea, Richard J.] SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia. [Brown, Anna L.; Lewis, Ian D.; D'Andrea, Richard J.] Univ South Australia, Adelaide, SA, Australia. [Brown, Anna L.; D'Andrea, Richard J.] Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA, Australia. [Brown, Anna L.; Lewis, Ian D.; To, Luen Bik; D'Andrea, Richard J.] SA Pathol, Dept Hematol, Adelaide, SA, Australia. [Brown, Anna L.; Lewis, Ian D.; To, Luen Bik; D'Andrea, Richard J.] Royal Adelaide Hosp, Adelaide, SA, Australia. [Perl, Alexander E.; Cannon, Joy; Luger, Selina; Carroll, Martin] Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19104 USA. [Bullinger, Lars; Doehner, Hartmut; Guzman, Monica L.] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany. [Becker, Michael] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Lewis, Ian D.; To, Luen Bik] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Park, Christopher Y.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Park, Christopher Y.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mason, Christopher E.] Feil Family Brain & Mind Res Inst, New York, NY USA. [Li, Sheng] Weill Cornell Med, Dept Neurosurg, New York, NY USA. RP Mason, CE (reprint author), Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.; Mason, CE (reprint author), Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al Sa, New York, NY 10065 USA.; Melnick, AM (reprint author), Weill Cornell Med, Div Hematol Med Oncol, Dept Med, New York, NY 10065 USA.; Mason, CE (reprint author), Feil Family Brain & Mind Res Inst, New York, NY USA. EM amm2014@med.cornell.edu; chm2042@med.cornell.edu FU Starr Cancer Consortium [I4-A442, I7-A765, I9-A9-071]; Irma T. Hirschl Charitable Trust; Monique Weill-Caulier Charitable Trust; Bert L. and N. Kuggie Vallee Foundation; WorldQuant Foundation; Pershing Square Sohn Cancer Research Alliance; NASA [NNX14AH50G]; LLS SCOR [7006-13]; NCI [K08CA169055]; American Society of Hematology award under the ASH-AMFDP partnership [ASHAMFDP-20121]; Robert Wood Johnson Foundation; ASH/EHA TRTH; Doris Duke Medical Foundation; Leukemia and Lymphoma Society Translational Research Program; Geoffrey Beene Cancer Center; Leukaemia and Lymphoma Research award; German Research Foundation (DFG) [SFB 1074]; DFG Heisenberg-Stipendium [BU 1339/3-1]; Australian National Health and Medical Research Council; Royal Adelaide Hospital Contributing Haematologists Fund; US National Institutes of Health [R01CA102031, R01NS076465]; Leukemia Fighters funding FX We thank J. Phillips, J. Ishii, L. Wang, J. Busuttil, T. Lee, P. Zumbo, J. Gandara, and A. Zeilemaker for technical support; C. Sheridan for technical support, assistance with organization, and maintenance of sample database and banking; M. Perugini, D. Iarossi, and I.S. Tiong for assistance with clinical database management; and Y. Neelamraju, Z. Li, J. Glass, and M.R. De Massy for data annotation and management. Next-generation sequencing protocols and sequencing were performed by the Weill Cornell Medicine Epigenomics Core and the New York Genome Center. We thank A. Viale from the Integrated Genomics Operation and N. Socci from the bioinformatics core at Memorial Sloan Kettering Cancer Center for sequencing services. We thank the South Australian Cancer Research Biobank for access to clinical samples. We thank F. Michor for recommendations regarding data analyses. This work was supported by Starr Cancer Consortium grant I4-A442 (A.M.M., R.L., and C.E.M.), STARR Cancer Consortium grant I7-A765 and I9-A9-071 (C.E.M.), the Irma T. Hirschl and Monique Weill-Caulier Charitable Trusts, Bert L. and N. Kuggie Vallee Foundation and the WorldQuant Foundation, Pershing Square Sohn Cancer Research Alliance, and NASA (NNX14AH50G) (C.E.M.); LLS SCOR 7006-13 (A.M.M.); NCI K08CA169055 (F.E.G.-B.); an American Society of Hematology (ASHAMFDP-20121) award under the ASH-AMFDP partnership with the Robert Wood Johnson Foundation and ASH/EHA TRTH (F.E.G.-B.); a Doris Duke Medical Foundation, Leukemia and Lymphoma Society Translational Research Program, and Geoffrey Beene Cancer Center (C.Y.P.); a Leukaemia and Lymphoma Research award (D.G. and R. Dillon); German Research Foundation (DFG) grant SFB 1074 (project B3; K.D. and L.B.); DFG Heisenberg-Stipendium BU 1339/3-1 (L.B.); an Australian National Health and Medical Research Council and the Royal Adelaide Hospital Contributing Haematologists Fund financial support (R.J.D., A.L.B., and I.D.L.); US National Institutes of Health R01CA102031 (G.J.R. and M.L.G.) and R01NS076465 (C.E.M. and A.M.M.); and Leukemia Fighters funding (G.J.R., M.L.G., and D.C.H.). NR 48 TC 17 Z9 18 U1 11 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2016 VL 22 IS 7 BP 792 EP 799 DI 10.1038/nm.4125 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DQ7DK UT WOS:000379366900018 PM 27322744 ER PT J AU Li, PL Kaiser, P Lampiris, HW Kim, P Yukl, SA Havlir, DV Greene, WC Wong, JK AF Li, Peilin Kaiser, Philipp Lampiris, Harry W. Kim, Peggy Yukl, Steven A. Havlir, Diane V. Greene, Warner C. Wong, Joseph K. TI Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation SO NATURE MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; RETINOIC ACID; SIGNAL-ACTIVATION; T-CELL; RNA; RECOGNITION; ACITRETIN; INFECTION; REPLICATION; RECEPTORS AB The persistence of latent HIV proviruses in long-lived CD4(+) T cells despite antiretroviral therapy (ART)(1-3) is a major obstacle to viral eradication(4-6). Because current candidate latency reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs(7,8), new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms(4-6,9). These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell(10). Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA(11-14). Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4(+) T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir. C1 [Li, Peilin; Kaiser, Philipp; Lampiris, Harry W.; Kim, Peggy; Yukl, Steven A.; Wong, Joseph K.] San Francisco VA Med Ctr, Med Serv, Infect Dis Sect, San Francisco, CA 94121 USA. [Li, Peilin; Lampiris, Harry W.; Yukl, Steven A.; Havlir, Diane V.; Greene, Warner C.; Wong, Joseph K.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Havlir, Diane V.] San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA 94110 USA. [Greene, Warner C.] Univ Calif San Francisco, Dept Microbiol & Biol, San Francisco, CA 94143 USA. [Greene, Warner C.] Gladstone Inst Virol & Immunol, San Francisco, CA USA. RP Li, PL (reprint author), San Francisco VA Med Ctr, Med Serv, Infect Dis Sect, San Francisco, CA 94121 USA.; Li, PL (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM peilin.li@ucsf.edu FU NIH [1R21AI104445-01A1, R56 AI116342, R21 AI116218]; Department of Veterans Affairs Merit Review Award [5101 BX001048]; UCSF-Gladstone Center for AIDS Research Virology Core [P30AI027763, U19 AI096113]; amfAR Institute for HIV Cure Research [109301] FX We thank the study participants, without whom this research could not have been performed. We thank S. Deeks, H. Gunthard, C. Lopez, and H. Hatano for their helpful comments and support, and M. Vu for assistance with participant recruitment. We thank J.C.W. Carroll for graphics arts, S. Ordway for editorial assistance, and S. Wilcox for administrative assistance. We thank the US National Institutes of Health (NIH) AIDS Reagent Program, Division of AIDS, NIAID, NIH for cell lines, plasmid, and reagents. This work was supported by the NIH (grants 1R21AI104445-01A1 (P.L.), R56 AI116342 and R21 AI116218 (J.K.W.)), the Department of Veterans Affairs Merit Review Award 5101 BX001048 (J.K.W.), the UCSF-Gladstone Center for AIDS Research Virology Core P30AI027763 (W.C.G. and J.K.W.), U19 AI096113 (W.C.G.) and research supported as part of the amfAR Institute for HIV Cure Research with grant number 109301(W.G., J.K.W., and P.L.). NR 39 TC 4 Z9 4 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2016 VL 22 IS 7 BP 807 EP 811 DI 10.1038/nm.4124 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DQ7DK UT WOS:000379366900020 PM 27294875 ER PT J AU Vodopivec, I Cho, TA Rizzo, JF Frosch, MP Sims, KB AF Vodopivec, Ivana Cho, Tracey A. Rizzo, Joseph F., III Frosch, Matthew P. Sims, Katherine B. TI Mitochondrial Encephalopathy and Optic Neuropathy Due to m.10158 MT-ND3 Complex I Mutation Presenting in an Adult Patient Case Report and Review of the Literature SO NEUROLOGIST LA English DT Review DE mitochondrial disease; MT-ND3; optic neuropathy; headache; stroke-like episodes; epilepsy ID ND3 GENE; LEIGH-SYNDROME; DNA MUTATION; MISSENSE MUTATION; DEFICIENCY; DISEASE; PREVALENCE; DISORDERS; CHILDREN; LESIONS AB Introduction: Establishing a diagnosis of mitochondrial disease in adults remains a clinician's challenge. We report a case of syndrome reminiscent of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in an adult patient who carries m.10158T>C mutation in complex I respiratory chain gene MT-ND3 (mitochondrially encoded NADH dehydrogenase 3). Case Report: This 26-year-old man from Thailand presented with new-onset headaches, seizures, stroke-like episodes, and poor vision due to optic neuropathy and cortical blindness. Instead of expected mutations in the mitochondrial tRNA gene that are frequently associated with MELAS, the mutation in MT-ND3 with variable tissue heteroplasmy (blood 5.3%, muscle 89.5%) was demonstrated. The patient's clinical features, blood biomarkers, neuroimaging findings, muscle biopsy with histochemical and functional in vitro analysis, and genetic studies were analyzed and compared with all previously reported ND3 disease cases. Conclusions: ND3 disease due to m.10158T>C mutation was previously described only in patients with Leigh or Leigh-like syndrome. Our findings thus indicate that ND3 disease can manifest with atypical phenotype in adults. The diagnosis of mitochondrial disease caused by other than typical MELAS-associated mutations in adults with stroke-like episodes, headaches, and seizures should be considered. An analysis of tissue other than blood, which is more likely to harbor a tissue-specific mitochondrial DNA mutation at a measurable level, may be necessary for diagnosis. C1 [Vodopivec, Ivana; Cho, Tracey A.; Rizzo, Joseph F., III; Frosch, Matthew P.; Sims, Katherine B.] Harvard Med Sch, Boston, MA USA. [Vodopivec, Ivana; Cho, Tracey A.; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. [Vodopivec, Ivana; Rizzo, Joseph F., III] Massachusetts Eye & Ear Infirm, Neuroophthalmol Serv, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Neuropathol Serv, Boston, MA 02114 USA. RP Vodopivec, I (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. EM ivodopivec@partners.org NR 26 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 1074-7931 J9 NEUROLOGIST JI Neurologist PD JUL PY 2016 VL 21 IS 4 BP 61 EP 65 DI 10.1097/NRL.0000000000000084 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DQ2LE UT WOS:000379033000004 PM 27348141 ER PT J AU Cardenas, DP Muir, ER Duong, TQ AF Cardenas, Damon P. Muir, Eric R. Duong, Timothy Q. TI MRI of cerebral blood flow under hyperbaric conditions in rats SO NMR IN BIOMEDICINE LA English DT Article DE arterial spin labeling; CBF; oxygen therapy; BOLD; magnetic susceptibility ID LONGITUDINAL RELAXATION-TIME; OXYGEN-TENSION; MAGNETIC-FIELD; FUNCTIONAL MRI; TRANSIT-TIME; BOLD FMRI; BRAIN; HYPEROXIA; HYPOXIA; CBF AB Hyperbaric oxygen (HBO) therapy has a number of clinical applications. However, the effects of acute HBO on basal cerebral blood flow (CBF) and neurovascular coupling are not well understood. This study explored the use of arterial spin labeling MRI to evaluate changes in baseline and forepaw stimulus-evoked CBF responses in rats (n = 8) during normobaric air (NB), normobaric oxygen (NBO) (100% O-2), 3 atm absolute (ATA) hyperbaric air (HB) and 3 ATA HBO conditions. T-1 was also measured, and the effects of changes in T-1 caused by increasing oxygen on the CBF calculation were investigated. The major findings were as follows: (i) increased inhaled oxygen concentrations led to a reduced respiration rate; (ii) increased dissolved paramagnetic oxygen had significant effects on blood and tissue T-1, which affected the CBF calculation using the arterial spin labeling method; (iii) the differences in blood T-1 had a larger effect than the differences in tissue T-1 on CBF calculation; (iv) if oxygen-induced changes in blood and tissue T-1 were not taken into account, CBF was underestimated by 33% at 3 ATA HBO, 10% at NBO and <5% at HB; (v) with correction, CBF values under HBO, HB and NBO were similar (p > 0.05) and all were higher than CBF under NB by similar to 40% (p < 0.05), indicating that hypercapnia from the reduced respiration rate masks oxygen-induced vasoconstriction, although blood gas was not measured; and (vi) substantial stimulus-evoked CBF increases were detected under HBO, similar to NB, supporting the notion that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism. CBF MRI provides valuable insights into the effects of oxygen on basal CBF and neurovascular coupling under hyperbaric conditions. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Cardenas, Damon P.; Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. [Cardenas, Damon P.] Univ Texas San Antonio, Grad Sch Biomed Sci, San Antonio, TX USA. [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. RP Muir, ER; Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM muire@uthscsa.edu; duongt@uthscsa.edu FU National Institute of General Medical Sciences, Minority Biomedical Research Support, Research Initiative for Scientific Enhancement fellowship [GM060655] FX This work was supported in part by a National Institute of General Medical Sciences, Minority Biomedical Research Support, Research Initiative for Scientific Enhancement GM060655 fellowship to D.P.C. NR 37 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD JUL PY 2016 VL 29 IS 7 BP 961 EP 968 DI 10.1002/nbm.3555 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DQ2JM UT WOS:000379028600012 PM 27192391 ER PT J AU Panagia, M Chen, YCI Chen, HH Ernande, L Chen, C Chao, W Kwong, K Scherrer-Crosbie, M Sosnovik, DE AF Panagia, Marcello Chen, Yin-Ching Iris Chen, Howard H. Ernande, Laura Chen, Chan Chao, Wei Kwong, Kenneth Scherrer-Crosbie, Marielle Sosnovik, David E. TI Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance SO NMR IN BIOMEDICINE LA English DT Article DE brown adipose tissue; BOLD; heart failure; MRI ID IN-VIVO; NATRIURETIC PEPTIDES; CONTRAST ULTRASOUND; SKELETAL-MUSCLE; PERFUSION; MICE; MRI; BRAIN; FLOW; IDENTIFICATION AB Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6weeks later. T-2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T-2* maps of BAT were obtained at multiple time points before and after administration of the (3) adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (511mm(3) versus 65 +/- 3mm(3); p<0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p<0.05). CL injection increased BAT T-2* in healthy animals but not in mice with heart failure (24 +/- 4% versus 6 +/- 2%; p<0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Panagia, Marcello] Boston Med Ctr, Cardiol Sect, Boston, MA USA. [Panagia, Marcello; Ernande, Laura; Scherrer-Crosbie, Marielle; Sosnovik, David E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Panagia, Marcello; Chen, Yin-Ching Iris; Chen, Howard H.; Kwong, Kenneth; Sosnovik, David E.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA USA. [Ernande, Laura] Hop Henri Mondor, AP HP, DHU Ageing Thorax Vessel Blood, Creteil, France. [Chen, Chan; Chao, Wei] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Sosnovik, DE (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02115 USA. EM sosnovik@nmr.mgh.harvard.edu FU National Institutes of Health [K08 HL123744-03, R01 HL093038, R01HL112831, P41RR14075, R01 GM080906, R01 GM097259]; SPARK grant from MGH; [DK R21 092909] FX This research was supported by the following National Institutes of Health grants: K08 HL123744-03 (M.P.), R01 HL093038 (D.E.S.), R01HL112831 (D.E.S.), P41RR14075 to the Martinos Center for Biomedical Imaging, R01 GM080906 (W.C.), R01 GM097259 (W.C.), a SPARK grant from MGH (M.S.-C.) and DK R21 092909 (M.S.-C.). NR 46 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD JUL PY 2016 VL 29 IS 7 BP 978 EP 984 DI 10.1002/nbm.3557 PG 7 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DQ2JM UT WOS:000379028600014 PM 27226402 ER PT J AU Ciris, PA Balasubramanian, M Seethamraju, RT Tokuda, J Scalera, J Penzkofer, T Fennessy, FM Tempany-Afdhal, CM Tuncali, K Mulkern, RV AF Ciris, Pelin Aksit Balasubramanian, Mukund Seethamraju, Ravi T. Tokuda, Junichi Scalera, Jonathan Penzkofer, Tobias Fennessy, Fiona M. Tempany-Afdhal, Clare M. Tuncali, Kemal Mulkern, Robert V. TI Characterization of gradient echo signal decays in healthy and cancerous prostate at 3T improves with a Gaussian augmentation of the mono-exponential (GAME) model SO NMR IN BIOMEDICINE LA English DT Article DE biophysical modeling; Lorentzian; Gaussian; transverse relaxation; prostate cancer; hypoxia ID MAGNETIC-FIELD INHOMOGENEITIES; TUMOR HYPOXIA; MRI; T-2; T-2-ASTERISK; OXYGENATION; CARCINOMA; ELECTRODE; PREDICTS; BEHAVIOR AB A biomarker of cancer aggressiveness, such as hypoxia, could substantially impact treatment decisions in the prostate, especially radiation therapy, by balancing treatment morbidity (urinary incontinence, erectile dysfunction, etc.) against mortality. R-2(*) mapping with Mono-Exponential (ME) decay modeling has shown potential for identifying areas of prostate cancer hypoxia at 1.5T. However, Gaussian deviations from ME decay have been observed in other tissues at 3T. The purpose of this study is to assess whether gradient-echo signal decays are better characterized by a standard ME decay model, or a Gaussian Augmentation of the Mono-Exponential (GAME) decay model, in the prostate at 3T. Multi-gradient-echo signals were acquired on 20 consecutive patients with a clinical suspicion of prostate cancer undergoing MR-guided prostate biopsies. Data were fitted with both ME and GAME models. The information contents of these models were compared using Akaike's information criterion (second order, AIC(C)), in skeletal muscle, the prostate central gland (CG), and peripheral zone (PZ) regions of interest (ROIs). The GAME model had higher information content in 30% of the prostate on average (across all patients and ROIs), covering up to 67% of cancerous PZ ROIs, and up to 100% of cancerous CG ROIs (in individual patients). The higher information content of GAME became more prominent in regions that would be assumed hypoxic using ME alone, reaching 50% of the PZ and 70% of the CG as ME R-2(*) approached 40 s(-1). R-2(*) mapping may have important applications in MRI; however, information lost due to modeling could mask differences in parameters due to underlying tissue anatomy or physiology. The GAME model improves characterization of signal behavior in the prostate at 3T, and may increase the potential for determining correlates of fit parameters with biomarkers, for example of oxygenation status. C1 [Ciris, Pelin Aksit] Akdeniz Univ, Dept Biomed Engn, Antalya, Turkey. [Ciris, Pelin Aksit; Balasubramanian, Mukund; Tokuda, Junichi; Scalera, Jonathan; Penzkofer, Tobias; Fennessy, Fiona M.; Tempany-Afdhal, Clare M.; Tuncali, Kemal; Mulkern, Robert V.] Harvard Med Sch, Boston, MA USA. [Ciris, Pelin Aksit; Tokuda, Junichi; Scalera, Jonathan; Penzkofer, Tobias; Fennessy, Fiona M.; Tempany-Afdhal, Clare M.; Tuncali, Kemal] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Balasubramanian, Mukund; Mulkern, Robert V.] Boston Childrens Hosp, Boston, MA USA. [Seethamraju, Ravi T.] Siemens Healthcare, Boston, MA USA. [Penzkofer, Tobias] Charite Univ Med Berlin, Berlin, Germany. [Fennessy, Fiona M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ciris, PA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, MR Phys, 75 Francis St,Thorn 328, Boston, MA 02115 USA. EM pelin.aksit@gmail.com OI Ciris, Pelin/0000-0002-6405-2462 FU NIH [5R25CA089017-10, 5-EB015898 10, CA 1112888] FX This research was partially supported by NIH 5R25CA089017-10, 5-EB015898 10, and CA 1112888. NR 39 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD JUL PY 2016 VL 29 IS 7 BP 999 EP 1009 DI 10.1002/nbm.3556 PG 11 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DQ2JM UT WOS:000379028600016 PM 27241215 ER PT J AU Hivert, MF Rifas-Shiman, SL Gillman, MW Oken, E AF Hivert, Marie-France Rifas-Shiman, Sheryl L. Gillman, Matthew W. Oken, Emily TI Greater Early and Mid-Pregnancy Gestational Weight Gains are Associated with Excess Adiposity in Mid-Childhood SO OBESITY LA English DT Article ID HYPOTHALAMIC NEURONS; OFFSPRING OBESITY; OUTCOMES; WOMEN; RISK; LEPTIN; GROWTH; RATIO; WAIST; MASS AB Objective: It is unclear how specific periods of gestational weight gain (GWG) during pregnancy relate to childhood adiposity. The goal of this study was to assess the differential impact of GWG timing on childhood body composition. Methods: In 979 mother-child pairs from the pre-birth Project Viva cohort, trimester-specific GWG was calculated using clinically recorded weights. Outcomes included body mass index (BMI) z-score, dual X-ray absorptiometry fat mass index (kg/m(2)), and fat-free mass index (kg/m(2)) in mid-childhood. Linear regression models were used to assess associations of each trimester's GWG (per 0.2 kg/week) with childhood outcomes, adjusted for maternal prepregnancy BMI, sociodemographic variables, lifestyle, and GWG in prior trimester(s). Results: Mean (SD) first trimester GWG was 0.22 (0.22) kg/week, second trimester 0.49 (0.18) kg/week, and third trimester 0.47 (0.20) kg/week. Faster first trimester GWG was associated with higher BMI z-score (0.06 units [95% CI: 0.01-0.12] per 0.2 kg/week) and with higher adiposity according to all indices; associations were strongest in women with prepregnancy BMI >30 kg/m(2). Faster second trimester GWG was associated with higher BMI z-score (0.11 [0.04-0.18]), fat mass (fat mass index = 0.16 [0.02-0.31] kg/m(2)), and lean mass (fat-free mass index = 0.11 [0.01-0.22] kg/m(2)). Third trimester GWG was not associated with childhood adiposity. Conclusions: These results reinforce the importance of addressing appropriate GWG in early pregnancy. C1 [Hivert, Marie-France; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.; Oken, Emily] Harvard Med Sch, Obes Prevent Program, Dept Populat Med, Boston, MA 02115 USA. [Hivert, Marie-France; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.; Oken, Emily] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada. RP Hivert, MF (reprint author), Harvard Med Sch, Obes Prevent Program, Dept Populat Med, Boston, MA 02115 USA.; Hivert, MF (reprint author), Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA.; Hivert, MF (reprint author), Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA.; Hivert, MF (reprint author), Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada. EM mhivert@partners.org FU NIH [R37 HD34568]; [K24 HD069408]; [P30 DK092924] FX Project Viva is supported by NIH grant R37 HD34568. EO received funding from K24 HD069408 and P30 DK092924. NR 40 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2016 VL 24 IS 7 BP 1546 EP 1553 DI 10.1002/oby.21511 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DQ6GT UT WOS:000379303200020 PM 27345963 ER PT J AU Okello, S Nasasira, B Muiru, ANW Muyingo, A AF Okello, Samson Nasasira, Benson Muiru, Anthony Ndichu Wa Muyingo, Anthony TI Validity and Reliability of a Self-Reported Measure of Antihypertensive Medication Adherence in Uganda SO PLOS ONE LA English DT Article ID CARDIOVASCULAR RISK; PREDICTIVE-VALIDITY; HYPERTENSION; POPULATION; HEALTH; SCALE; CARE; SERVICES; VERSION; INCOME AB Background The Morisky Medication Adherence scale (MMAS-8) is a widely used self-reported measure of adherence to antihypertensive medications that has not been validated in hypertensive patients in sub-Saharan Africa. Methods We carried out a cross-sectional study to examine psychometric properties of a translated MMAS-8 (MMAS-U) in a tertiary care hypertension clinic in Uganda. We administered the MMAS-U to consecutively selected hypertensive adults and used principal factor analysis and Cronbach's alpha to determine its validity and internal consistency respectively. Then we randomly selected one-sixth of participants for a 2-week test-retest telephone interview. Lastly, we used ordinal logistic regression modeling to explore factors associated with levels of medication adherence. Results Of the 329 participants, 228 (69%) were females, median age of 55 years [Interquartile range (IQR) (46-66)], and median duration of hypertension of 4 years [IQR (2-8)]. The adherence levels were low (MMAS-U score <= 5) in 85%, moderate (MMAS-U score 6-7) in 12% and high (MMAS-U score >= 8) in 3%. The factor analysis of construct validity was good (overall Kaiser's measure of sampling adequacy for residuals of 0.72) and identified unidimensionality of MMAS-U. The internal consistency of MMAS-U was moderate (Cronbach alpha = 0.65), and test-retest reliability was low (weighted kappa = 0.36; 95% CI -0.01, 0.73). Age of 40 years or greater was associated with low medication adherence (p = 0.02) whereas a family member buying medication for participants (p = 0.02) and purchasing medication from a private clinic (p = 0.02) were associated with high adherence. Conclusion The Ugandan version of the MMAS-8 (MMAS-U) is a valid and reliable measure of adherence to antihypertensive medication among Ugandan outpatients receiving care at a public tertiary facility. Though the limited supply of medication affected adherence, this easy to use tool can be adapted to assess medication adherence among adults with hypertension in Uganda. C1 [Okello, Samson; Nasasira, Benson; Muyingo, Anthony] Mbarara Univ Sci & Technol, Dept Internal Med, Mbarara, Uganda. [Okello, Samson; Muiru, Anthony Ndichu Wa] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Muiru, Anthony Ndichu Wa] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Okello, S (reprint author), Mbarara Univ Sci & Technol, Dept Internal Med, Mbarara, Uganda.; Okello, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM okello.samson@must.ac.ug OI Okello, Samson/0000-0001-7377-6094 FU Bernard Lown Scholars in Cardiovascular Health Program at Harvard T.H. School of Public Health, Boston, MA, USA FX Author SO receives support from the Bernard Lown Scholars in Cardiovascular Health Program at Harvard T.H. School of Public Health, Boston, MA, USA. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 1 PY 2016 VL 11 IS 7 AR e0158499 DI 10.1371/journal.pone.0158499 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0TX UT WOS:000378914900037 PM 27367542 ER PT J AU Wolf, EJ Bovin, MJ Green, JD Mitchell, KS Stoop, TB Barretto, KM Jackson, CE Lee, LO Fang, SC Trachtenberg, F Rosen, RC Keane, TM Marx, BP AF Wolf, E. J. Bovin, M. J. Green, J. D. Mitchell, K. S. Stoop, T. B. Barretto, K. M. Jackson, C. E. Lee, L. O. Fang, S. C. Trachtenberg, F. Rosen, R. C. Keane, T. M. Marx, B. P. TI Longitudinal associations between post-traumatic stress disorder and metabolic syndrome severity SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Accelerated aging; cross-lagged design; longitudinal; metabolic syndrome; PTSD; veterans ID TYPE-2 DIABETES-MELLITUS; EARLY-LIFE ADVERSITY; BODY-MASS INDEX; CARDIOVASCULAR-DISEASE; RISK-FACTORS; CARDIOMETABOLIC RISK; PHYSICAL-ACTIVITY; OXIDATIVE STRESS; UNITED-STATES; METAANALYSIS AB Background. Post-traumatic stress disorder (PTSD) is associated with elevated risk for metabolic syndrome (MetS). However, the direction of this association is not yet established, as most prior studies employed cross-sectional designs. The primary goal of this study was to evaluate bidirectional associations between PTSD and MetS using a longitudinal design. Method. A total of 1355 male and female veterans of the conflicts in Iraq and Afghanistan underwent PTSD diagnostic assessments and their biometric profiles pertaining to MetS were extracted from the electronic medical record at two time points (spanning similar to 2.5 years, n = 971 at time 2). Results. The prevalence of MetS among veterans with PTSD was just under 40% at both time points and was significantly greater than that for veterans without PTSD; the prevalence of MetS among those with PTSD was also elevated relative to age-matched population estimates. Cross-lagged panel models revealed that PTSD severity predicted subsequent increases in MetS severity (beta = 0.08, p = 0.002), after controlling for initial MetS severity, but MetS did not predict later PTSD symptoms. Logistic regression results suggested that for every 10 PTSD symptoms endorsed at time 1, the odds of a subsequent MetS diagnosis increased by 56%. Conclusions. Results highlight the substantial cardiometabolic concerns of young veterans with PTSD and raise the possibility that PTSD may predispose individuals to accelerated aging, in part, manifested clinically as MetS. This demonstrates the need to identify those with PTSD at greatest risk for MetS and to develop interventions that improve both conditions. C1 [Wolf, E. J.; Bovin, M. J.; Mitchell, K. S.; Keane, T. M.; Marx, B. P.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Wolf, E. J.; Bovin, M. J.; Green, J. D.; Mitchell, K. S.; Jackson, C. E.; Lee, L. O.; Keane, T. M.; Marx, B. P.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Green, J. D.; Barretto, K. M.; Lee, L. O.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Stoop, T. B.] Boston VA Res Inst, Boston, MA USA. [Jackson, C. E.] VA Boston Healthcare Syst, Educ & Clin Ctr, Geriatr Res, Boston, MA USA. [Jackson, C. E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders, Boston, MA USA. [Fang, S. C.; Trachtenberg, F.; Rosen, R. C.] New England Res Inst, Watertown, MA USA. RP Wolf, EJ; Marx, BP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 2, 150 South Huntington Ave, Boston, MA 02130 USA. EM erika.wolf@va.gov; brian.marx@va.gov FU United States Department of Veterans Affairs, Clinical Sciences Research and Development Program; Department of Defense [W81XWH-08-2-0100, W81XWH-12-2-0117, W81XWH-10-2-0181, W81XWH-12-1-0532, W81XWH-14-2-0139, W81XWH-08-2-0102, W81XWH-12-2-0121]; National Institute of Mental Health [1R01MH095737-01A1, 5T32MH019836-16, K01MH093750]; Defense Advanced Research Programs Agency [N66001-11-C-4006]; Department of Veterans Affairs [591]; Consortium to Alleviate PTSD; National Institute on Aging [K08AG048221]; National Center for Advancing Translational Sciences [1UL1TR001430] FX This work was supported by a Career Development Award to Erika J. Wolf from the United States Department of Veterans Affairs, Clinical Sciences Research and Development Program. Brian Marx and Terence Keane were supported by funding from the Department of Defense (W81XWH-08-2-0100, W81XWH-12-2-0117). Dr. Marx was additionally supported by funding from the National Institute of Mental Health (1R01MH095737-01A1), Defense Advanced Research Programs Agency (N66001-11-C-4006), and Department of Defense (W81XWH-10-2-0181), and the Department of Veterans Affairs (Cooperative Studies Program no. 591). Dr. Keane was additionally supported by funding from the Consortium to Alleviate PTSD and National Institute of Mental Health (5T32MH019836-16). Raymond Rosen was supported by funding from the Department of Defense, (W81XWH-12-1-0532; W81XWH-14-2-0139; W81XWH-08-2-0102, and W81XWH-12-2-0121). Karen Mitchell's contribution was partly supported by funding from the National Institute of Mental Health (K01MH093750). Lewina Lee was supported by funding from the National Institute on Aging (K08AG048221) and the National Center for Advancing Translational Sciences (BU-CTSI Grant Number 1UL1TR001430). The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 65 TC 2 Z9 2 U1 4 U2 5 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 2016 VL 46 IS 10 BP 2215 EP 2226 DI 10.1017/S0033291716000817 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DQ4GV UT WOS:000379163000017 PM 27087657 ER PT J AU Bai, XY Oberley-Deegan, RE Bai, A Ovrutsky, AR Kinney, WH Weaver, M Zhang, G Honda, JR Chan, ED AF Bai, Xiyuan Oberley-Deegan, Rebecca E. Bai, An Ovrutsky, Alida R. Kinney, William H. Weaver, Michael Zhang, Gong Honda, Jennifer R. Chan, Edward D. TI Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection SO RESPIROLOGY LA English DT Article DE apoptosis; autophagy; curcumin; nuclear-factor kappa B; tuberculosis ID NF-KAPPA-B; MULTIDRUG-RESISTANT TUBERCULOSIS; NITRIC-OXIDE; IN-VIVO; APOPTOSIS; CANCER; ACTIVATION; PATHWAY; LIPOARABINOMANNAN; AUTOPHAGOSOME AB Background and objectiveWith the worldwide emergence of highly drug-resistant tuberculosis (TB), novel agents that have direct antimycobacterial effects or that enhance host immunity are urgently needed. Curcumin is a polyphenol responsible for the bright yellow-orange colour of turmeric, a spice derived from the root of the perennial herb Curcuma longa. Curcumin is a potent inducer of apoptosisan effector mechanism used by macrophages to kill intracellular Mycobacterium tuberculosis (MTB). MethodsAn in vitro human macrophage infection model was used to determine the effects of curcumin on MTB survival. ResultsWe found that curcumin enhanced the clearance of MTB in differentiated THP-1 human monocytes and in primary human alveolar macrophages. We also found that curcumin was an inducer of caspase-3-dependent apoptosis and autophagy. Curcumin mediated these anti-MTB cellular functions, in part, via inhibition of nuclear factor-kappa B (NFB) activation. ConclusionCurcumin protects against MTB infection in human macrophages. The host-protective role of curcumin against MTB in macrophages needs confirmation in an animal model; if validated, the immunomodulatory anti-TB effects of curcumin would be less prone to drug resistance development. The effects of curcumin (a polyphenol of tumeric) on Mycobacterium tuberculosis (MTB) infection using human macrophages were investigated in this study. Curcumin reduced the intracellular burden of MTB in infected macrophages through inhibition of NFB activation resulting in the induction of caspase-3-dependent apoptosis and autophagy. C1 [Bai, Xiyuan; Bai, An; Chan, Edward D.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [Bai, Xiyuan; Oberley-Deegan, Rebecca E.; Bai, An; Ovrutsky, Alida R.; Kinney, William H.; Weaver, Michael; Honda, Jennifer R.; Chan, Edward D.] Natl Jewish Hlth, Dept Med & Acad Affairs, Denver, CO USA. [Bai, Xiyuan; Ovrutsky, Alida R.; Kinney, William H.; Honda, Jennifer R.; Chan, Edward D.] Univ Colorado, Sch Med, Dept Med, Div Pulm Sci & Crit Care Med, Aurora, CO USA. [Oberley-Deegan, Rebecca E.] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE USA. [Zhang, Gong] Shaanxi Univ Chinese Med, Coll Pharm, Xianyang, Shaanxi, Peoples R China. RP Bai, XY (reprint author), Natl Jewish Hlth, D509 Neustadt Bldg,1400 Jackson St, Denver, CO 80206 USA. EM baix@njhealth.org NR 45 TC 0 Z9 0 U1 6 U2 14 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 2016 VL 21 IS 5 BP 951 EP 957 DI 10.1111/resp.12762 PG 7 WC Respiratory System SC Respiratory System GA DQ2VQ UT WOS:000379061900024 PM 27012592 ER PT J AU Dionigi, G Kim, HY Randolph, GW Wu, CW Sun, H Liu, XL Barczynski, M Chiang, FY AF Dionigi, Gianlorenzo Kim, Hoon Yub Randolph, Gregory W. Wu, Che-Wei Sun, Hui Liu, Xiaoli Barczynski, Marcin Chiang, Feng-Yu TI Prospective validation study of Cernea classification for predicting EMG alterations of the external branch of the superior laryngeal nerve SO SURGERY TODAY LA English DT Article DE Cernea classification; External branch of the superior laryngeal nerve; EBSLN; Intraoperative nerve monitoring; IONM; Nerve injury; Neural monitoring study group; INMSG ID VIDEO-ASSISTED THYROIDECTOMY; SURGICAL ANATOMY; SURGERY; IDENTIFICATION; RECURRENT; INJURY; NECK AB Purposes Cernea classification is applied to describe the external branch of the superior laryngeal nerve (EBSLN). Using intraoperative neural monitoring we evaluated whether or not this classification is useful for predicting which EBSLN subtype has an increased risk of injury. Methods An analysis of 400 EBSLN. The identification of EBSLN was achieved with both cricothyroid muscle twitch and the glottis evoked electromyography response. We defined S1 initial EBSLN stimulation at identification and S2 final nerve stimulation achieved in the most cranial aspect of the nerve exposed above the area of surgical dissection after superior artery ligation. Results The mean S1 amplitude acquired was 259+/67 (180-421), 321 +/79 (192-391), 371 +/38 (200-551) mu V, respectively, for type 1, 2A, 2B (p = 0.08). The S1 and S2 amplitudes were similar in type 1 (p = 0.3). The S1 and S2 determinations changed significantly in type 2A and 2B (p = 0.04 and 0.03). EBSLN which demonstrated a >25 % decreased amplitude in S2 increased significantly from Type 1 (4.9 %) to Type 2A (11.2 %) and 2B (18 %) (p = 0.01). None of type 1, 2.8 % type 2A and 3 % type 2B showed a loss of EBSLN conductivity. The latency determinations did not vary significantly for any parameter compared. Conclusions The Cernea classification was, therefore, found to predict the risk of EBSLN stress. We identified amplitude differences between S1 and S2 determinations in type 2A and 2B, thus confirming that surgical dissection in these subtypes is, therefore, extremely difficult to perform. C1 [Dionigi, Gianlorenzo] Univ Insubria Como Varese, Div Surg 1, Dept Surg Sci & Human Morphol, Res Ctr Endocrine Surg, Via Guicciardini 9, I-21100 Varese, Italy. [Kim, Hoon Yub] Korea Univ, Minimally Invas Surg & Robot Surg Ctr, Div Breast & Endocrine Surg, Dept Surg,KUMC Thyroid Ctr,Anam Hosp,Coll Med, 73 Inchon Ro, Seoul 136705, South Korea. [Randolph, Gregory W.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Thyroid & Parathyroid Endocrine Surg, Boston, MA USA. [Wu, Che-Wei; Chiang, Feng-Yu] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Otolaryngol Head & Neck Surg, Kaohsiung, Taiwan. [Sun, Hui; Liu, Xiaoli] Jilin Univ, China Japan Union Hosp, Jilin Prov Key Lab Surg Translat Med, Div Thyroid Surg, Changchun, Jilin Province, Peoples R China. [Barczynski, Marcin] Jagiellonian Univ, Chair & Dept Gen Surg 3, Coll Med, Krakow, Poland. RP Kim, HY (reprint author), Korea Univ, Minimally Invas Surg & Robot Surg Ctr, Div Breast & Endocrine Surg, Dept Surg,KUMC Thyroid Ctr,Anam Hosp,Coll Med, 73 Inchon Ro, Seoul 136705, South Korea. EM hoonyubkim@gmail.com OI dionigi, gianlorenzo/0000-0003-0864-6087; Wu, Che-Wei/0000-0003-1052-5348 NR 39 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-1291 EI 1436-2813 J9 SURG TODAY JI Surg. Today PD JUL PY 2016 VL 46 IS 7 BP 785 EP 791 DI 10.1007/s00595-015-1245-9 PG 7 WC Surgery SC Surgery GA DQ4QB UT WOS:000379187300005 PM 26362419 ER PT J AU Jones, JA AF Jones, Jeffrey A. TI Editorial Commentary: Understanding Marfan syndrome, or "how not to invent the light bulb" SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Editorial Material ID SMOOTH-MUSCLE-CELLS; II TYPE-1 RECEPTOR; AORTIC-ANEURYSM; BETA RECEPTOR; MOUSE MODEL; ACTIVATION; MUTATIONS; LOSARTAN; MICE; ALPHA-V-BETA-3 C1 [Jones, Jeffrey A.] Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg Res, Strom Thurmond Res Bldg, Charleston, SC 29425 USA. [Jones, Jeffrey A.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Strom Thurmond Res Bldg, Charleston, SC 29425 USA. RP Jones, JA (reprint author), Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg Res, Strom Thurmond Res Bldg, Charleston, SC 29425 USA.; Jones, JA (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Strom Thurmond Res Bldg, Charleston, SC 29425 USA. EM jonesja@musc.edu FU BLRD VA [I01 BX000904] NR 35 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD JUL PY 2016 VL 26 IS 5 BP 429 EP 432 DI 10.1016/j.tcm.2016.02.005 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP7FD UT WOS:000378663700006 PM 27013137 ER PT J AU Atkinson, W Catana, C Abramson, JS Arabasz, G McDermott, S Catalano, O Muse, V Blake, MA Barnes, J Shelly, M Hochberg, E Rosen, BR Guimaraes, AR AF Atkinson, Wendy Catana, Ciprian Abramson, Jeremy S. Arabasz, Grae McDermott, Shanaugh Catalano, Onofrio Muse, Victorine Blake, Michael A. Barnes, Jeffrey Shelly, Martin Hochberg, Ephraim Rosen, Bruce R. Guimaraes, Alexander R. TI Hybrid FDG-PET/MR compared to FDG-PET/CT in adult lymphoma patients SO ABDOMINAL RADIOLOGY LA English DT Article DE PET/MRI; FDG; Lymphoma; Diffusion weighted imaging; SUV ID APPARENT DIFFUSION-COEFFICIENT; POSITRON-EMISSION-TOMOGRAPHY; STANDARDIZED UPTAKE VALUES; NON-HODGKINS-LYMPHOMA; SQUAMOUS-CELL CARCINOMA; WHOLE-BODY PET/CT; WEIGHTED MRI; MALIGNANT-LYMPHOMA; ATTENUATION CORRECTION; CLINICAL-EXPERIENCE AB The goal of this study is to evaluate the diagnostic performance of simultaneous FDG-PET/MR including diffusion compared to FDG-PET/CT in patients with lymphoma. Eighteen patients with a confirmed diagnosis of non-Hodgkin's (NHL) or Hodgkin's lymphoma (HL) underwent an IRB-approved, single-injection/dual-imaging protocol consisting of a clinical FDG-PET/CT and subsequent FDG-PET/MR scan. PET images from both modalities were reconstructed iteratively. Attenuation correction was performed using low-dose CT data for PET/CT and Dixon-MR sequences for PET/MR. Diffusion-weighted imaging was performed. SUVmax was measured and compared between modalities and the apparent diffusion coefficient (ADC) using ROI analysis by an experienced radiologist using OsiriX. Strength of correlation between variables was measured using the Pearson correlation coefficient (r (p)). Of the 18 patients included in this study, 5 had HL and 13 had NHL. The median age was 51 +/- 14.8 years. Sixty-five FDG-avid lesions were identified. All FDG-avid lesions were visible with comparable contrast, and therefore initial and follow-up staging was identical between both examinations. SUVmax from FDG-PET/MR [(mean +/- sem) (21.3 +/- 2.07)] vs. FDG-PET/CT (mean 23.2 +/- 2.8) demonstrated a strongly positive correlation [r (s) = 0.95 (0.94, 0.99); p < 0.0001]. There was no correlation found between ADC(min) and SUVmax from FDG-PET/MR [r = 0.17(-0.07, 0.66); p = 0.09]. FDG-PET/MR offers an equivalent whole-body staging examination as compared with PET/CT with an improved radiation safety profile in lymphoma patients. Correlation of ADC to SUVmax was weak, understating their lack of equivalence, but not undermining their potential synergy and differing importance. C1 [Atkinson, Wendy; Catana, Ciprian; Arabasz, Grae; Catalano, Onofrio; Rosen, Bruce R.; Guimaraes, Alexander R.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Abramson, Jeremy S.; Barnes, Jeffrey; Hochberg, Ephraim] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. [Muse, Victorine] Massachusetts Gen Hosp, Dept Radiol, Div Thorac Radiol, Boston, MA 02114 USA. [McDermott, Shanaugh; Blake, Michael A.; Shelly, Martin; Guimaraes, Alexander R.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA 02114 USA. [Guimaraes, Alexander R.] Oregon Hlth & Sci Univ, Div Body Imaging, Dept Diagnost Radiol, 3181 SW Sam Jackson Pk Rd,Mail Code L340, Portland, OR 97239 USA. RP Guimaraes, AR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Guimaraes, AR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA 02114 USA.; Guimaraes, AR (reprint author), Oregon Hlth & Sci Univ, Div Body Imaging, Dept Diagnost Radiol, 3181 SW Sam Jackson Pk Rd,Mail Code L340, Portland, OR 97239 USA. EM guimaraa@ohsu.edu NR 56 TC 2 Z9 2 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2366-004X EI 2366-0058 J9 ABDOM RADIOL JI Abdom. Radiol. PD JUL PY 2016 VL 41 IS 7 BP 1338 EP 1348 DI 10.1007/s00261-016-0638-6 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8XR UT WOS:000378781800016 PM 27315095 ER PT J AU Leibovici, V Keuthen, NJ AF Leibovici, Vera Keuthen, Nancy J. TI SENSE OF TENSION BEFORE PICKING AND RELIEF DURING OR AFTER PICKING IN ISRAELI ADULTS SCREENING POSITIVE FOR EXCORIATION (SKIN PICKING) DISORDER SO ACTA DERMATO-VENEREOLOGICA LA English DT Meeting Abstract C1 Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACTA DERMATO-VENEREOLOGICA PI UPPSALA PA TRADGARDSGATAN 14, UPPSALA, SE-753 09, SWEDEN SN 0001-5555 EI 1651-2057 J9 ACTA DERM-VENEREOL JI Acta Derm.-Venereol. PD JUL PY 2016 VL 96 SU 217 MA PL26 BP 124 EP 124 PG 1 WC Dermatology SC Dermatology GA DQ0FJ UT WOS:000378873700052 ER PT J AU Sher, L AF Sher, L. TI Buprenorphine and the treatment of depression, anxiety, non-suicidal self-injury, and suicidality SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Letter C1 [Sher, L.] James J Peters Vet Adm Med Ctr, New York, NY USA. [Sher, L.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Sher, L (reprint author), James J Peters Vet Adm Med Ctr, New York, NY USA.; Sher, L (reprint author), Icahn Sch Med Mt Sinai, New York, NY 10029 USA. EM leo.sher@mssm.edu NR 5 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JUL PY 2016 VL 134 IS 1 BP 84 EP 85 DI 10.1111/acps.12577 PG 2 WC Psychiatry SC Psychiatry GA DP7UZ UT WOS:000378706000011 PM 27009622 ER PT J AU Denburg, A Galindo, CR Joffe, S AF Denburg, Avram Galindo, Carlos Rodriguez Joffe, Steven TI Trials Infrastructure as Good Old-Fashioned Health System Strengthening SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter ID MIDDLE-INCOME COUNTRIES; CLINICAL-TRIALS; CARE C1 [Denburg, Avram] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Denburg, Avram] McMaster Univ, Hamilton, ON L8S 4L8, Canada. [Galindo, Carlos Rodriguez] Dana Farber Canc Inst, Boston, MA 02115 USA. [Joffe, Steven] Univ Penn, Philadelphia, PA 19104 USA. RP Denburg, A (reprint author), Hosp Sick Children, Haematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM avram.denburg@sickkids.ca OI Denburg, Avram/0000-0003-0039-0742 NR 8 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUL PY 2016 VL 16 IS 7 BP W3 EP W5 DI 10.1080/15265161.2016.1180465 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DP5VS UT WOS:000378566900002 PM 27292865 ER PT J AU Lewiss, RE Adhikari, S Carmody, K Fields, JM Hunt, P Liteplo, AS Nagdev, A Raio, C Gaspari, R AF Lewiss, Resa E. Adhikari, Srikar Carmody, Kristin Fields, J. Matthew Hunt, Patrick Liteplo, Andrew S. Nagdev, Arun Raio, Christopher Gaspari, Romolo TI The Society of Clinical Ultrasound Fellowships: An innovation in the point of care ultrasound fellowship application process SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Letter C1 [Lewiss, Resa E.] Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO USA. [Adhikari, Srikar] Univ Arizona, Dept Emergency Med, Tucson, AZ USA. [Carmody, Kristin] NYU, Sch Med, Dept Emergency Med, New York, NY USA. [Fields, J. Matthew] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA. [Hunt, Patrick] Univ S Carolina, Dept Emergency Med, Columbia, SC 29208 USA. [Liteplo, Andrew S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Nagdev, Arun] Alameda Hlth Syst, Dept Emergency Med, Oakland, CA USA. [Raio, Christopher] Good Samaritan Hosp, Med Ctr, Dept Emergency Med, West Islip, NY USA. [Gaspari, Romolo] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA USA. RP Lewiss, RE (reprint author), Leprino Bldg,12401 East 17th Ave Box B215, Aurora, CO 80045 USA. EM Resa.Lewiss@ucdenver.edu OI Carmody, Kristin/0000-0003-1223-5280 NR 4 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JUL PY 2016 VL 34 IS 7 BP 1303 EP 1305 DI 10.1016/j.ajem.2016.03.070 PG 5 WC Emergency Medicine SC Emergency Medicine GA DP9HR UT WOS:000378807800023 PM 27131632 ER PT J AU Baltajian, K Bajracharya, S Salahuddin, S Berg, AH Geahchan, C Wenger, JB Thadhani, R Karumanchi, SA Rana, S AF Baltajian, Kedak Bajracharya, Surichhya Salahuddin, Saira Berg, Anders H. Geahchan, Carl Wenger, Julia B. Thadhani, Ravi Karumanchi, S. Ananth Rana, Sarosh TI Sequential plasma angiogenic factors levels in women with suspected preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE angiogenic factors; preeclampsia; sequential changes; adverse outcomes ID LATE-ONSET PREECLAMPSIA; HYPERTENSION; ENDOTHELIUM; ECLAMPSIA; OUTCOMES; REMOVAL AB BACKGROUND: Alterations in circulating angiogenic factors are associated with the diagnosis of preeclampsia and correlate with adverse perinatal outcomes during the third trimester. OBJECTIVE: Analysis of the sequential levels of plasma angiogenic factors among patients admitted for evaluation of preeclampsia. STUDY DESIGN: We performed an observational study among women with singleton pregnancies admitted to Beth Israel Deaconess Medical Center, Boston, Massachusetts, for evaluation of preeclampsia at less than 37 weeks of gestation. Plasma samples were collected on admission and daily for the first 3 days and then weekly until delivery. Doppler ultrasound was performed on admission (within 48 hours) and then weekly (within 24 hours of blood collection) to evaluate uteroplacental and umbilical blood flows. Maternal demographics, hospital course, mode of delivery, diagnosis of hypertensive disorder, adverse maternal outcomes (elevated liver function enzymes, low platelet count, pulmonary edema, cerebral hemorrhage, convulsion, acute renal insufficiency, or maternal death), and adverse fetal/neonatal outcomes (small for gestational age, abnormal umbilical artery Doppler, fetal death, and neonatal death) were recorded. Circulating angiogenic factors (soluble fms-like tyrosine kinase and placental growth factor were measured on automated platform in a single batch after delivery and in a blinded fashion. Data are presented as median (25th to 75th centile), mean, or proportions as appropriate. RESULTS: During the study period, data from 100 women were analyzed for the study, and 43 had adverse outcomes. Women with adverse outcomes had lower gestational age of delivery, higher systolic and diastolic blood pressures during hospitalization, and lower birthweight and placental weight (all P < .01). These patients had higher soluble fms-like tyrosine kinase and soluble fms-like tyrosine kinase/placental growth factor ratio on admission and continued to have an increase in levels throughout hospital course. The median (25th to 75th) soluble fms-like tyrosine kinase/placental growth factor ratio among patients with adverse outcomes was 205.9 (72.5, 453.1) versus 47.5 (9.7, 87.0) among women without adverse outcomes (P < .001). The median (25th to 75th) absolute change per day in soluble fms-like tyrosine kinase levels (pg/mL) was 491.0 pg/mL (120.3, 1587.2) among women with adverse outcomes versus 81.3 pg/mL (-177.9, 449.0) among women without adverse outcomes (P = .01). Similarly the absolute change per day for soluble fms-like tyrosine kinase/placental growth factor ratio was 15.1 (1.8, 58.1) versus 2.7 (-0.6, 8.3) between the two groups (P = .004). The mean (range) days from admission to delivery was 6 (0-35) among subjects with soluble fms-like tyrosine kinase/placental growth factor ratio >= 85 and 14 (0-39) below a ratio of 85 (P<.001). The positive predictive value for plasma soluble fms-like tyrosine kinase/placental growth factor ratio >= 85 at admission for indicated delivery within 2 weeks was 91% (83-99%). Admission plasma soluble fms-like tyrosine kinase/placental growth factor ratio positively correlated with pre-delivery uterine artery resistive index (r = 0.35; P = .004). CONCLUSION: Among women admitted for evaluation of preeclampsia, women at risk for adverse pregnancy outcomes have higher soluble fms-like tyrosine kinase/placental growth factor ratio on admission, which continued to rise until delivery. Women with high soluble fms-like tyrosine kinase/placental growth factor ratios delivered sooner than women with low soluble fms-like tyrosine kinase/placental growth factor levels. These data support the hypothesis that targeting angiogenic imbalance in preeclampsia may lead to prolongation of pregnancy. C1 [Baltajian, Kedak; Bajracharya, Surichhya; Salahuddin, Saira; Geahchan, Carl; Karumanchi, S. Ananth; Rana, Sarosh] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02215 USA. [Baltajian, Kedak; Bajracharya, Surichhya; Salahuddin, Saira; Berg, Anders H.; Geahchan, Carl; Wenger, Julia B.; Thadhani, Ravi; Karumanchi, S. Ananth; Rana, Sarosh] Harvard Univ, Sch Med, Boston, MA USA. [Berg, Anders H.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Wenger, Julia B.; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Rana, Sarosh] Univ Chicago, Dept Obstet & Gynecol, Maternal Fetal Med, Chicago, IL 60637 USA. RP Rana, S (reprint author), Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02215 USA.; Rana, S (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Rana, S (reprint author), Univ Chicago, Dept Obstet & Gynecol, Maternal Fetal Med, Chicago, IL 60637 USA. EM srana@bsd.uchicago.edu FU American Heart Association (AHA); K24 award from the NIH; Howard Hughes Medical Institute FX Supported by the American Heart Association (AHA) grant given to S.R. AHA had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. R.T. is supported by K24 award from the NIH; S.A.K was supported by Howard Hughes Medical Institute. NR 26 TC 0 Z9 1 U1 7 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2016 VL 215 IS 1 AR 89.e1-e10 DI 10.1016/j.ajog.2016.01.168 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DP6SV UT WOS:000378630000020 PM 26827880 ER PT J AU Strittmatter, K Pomeroy, H Marneros, AG AF Strittmatter, Karin Pomeroy, Hayley Marneros, Alexander G. TI Targeting Platelet-Derived Growth Factor Receptor beta(+) Scaffold Formation Inhibits Choroidal Neovascularization SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID VEGF-A; MACULAR DEGENERATION; THERAPY; MICE AB Neovascular age-related macular degeneration is among the most common causes of irreversible blindness and manifests with choroidal neovascularization (CNV). Anti-vascular endothelial growth factor-A therapies are only partially effective and their chronic administration may impair functions of the choriocapillaris and retina. Thus, novel therapeutic targets are needed urgently. We have observed in a laser-induced model of CNV that a platelet-derived growth factor receptor beta positive (PDGFR beta(+)) scaffold is formed before infiltration of neovessels into this scaffold to form CNV lesions, and that this scaffold limits the extent of neovascularization. Based on these observations we hypothesized that ablation of proliferating PDGFR beta(+) cells to prevent the formation of this scaffold might inhibit CNV growth and present a novel therapeutic approach for neovascular age-related macular degeneration. To test this hypothesis we targeted proliferating PDGFR beta(+) cells through independent distinct approaches after laser injury: i) by using an inducible genetic model to inhibit specifically proliferating PDGFR beta cells, ii) by treating mice with a neutralizing anti-PDGFR beta antibody, iii) by administering an anti-PDGF-AB/BB aptamer, and iv) by using small chemical inhibitor approaches. The results show that therapeutic targeting of proliferating PDGFR beta(+) cells potently inhibits the formation of the pericyte-like scaffold, with concomitant attenuation of CNV. Moreover, we show that early inhibition of PDGFR beta cell proliferation before neovessel formation is sufficient to inhibit scaffold formation and neovascularization. C1 [Marneros, Alexander G.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, CNY 149,Rm 3-216,13th St, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Marneros, AG (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, CNY 149,Rm 3-216,13th St, Charlestown, MA 02129 USA. EM amarneros@mgh.harvard.edu FU Ophthotech Corporation FX Supported by a grant from Ophthotech Corporation. NR 15 TC 2 Z9 2 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2016 VL 186 IS 7 BP 1890 EP 1899 DI 10.1016/j.ajpath.2016.02.018 PG 10 WC Pathology SC Pathology GA DP8OV UT WOS:000378758400016 PM 27338108 ER PT J AU Greenwald, SH Charette, JR Staniszewska, M Shi, LY Brown, SDM Stone, L Liu, Q Hicks, WL Collin, GB Bowl, MR Krebs, MP Nishina, PM Pierce, EA AF Greenwald, Scott H. Charette, Jeremy R. Staniszewska, Magdalena Shi, Lan Ying Brown, Steve D. M. Stone, Lisa Liu, Qin Hicks, Wanda L. Collin, Gayle B. Bowl, Michael R. Krebs, Mark P. Nishina, Patsy M. Pierce, Eric A. TI Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID PUPILLARY LIGHT RESPONSES; APOPTOSIS-INDUCING FACTOR; GENE-THERAPY; WALLERIAN DEGENERATION; RETINAL DEGENERATION; MONONUCLEOTIDE ADENYLYLTRANSFERASE; CONE ELECTRORETINOGRAM; KNOCKOUT MICE; CELL-DEATH; MELANOPSIN AB The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options. To this end, we identified two separate N-ethyl-N-nitrosourea-generated mouse lines that harbor either a p.V9M or a p.D243G mutation. Both mouse models recapitulate key aspects of the human disease and confirm the pathogenicity of mutant NMNAT1. Homozygous Nmnat1 mutant mice develop a rapidly progressing chorioretinal disease that begins with photoreceptor degeneration and includes attenuation of the retinal vasculature, optic atrophy, and retinal pigment epithelium Loss. Retinal function deteriorates in both mouse lines, and, in the more rapidly progressing homozygous Nmnat1(V9M) mutant mice, the electroretinogram becomes undetectable and the pupillary light response weakens. These mouse models offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis, evaluating potential therapies for NMNAT1-Leber congenital amaurosis, and conducting in situ studies on NMNAT1 function and NAD+ metabolism. C1 [Greenwald, Scott H.; Staniszewska, Magdalena; Liu, Qin; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Ocular Genom Inst, Sch Med,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. [Charette, Jeremy R.; Shi, Lan Ying; Stone, Lisa; Hicks, Wanda L.; Collin, Gayle B.; Krebs, Mark P.; Nishina, Patsy M.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Brown, Steve D. M.; Bowl, Michael R.] MRC, Mammalian Genet Unit, Harwell Campus, London W1N 4AL, Oxon, England. RP Pierce, EA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Ocular Genom Inst, Sch Med,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM eric_pierce@meei.harvard.edu OI Krebs, Mark/0000-0001-9017-6066; Pierce, Eric/0000-0002-2354-4102 FU NIH/National Eye Institute [EY012910, 5T32 EY-007145-16, EY016501, P30 EY003790, P30 EY014104]; Foundation for Retinal Research/Gavin R. Stevens Foundation; Fight for Sight [PD15001]; NIH/National Cancer Institute [CA34196] FX Supported by NIH/National Eye Institute grants EY012910 (E.A.P.), 5T32 EY-007145-16 (S.H.G.), EY016501 (P.M.N.), P30 EY003790 (Schepens Ophthalmology Core), P30 EY014104 (Massachusetts Eye and Ear Infirmary Ophthalmology Core); the Foundation for Retinal Research/Gavin R. Stevens Foundation (E.A.P.); Fight for Sight (PD15001; S.H.G.); and NIH/National Cancer Institute grant CA34196 (The Jackson Laboratory). NR 80 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 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2016 VL 186 IS 7 BP 1925 EP 1938 DI 10.1016/j.ajpath.2016.03.013 PG 14 WC Pathology SC Pathology GA DP8OV UT WOS:000378758400019 PM 27207593 ER PT J AU Ho, JE Gao, W Levy, D Santhanakrishnan, R Araki, T Rosas, IO Hatabu, H Latourelle, JC Nishino, M Dupuis, J Washko, GR O'Connor, GT Hunninghake, GM AF Ho, Jennifer E. Gao, Wei Levy, Daniel Santhanakrishnan, Rajalakshmi Araki, Tetsuro Rosas, Ivan O. Hatabu, Hiroto Latourelle, Jeanne C. Nishino, Mizuki Dupuis, Josee Washko, George R. O'Connor, George T. Hunninghake, Gary M. TI Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE biomarker; epidemiology; interstitial lung disease; pulmonary fibrosis ID IDIOPATHIC PULMONARY-FIBROSIS; HEART-FAILURE; PROGNOSTIC VALUE; INFLAMMATION; EXPRESSION; PNEUMONIA; MACROPHAGES; COMMUNITY; PROTEIN; MARKER AB Rationale: Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis. Objectives: We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis. Methods: We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal-3 assessment using plasma samples and pulmonary function testing between 1995 and 1998. Of this sample, 1,148 underwent subsequent volumetric chest computed tomography. Measurements and Main Results: Higher Gal-3 concentrations were associated with lower lung volumes (1.4% decrease in percentage of predicted FEV1 per 1 SD increase in log Gal-3; 95% confidence interval [CI], 0.8-2.0%; P < 0.001; 1.2% decrease in percentage of predicted FVC; 95% CI, 0.6-1.8%; P < 0.001) and decreased diffusing capacity of the lung for carbon monoxide (2.1% decrease; 95% CI, 1.3-2.9%; P < 0.001). These associations remained significant after multivariable adjustment (P <= 0.008 for all). Compared with the lowest quartile, participants in the highest Gal-3 quartile were more than twice as likely to have interstitial lung abnormalities visualized by computed tomography (multivariable-adjusted odds ratio, 2.67; 95% CI, 1.49-4.76; P < 0.001). Conclusions: Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange. These findings suggest a potential role for Gal-3 in early stages of pulmonary fibrosis. C1 [Ho, Jennifer E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. [Ho, Jennifer E.; Levy, Daniel; Dupuis, Josee; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Gao, Wei; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Santhanakrishnan, Rajalakshmi] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Latourelle, Jeanne C.; O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. [Latourelle, Jeanne C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Araki, Tetsuro; Hatabu, Hiroto; Nishino, Mizuki; Washko, George R.; Hunninghake, Gary M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Pulm Funct Imaging, Boston, MA 02115 USA. [Araki, Tetsuro; Hatabu, Hiroto; Nishino, Mizuki] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Rosas, Ivan O.; Washko, George R.; Hunninghake, Gary M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Pulm & Crit Care Div, Boston, MA 02115 USA. RP Ho, JE (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, CPZN 185 Cambridge St 3224, Boston, MA 02114 USA. EM jho1@mgh.harvard.edu FU NHLBI's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; National Institutes of Health [NIH] [R01 HL111024, K23-HL116780, 5K23-CA157631, R01 HL107246, R01 HL116473, R01 HL122464, P01 HL114501]; Boston University School of Medicine, Department of Medicine Career Investment Award FX This work was partially supported by the NHLBI's Framingham Heart Study (contract numbers N01-HC-25195 and HHSN268201500001I, and National Institutes of Health [NIH] grant R01 HL111024); NIH grants K23-HL116780 (J.E.H.), 5K23-CA157631 (M.N.), R01 HL107246 (G.R.W.), R01 HL116473 (G.R.W.), R01 HL122464 (G.R.W.), P01 HL114501 (I.O.R. and G.M.H.), and R01 HL111024 (G.M.H.); and a Boston University School of Medicine, Department of Medicine Career Investment Award (J.E.H.). Galectin-3 assays were provided by BG Medicine (Waltham, MA). NR 40 TC 5 Z9 5 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2016 VL 194 IS 1 BP 77 EP 83 DI 10.1164/rccm.201509-1753OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DQ1RW UT WOS:000378979100015 PM 26771117 ER PT J AU Howard, SAH Krajewski, KM Jagannathan, JP Braschi-Amirfarzan, M Tirumani, SH Shinagare, AB Ramaiya, NH AF Howard, Stephanie A. Holler Krajewski, Katherine M. Jagannathan, Jyothi P. Braschi-Amirfarzan, Marta Tirumani, Sree H. Shinagare, Atul B. Ramaiya, Nikhil H. TI A New Look at Toxicity in the Era of Precision Oncology: Imaging Findings, Their Relationship With Tumor Response, and Effect on Metastasectomy SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE adverse events; biomarker; metastasectomy; toxicity ID METASTATIC COLORECTAL-CANCER; RENAL-CELL CARCINOMA; LONG-TERM SURVIVAL; LIVER RESECTION; HEPATIC RESECTION; TARGETED THERAPY; ADVERSE EVENTS; RADIOLOGIC MANIFESTATIONS; HEPATOCELLULAR-CARCINOMA; BEVACIZUMAB TREATMENT AB OBJECTIVE. As cancer care becomes increasingly personalized and patients with metastatic disease live longer, oncologists' approach to drug toxicity is also evolving. CONCLUSION. This article aims to broaden the radiologist's understanding of imaging-evident toxicity by describing how oncologists grade toxicity, exploring toxicity as a biomarker of treatment response, discussing the effect of toxicity in patients who are candidates for metastasectomy, and illustrating how combining drugs of varying classes amplifies toxicity. C1 [Howard, Stephanie A. Holler; Krajewski, Katherine M.; Jagannathan, Jyothi P.; Braschi-Amirfarzan, Marta; Tirumani, Sree H.; Shinagare, Atul B.; Ramaiya, Nikhil H.] Dana Farber Canc Inst, Dept Radiol, 450 Brookline Ave, Boston, MA 02115 USA. [Howard, Stephanie A. Holler; Krajewski, Katherine M.; Jagannathan, Jyothi P.; Braschi-Amirfarzan, Marta; Tirumani, Sree H.; Shinagare, Atul B.; Ramaiya, Nikhil H.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Howard, SAH (reprint author), Dana Farber Canc Inst, Dept Radiol, 450 Brookline Ave, Boston, MA 02115 USA.; Howard, SAH (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM sahoward@partners.org NR 66 TC 1 Z9 1 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2016 VL 207 IS 1 BP 4 EP 14 DI 10.2214/AJR.15.15480 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP7DE UT WOS:000378658500009 PM 27065346 ER PT J AU Chesebro, AL Chikarmane, SA Gombos, EC Giardino, AA AF Chesebro, Allyson L. Chikarmane, Sona A. Gombos, Eva C. Giardino, Angela A. TI Radiation-Associated Angiosarcoma of the Breast: What the Radiologist Needs to Know SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE angiosarcoma; breast; radiation ID CUTANEOUS ANGIOSARCOMA; IMAGING FINDINGS; SECONDARY ANGIOSARCOMA; LOCAL EXCISION; POOR SURVIVAL; CANCER; RADIOTHERAPY; THERAPY; RISK; CARCINOMA AB OBJECTIVE. The purpose of this article is to describe the diagnosis, treatment, and follow-up of radiation-associated angiosarcoma (RAS) of the breast. CONCLUSION. Radiologists play an important role in the diagnosis of RAS, which may initially present clinically as erythema, ecchymosis, or skin thickening. Conventional imaging with mammography and ultrasound is less sensitive than MRI for the diagnosis of RAS. Follow-up CT is important to monitor treatment response. C1 [Chesebro, Allyson L.; Chikarmane, Sona A.; Gombos, Eva C.; Giardino, Angela A.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Chesebro, Allyson L.; Chikarmane, Sona A.; Gombos, Eva C.; Giardino, Angela A.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. RP Chesebro, AL (reprint author), Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA.; Chesebro, AL (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM allyson.chesebro@gmail.com NR 42 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2016 VL 207 IS 1 BP 217 EP 225 DI 10.2214/AJR.15.15888 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP7DE UT WOS:000378658500036 PM 27099969 ER PT J AU Johnson, SD Levingston, C Young, MRI AF Johnson, Sara D. Levingston, Corinne Young, M. Rita I. TI Premalignant Oral Lesion Cells Elicit Increased Cytokine Production and Activation of T-cells SO ANTICANCER RESEARCH LA English DT Article DE head and neck cancer; premalignant oral lesions; cytokines; T cell activation ID UPPER AERODIGESTIVE TRACT; NECK-CANCER; HEAD; CARCINOMA; MECHANISMS; IL-6; CARCINOGENESIS; PROGRESSION; DISEASE; CAVITY AB Background: Head and neck squamous cell carcinomas (HNSCC) are known to evade the host immune response. How premalignant oral lesions modulate the immune response, however, has yet to be elucidated. Materials and Methods: A mouse model of oral carcinogenesis was used to determine how mediators from premalignant oral lesion cells vs. HNSCC cells impact on immune cytokine production and activation. Results: Media conditioned by premalignant lesion cells elicited an increased production of T cell-associated cytokines and proinflammatory mediators from cervical lymph node cells compared to media conditioned by HNSCC cells or media alone. In the presence of premalignant lesion cell-conditioned media, CD4(+) T cell expression of the IL-2 receptor CD25 and CD8(+) T cell expression of the activation marker CD69 was greater, compared to what was induced in HNSCC cell-conditioned media or media alone. Conclusion: Premalignant lesion cells promote a proinflammatory environment and induce immune changes before HNSCC tumors are established. C1 [Johnson, Sara D.; Levingston, Corinne; Young, M. Rita I.] Res Serv 151 Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Johnson, Sara D.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Johnson, Sara D.; Young, M. Rita I.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Young, M. Rita I.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Ralph H Johnson VA Med Ctr, Res Serv 151, Charleston, SC 29401 USA. EM rita.young@va.gov FU Clinical Sciences Research and Development Program of the Department of Veterans Affairs [I01-CX000851]; National Institutes of Health [RO1-CA128837] FX This work was supported by the Clinical Sciences Research and Development Program (I01-CX000851) of the Department of Veterans Affairs and by grants from the National Institutes of Health (RO1-CA128837) (MRIY). NR 39 TC 1 Z9 1 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JUL PY 2016 VL 36 IS 7 BP 3261 EP 3270 PG 10 WC Oncology SC Oncology GA DQ0DC UT WOS:000378867600004 PM 27354582 ER PT J AU Battista, MC Boutin, M Venne, P Blais, L Berard, A Lacroix, M Patenaude, J Guillemette, L Cossette, B Hivert, MF Auray-Blais, C AF Battista, Marie-Claude Boutin, Michel Venne, Philippe Blais, Lucie Berard, Anick Lacroix, Marilyn Patenaude, Julie Guillemette, Laetitia Cossette, Benoit Hivert, Marie-France Auray-Blais, Christiane TI Maternal inhaled fluticasone propionate intake during pregnancy is detected in neonatal cord blood SO BIOANALYSIS LA English DT Article DE asthma; cord blood; fluticasone propionate; pregnancy; UPLC-MS/MS ID TANDEM MASS-SPECTROMETRY; BUDESONIDE FOLLOWING INHALATION; DRY-POWDER INHALERS; FABRY-DISEASE; LC-MS/MS; INTRANASAL CORTICOSTEROIDS; PLASMA-CONCENTRATIONS; MULTIPLEX ANALYSIS; ASTHMA; SALMETEROL AB Background: Despite recommendations to use inhaled corticosteroids as treatment to control asthma during pregnancy, it is unknown whether inhaled fluticasone propionate (FP) reaches the fetus. Results & methodology: We collected maternal blood on the morning following delivery. FP was detected by ultra-performance LC-MS/MS (UPLC-MS/MS) in 9/17 asthmatic women using FP. Delay between last FP inhalation and maternal blood sampling ranged between 3 and 33 h and FP was detected in a range of 1.572-46.440 pg/ml. Among the nine offspring of these FP users, FP was detected in five cord blood samples. Delay between last predelivery FP inhalation and cord blood sampling ranged from 4 to 20 h and FP was detected in a range of 0.423-4.510 pg/ml. Conclusion: Our findings demonstrate placental passage of inhaled FP. C1 [Battista, Marie-Claude; Lacroix, Marilyn; Patenaude, Julie; Guillemette, Laetitia; Hivert, Marie-France] Univ Sherbrooke, Div Endocrinol, Dept Med, Fac Med & Hlth Sci, Sherbrooke, PQ J1K 2R1, Canada. [Boutin, Michel; Venne, Philippe; Auray-Blais, Christiane] Univ Sherbrooke, Dept Pediat, Fac Med & Hlth Sci, Div Med Genet, Sherbrooke, PQ J1K 2R1, Canada. [Blais, Lucie; Cossette, Benoit; Hivert, Marie-France; Auray-Blais, Christiane] CHU Sherbrooke, Ctr Rech, Sherbrooke, PQ J1H 5N4, Canada. [Blais, Lucie; Berard, Anick; Cossette, Benoit] Univ Montreal, Fac Pharm, Quebec City, PQ, Canada. [Blais, Lucie] Hop Sacre Coeur Montreal, Res Ctr, Quebec City, PQ, Canada. [Berard, Anick] CHU Ste Justine, Res Ctr, Montreal, PQ, Canada. [Cossette, Benoit] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Pharm, Sherbrooke, PQ J1K 2R1, Canada. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hivert, MF (reprint author), Univ Sherbrooke, Div Endocrinol, Dept Med, Fac Med & Hlth Sci, Sherbrooke, PQ J1K 2R1, Canada.; Auray-Blais, C (reprint author), Univ Sherbrooke, Dept Pediat, Fac Med & Hlth Sci, Div Med Genet, Sherbrooke, PQ J1K 2R1, Canada.; Hivert, MF; Auray-Blais, C (reprint author), CHU Sherbrooke, Ctr Rech, Sherbrooke, PQ J1H 5N4, Canada.; Hivert, MF (reprint author), Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA.; Hivert, MF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM marie-france_hivert@harvardpilgrim.org; christiane.auray-blais@usherbrooke.ca FU 'Fonds de Recherche du Quebec - Sante' (FRQS); Le Reseau Quebecois de Recherche sur les Medicaments FX This study was conducted at the CR-CHUS which is a 'Fonds de Recherche du Quebec - Sante' (FRQS) supported research center. This study was supported by 'Le Reseau Quebecois de Recherche sur les Medicaments.' A Berard holds a "Chaire FRQ-S" on Medications and Pregnancy. 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 37 TC 0 Z9 0 U1 3 U2 3 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PD JUL PY 2016 VL 8 IS 14 BP 1441 EP 1450 DI 10.4155/bio-2016-0065 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DP9EV UT WOS:000378800400003 ER PT J AU Flowers, CR Costa, LJ Pasquini, MC Le-Rademacher, J Lill, M Shore, TB Vaughan, W Craig, M Freytes, CO Shea, TC Horwitz, ME Fay, JW Mineishi, S Rondelli, D Mason, J Braunschweig, I Ai, WY Yeh, RF Rodriguez, TE Flinn, I Comeau, T Yeager, AM Pulsipher, MA Bence-Bruckler, I Laneuyille, P Bierman, P Chen, AI Kato, K Wang, YL Xu, C Smith, AJ Waller, EK AF Flowers, Christopher R. Costa, Luciano J. Pasquini, Marcelo C. Le-Rademacher, Jennifer Lill, Michael Shore, Tsiporah B. Vaughan, William Craig, Michael Freytes, Cesar O. Shea, Thomas C. Horwitz, Mitchell E. Fay, Joseph W. Mineishi, Shin Rondelli, Damiano Mason, James Braunschweig, Ira Ai, Weiyun Yeh, Rosa F. Rodriguez, Tulio E. Flinn, Ian Comeau, Terrance Yeager, Andrew M. Pulsipher, Michael A. Bence-Bruckler, Isabelle Laneuyille, Pierre Bierman, Philip Chen, Andy I. Kato, Kazunobu Wang, Yanlin Xu, Cong Smith, Angela J. Waller, Edmund K. TI Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Non-Hodgkin lymphoma; Hodgkin lymphoma; Busulfan; Autologous stem cell transplantation; Stem cell transplantation; Lymphoma; Chemotherapy ID HIGH-DOSE CHEMOTHERAPY; NON-HODGKINS-LYMPHOMA; BONE-MARROW-TRANSPLANTATION; DAILY INTRAVENOUS BUSULFAN; HIGH-RISK PATIENTS; DAILY IV BUSULFAN; PREPARATIVE REGIMENS; AGGRESSIVE LYMPHOMA; BEAM CHEMOTHERAPY; RANDOMIZED-TRIAL AB Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended, due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients <= 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (Ma; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients <= 65 years but produced worse PFS in HL patients when compared with BEAM. (C) 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. C1 [Flowers, Christopher R.; Waller, Edmund K.] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Div BMT, 1365B Clifton Rd,Suite B5119, Atlanta, GA 30322 USA. [Costa, Luciano J.] Med Univ S Carolina, Charleston, SC 29425 USA. [Pasquini, Marcelo C.; Le-Rademacher, Jennifer] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Lill, Michael] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Shore, Tsiporah B.] New York Hosp, Weill Cornell Med Ctr Hematol Oncol, New York, NY 10021 USA. [Vaughan, William] Univ Alabaman Birmingham, Bone Marrow Transplantat Program, Birmingham, AL USA. [Craig, Michael] W Virginia Univ, Hlth Sci Ctr, Morgantown, WV 26506 USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Shea, Thomas C.] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. [Horwitz, Mitchell E.] Duke Univ, Med Ctr, Dept Med, Adult Stem Cell Transplant Program,Div Cellular T, Durham, NC 27710 USA. [Fay, Joseph W.] Baylor Univ, Med Ctr, Dallas, TX USA. [Mineishi, Shin] Univ Michigan, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Rondelli, Damiano] Univ Illinois, Dept Med, Hematol Oncol Sect, Chicago, IL USA. [Mason, James] Scripps Clin, La Jolla, CA USA. [Braunschweig, Ira] Montefiore Med Ctr, Dept Oncol, 111 E 210Th St, Bronx, NY 10467 USA. [Ai, Weiyun] Univ Calif San Francisco, Med, San Francisco, CA 94143 USA. [Yeh, Rosa F.] Seattle Canc Care Alliance, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Rodriguez, Tulio E.] Loyola Univ Chicago, Cardinal Bernardin Canc Ctr, Maywood, IL USA. [Flinn, Ian] Sarah Cannon Res Inst, Nashville, TN USA. [Comeau, Terrance] New Brunswick Stem Cell Transplant Program, St John, NB, Canada. [Yeager, Andrew M.] Univ Arizona, Ctr Canc, Blood & Marrow Transplantat Program, Tucson, AZ USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Keck Sch Med, Div Hematol Oncol & Blood & Marrow Transplant, Los Angeles, CA 90027 USA. [Pulsipher, Michael A.] Univ So Calif, Los Angeles, CA USA. [Bence-Bruckler, Isabelle] Univ Ottawa, Ottawa Hosp, Ottawa, ON, Canada. [Laneuyille, Pierre] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Montreal, PQ, Canada. [Bierman, Philip] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Chen, Andy I.] Oregon Hlth & Sci Univ, Ctr Hematol Malignancies, Portland, OR 97201 USA. [Kato, Kazunobu; Wang, Yanlin; Xu, Cong; Smith, Angela J.] Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ USA. [Costa, Luciano J.; Mineishi, Shin] Univ Alabama Birmingham, Bone Marrow Transplantat Program, Birmingham, AL USA. [Le-Rademacher, Jennifer] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Kato, Kazunobu] Bristol Myers Squibb, Princeton, NJ USA. RP Waller, EK (reprint author), Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Div BMT, 1365B Clifton Rd,Suite B5119, Atlanta, GA 30322 USA.; Waller, EK (reprint author), Emory Univ, Winship Canc Inst, 1365B Clifton Rd,Suite B5119, Atlanta, GA 30322 USA. EM ewaller@emory.edu RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 FU Otsuka Pharmaceutical Development & Commercialization, Inc. FX Otsuka Pharmaceutical Development & Commercialization, Inc. sponsored this study and provided the i.v. Bu for the analyses. NR 51 TC 3 Z9 3 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2016 VL 22 IS 7 BP 1197 EP 1205 DI 10.1016/j.bbmt.2016.03.018 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DP4JR UT WOS:000378462700008 PM 27040394 ER PT J AU Rowe, RG Guo, DJ Lee, M Margossian, S London, WB Lehmann, L AF Rowe, R. Grant Guo, Dongjing Lee, Michelle Margossian, Steven London, Wendy B. Lehmann, Leslie TI Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Risk Factors for Primary Infection and Cases of Recurrent and Late Infection at a Single Center SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Cytomegalovirus; Umbilical cord transplant; Graft-versus host disease ID BONE-MARROW-TRANSPLANTATION; CORD BLOOD TRANSPLANTATION; PREEMPTIVE THERAPY; HOST-DISEASE; CMV REACTIVATION; GANCICLOVIR PROPHYLAXIS; REDUCED-INTENSITY; ACUTE GRAFT; RECIPIENTS; DONOR AB Cytomegalovirus (CMV) infection is a significant source of morbidity and mortality in allogeneic stem cell transplantation (SCT). We identified a cohort of 91 pediatric SCT patients at risk (defined as either donor and/or recipient seropositivity) for CMV infection at our institution. We retrospectively categorized at-risk SCT recipients as those who (1) were at risk of CMV infection in the post-SCT period, (2) had documented CMV infection before SCT, (3) experienced recurrence of post-SCT CMV viremia, or (4) experienced late post-SCT CMV viremia; categories were not mutually exclusive. We analyzed the impact of SCT-related factors on incidence of CMV infection and outcome, and we described the outcome of each of these cohorts. In univariate analysis, recipient CMV seropositivity, use of umbilical cord blood graft, and acute graft-versus-host disease (GVHD) predicted post-SCT CMV viremia, and the effects of acute GVHD (odds ratio, 4.018; 95% confidence interval, 1.032 to 15.643) and CMV seropositivity (odds ratio, 16.525; 95% confidence interval, 2.041 to 133.803) were confirmed in multivariate analysis. Patients with recurrence of post-SCT CMV viremia had a 50% all-cause mortality rate, compared with 12% in all 91 patients. Patients with pre-SCT CMV infection had a high incidence of post-SCT CMV infection but could successfully undergo SCT with antiviral prophylaxis and pre-emptive CMV treatment. All patients with late CMV infection had prior GVHD. Theses findings identify risk factors for post-SCT CMV infection and provide novel descriptions of childhood SCT recipients with pre-SCT, recurrent, and late CMV infection, which may contribute to risk stratification strategies for CMV at-risk patients in pediatric allogeneic SCT. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Rowe, R. Grant; Lee, Michelle; Margossian, Steven; London, Wendy B.; Lehmann, Leslie] Dana Farber Canc Inst, Dana Farber Boston Childrens Canc & Blood Disorde, Stem Cell Transplantat Program, 450 Brookline Ave, Boston, MA 02215 USA. [Rowe, R. Grant; Guo, Dongjing; Lee, Michelle; Margossian, Steven; London, Wendy B.; Lehmann, Leslie] Boston Childrens Hosp, Boston, MA USA. [Lee, Michelle; Margossian, Steven; London, Wendy B.] Harvard Univ, Sch Med, Boston, MA USA. RP Lehmann, L (reprint author), Dana Farber Canc Inst, Dana Farber Boston Childrens Canc & Blood Disorde, Stem Cell Transplantat Program, 450 Brookline Ave, Boston, MA 02215 USA. EM leslie_lehmann@dfci.harvard.edu FU Natalia Fund at the Dana-Farber Cancer Institute FX This research was supported by the Natalia Fund at the Dana-Farber Cancer Institute. NR 34 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2016 VL 22 IS 7 BP 1275 EP 1283 DI 10.1016/j.bbmt.2016.04.004 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DP4JR UT WOS:000378462700019 PM 27090959 ER PT J AU Loggers, ET LeBlanc, TW El-Jawahri', A Fihn, J Bumpus, M David, J Horak, P Lee, SJ AF Loggers, Elizabeth T. LeBlanc, Thomas W. El-Jawahri', Areej Fihn, Judy Bumpus, Molly David, Jodie Horak, Petr Lee, Stephanie J. TI Pretransplantation Supportive and Palliative Care Consultation for High-Risk Hematopoietic Cell Transplantation Patients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Palliative care; Hematopoietic cell transplantation ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; HEMATOLOGIC MALIGNANCIES; FUNCTIONAL ASSESSMENT; SYMPTOM BURDEN; RETROSPECTIVE COHORT; CLINICAL ONCOLOGY; AMERICAN SOCIETY; CANCER-PATIENTS; CHRONIC ILLNESS AB Early palliative care (EPC) for patients with metastatic solid tumors is now standard of care, but the effect of EPC in hematopoietic cell transplantation (HCT) is less well understood. We studied the acceptability of pre-HCT EPC as measured by trial participation, changes in patient-reported outcomes, and follow-up with palliative care providers. English-speaking adults (age >17 years) with an HCT comorbidity index of >= 3, relapse risk > 25%, or planned HLA-mismatched allogeneic or myeloablative HCT received EPC before HCT admission with monthly or more frequent visits. Twenty-two (69%) of 32 subjects provided consent; 2 were later excluded (HCT cancelled, consent retracted) for a 63% participation rate. Comfort with EPC was high (82% very comfortable). Subjects reported stable or improved mood and sense of hope, without apparent negative effects with a median of 3 visits. Follow-up surveys were returned by 75% of participants at 60 days and by 65% at 90 days. Four (20%) were admitted to the intensive care unit before day 100 and 3 (15%) received life-support measures. Five (25%) died with median follow-up of 14 months. EPC is feasible, acceptable, and has the potential to improve the HCT experience, whether or not the patient survives. EPC for HCT patients should be tested in a randomized trial. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Loggers, Elizabeth T.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Loggers, Elizabeth T.; Lee, Stephanie J.] Univ Washington, Div Hematol & Oncol, Seattle, WA 98195 USA. [Loggers, Elizabeth T.; Fihn, Judy; Bumpus, Molly; David, Jodie; Horak, Petr] Seattle Canc Care Alliance, Palliat Care Serv, Seattle, WA USA. [LeBlanc, Thomas W.] Duke Univ, Sch Med, Dept Med, Div Hematol Malignancies & Cellular Therapy, Durham, NC 27706 USA. [LeBlanc, Thomas W.] Duke Canc Inst, Program Canc Control & Populat Sci, Durham, NC USA. [El-Jawahri', Areej] Massachusetts Gen Hosp, Ctr Canc, Bone Marrow Transplant Program, Boston, MA USA. [El-Jawahri', Areej] Harvard Univ, Sch Med, Boston, MA USA. RP Loggers, ET (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave,Mailstop D5-380, Seattle, WA 98109 USA. EM eloggers@seattlecca.org OI Loggers, Elizabeth/0000-0003-3432-0443 FU Cambia Foundation Sojourns Scholar Award FX T.W.L. is supported by a Cambia Foundation Sojourns Scholar Award. NR 43 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2016 VL 22 IS 7 BP 1299 EP 1305 DI 10.1016/j.bbmt.2016.03.006 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DP4JR UT WOS:000378462700022 PM 26976242 ER PT J AU Strouse, C Richardson, P Prentice, G Korman, S Hume, R Nejadnik, B Horowitz, MM Saber, W AF Strouse, Christopher Richardson, Paul Prentice, Grant Korman, Sandra Hume, Robin Nejadnik, Bijan Horowitz, Mary M. Saber, Wael TI Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Defibrotide; Veno-occlusive disease; Hematopoietic cell transplantation ID STEM-CELL TRANSPLANTATION; SINUSOIDAL OBSTRUCTION SYNDROME AB Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Strouse, Christopher; Korman, Sandra; Horowitz, Mary M.; Saber, Wael] Med Coll Wisconsin, Dept Med, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Richardson, Paul] Dana Farber Canc Inst, Dept Hematol Oncol, Boston, MA 02115 USA. [Prentice, Grant; Hume, Robin; Nejadnik, Bijan] Jazz Pharmaceut, Palo Alto, CA USA. RP Saber, W (reprint author), Med Coll Wisconsin, CIBMTR Milwaukee, Dept Med, Div Hematol Oncol, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM wsaber@mcw.edu FU Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Alexion; Amgen, Inc.; Match Foundation; Bristol Myers Squibb Oncology; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co, Inc.; Mesoblast; Takeda Oncology Co.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. Japan; Oxford Immunotec; Perkin Elmer, Inc.; Pharmacyclics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Telomere Diagnostics, Inc.; TerumoBCT; Therakos, Inc.; University of Minnesota; Wellpoint, Inc.; National Cancer Institute (NCI) [5U24-CA076518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI [5U10HL069294]; NCI FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; contract HHSH250201200016C with Health Resources and Services Administration; 2 grants (N00014-13-1-0039 and N00014-14-1-0028) from the Office of Naval Research; and grants from Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Be the Match Foundation; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; *Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Mesoblast; The Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. Japan; Oxford Immunotec; Perkin Elmer, Inc.; Pharmacyclics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; *Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Telomere Diagnostics, Inc.; TerumoBCT; Therakos, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration or any other agency of the U.S. Government. NR 21 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2016 VL 22 IS 7 BP 1306 EP 1312 DI 10.1016/j.bbmt.2016.04.011 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DP4JR UT WOS:000378462700023 PM 27108694 ER PT J AU Yang, MZ Orgah, J Zhu, J Fan, GW Han, JH Wang, XY Zhang, BL Zhu, Y AF Yang, Mingzhu Orgah, John Zhu, Jie Fan, Guanwei Han, Jihong Wang, Xiaoying Zhang, Boli Zhu, Yan TI Danhong injection attenuates cardiac injury induced by ischemic and reperfused neuronal cells through regulating arginine vasopressin expression and secretion SO BRAIN RESEARCH LA English DT Article DE Arginine vasopressin; Ischemic; Reperfusion; Cerebrovascular; Cardiac function; Danhong injection ID CONGESTIVE-HEART-FAILURE; RECEPTOR ANTAGONIST; ATRIAL-FIBRILLATION; CRYPTOGENIC STROKE; RAT-HEART; SYSTEM; DEATH; LATERALIZATION; FIBROBLASTS; ACTIVATION AB Ischemic stroke is associated with cardiac myocyte vulnerability through some unknown mechanisms. Arginine vasopressin (AVP) may exert considerable function in the relationship of brain damage and heart failure. Danhong injection (DHI) can protect both stroke and heart failure patients with good efficacy in clinics. The aim of this study is to investigate the mechanism of DHI in heart and brain co-protection effects to determine whether AVP plays key role in this course. In the present study, we found that both the supernatant from oxygen-glucose deprivation (OGD) and reperfused primary rat neuronal cells (PRNCs) and AVP treatment caused significant reduction in cell viability and mitochondrial activity in primary rat cardiac myocytes (RCMs). Besides, DHI had the same protective effects with conivaptan, a dual vasopressin V-1A and V-2 receptor antagonist, in reducing the RCM damage induced by overdose AVP. DHI significantly decreased the injury of both PRNCs and RCMs. Meanwhile, the AVP level was elevated dramatically in OGD and reperfusion PRNCs, and DHI was able to decrease the AVP expression in the injured PRNCs. Therefore, our present results suggested that OGD and reperfusion PRNCs might induce myocyte injury by elevating the AVP expression in PRNCs. The ability of DHI to reinstate AVP level may be one of the mechanisms of its brain and heart co-protection effects. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yang, Mingzhu; Orgah, John; Zhu, Jie; Fan, Guanwei; Wang, Xiaoying; Zhang, Boli; Zhu, Yan] Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, 312 Anshanxi Rd, Tianjin 300193, Peoples R China. [Yang, Mingzhu; Orgah, John; Zhu, Jie; Wang, Xiaoying; Zhu, Yan] Tianjin Int Joint Acad Biotechnol & Med, TEDA, Res & Dev Ctr TCM, 220 Dongting Rd, Tianjin 300457, Peoples R China. [Zhu, Yan] Tufts Med Ctr, Mol Cardiol Res Inst, 750 Washington St, Boston, MA 02111 USA. [Zhu, Yan] Tufts Univ, Sch Med, 750 Washington St, Boston, MA 02111 USA. [Han, Jihong] Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China. [Han, Jihong] Nankai Univ, Collaborat Innovat Ctr Biotherapy, Tianjin 300071, Peoples R China. [Wang, Xiaoying] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurosci Program,Neuroprotect Res Lab,Dept Neurol, Boston, MA 02135 USA. RP Zhu, Y (reprint author), Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, 312 Anshanxi Rd, Tianjin 300193, Peoples R China. EM yanzhu.harvard@iCloud.com FU National Major New Drug Discovery Grant [2013ZX 0920102]; National Natural Science Foundation of China (NSFC) [81274128]; Program for Tianjin Innovative Research Team in University [TD12-5031]; International Cooperation Project of MOST, China [2013DFA31620] FX This study was supported by the National Major New Drug Discovery Grant (2013ZX 0920102), the National Natural Science Foundation of China (NSFC) Grant (81274128); the Program for Tianjin Innovative Research Team in University (TD12-5031), and International Cooperation Project of MOST, China (2013DFA31620). NR 44 TC 2 Z9 2 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUL 1 PY 2016 VL 1642 BP 516 EP 523 DI 10.1016/j.brainres.2016.04.046 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DP7EI UT WOS:000378661600058 PM 27107944 ER PT J AU Saleh, MH Wang, L Goldberg, MS AF Saleh, Mohammad H. Wang, Lei Goldberg, Michael S. TI Improving cancer immunotherapy with DNA methyltransferase inhibitors SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Review DE CITIM 2015; Epigenetic modifier; DNA methyltransferase inhibitor; Decitabine; Immunotherapy; Ovarian cancer ID HISTONE DEACETYLASE INHIBITORS; RENAL-CELL CARCINOMA; CD8 T-CELLS; IFN-GAMMA; ANTIGENS EXPRESSION; SUPPRESSOR-CELLS; AGENT 5-AZACYTIDINE; CUTANEOUS MELANOMA; IMMUNE-RESPONSE; GENE-EXPRESSION AB Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity. C1 [Saleh, Mohammad H.; Wang, Lei; Goldberg, Michael S.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. RP Goldberg, MS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. EM michael_goldberg1@dfci.harvard.edu OI Saleh, Mohammad H./0000-0001-8828-4367 FU Ovarian Cancer Research Fund (Liz Tilberis Scholar award); Susan F. Smith Center for Women's Cancer FX We thank the Ovarian Cancer Research Fund (Liz Tilberis Scholar award) and the Susan F. Smith Center for Women's Cancer for supporting this work. NR 65 TC 5 Z9 5 U1 9 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD JUL PY 2016 VL 65 IS 7 BP 787 EP 796 DI 10.1007/s00262-015-1776-3 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA DQ0EU UT WOS:000378872000003 PM 26646852 ER PT J AU Khalil, HA Lei, NY Brinkley, G Scott, A Wang, JF Kar, UK Jabaji, ZB Lewis, M Martin, MG Dunn, JCY Stelzner, MG AF Khalil, Hassan A. Lei, Nan Ye Brinkley, Garrett Scott, Andrew Wang, Jiafang Kar, Upendra K. Jabaji, Ziyad B. Lewis, Michael Martin, Martin G. Dunn, James C. Y. Stelzner, Matthias G. TI A novel culture system for adult porcine intestinal crypts SO CELL AND TISSUE RESEARCH LA English DT Article DE Porcine intestinal culture; Enteroid; Intestinal spheroid; Intestinal subepithelial myofibroblast; Transduction of intestinal epithelium ID STEM-CELL; IN-VITRO; ANIMAL-MODELS; TRANSPLANTATION; EPITHELIUM; ORGANOIDS; COLON; DIFFERENTIATION; PROGENITORS; ENGRAFTMENT AB Porcine models are useful for investigating therapeutic approaches to short bowel syndrome and potentially to intestinal stem cell (ISC) transplantation. Whereas techniques for the culture and genetic manipulation of ISCs from mice and humans are well established, similar methods for porcine stem cells have not been reported. Jejunal crypts were isolated from murine, human, and juvenile and adult porcine small intestine, suspended in Matrigel, and co-cultured with syngeneic intestinal subepithelial myofibroblasts (ISEMFs) or cultured without feeder cells in various culture media. Media containing epidermal growth factor, noggin, and R-spondin 1 (ENR medium) were supplemented with various combinations of Wnt3a- or ISEMF-conditioned medium (CM) and with glycogen synthase kinase 3 inhibitor (GSK3i), and their effects were studied on cultured crypts. Cell lineage differentiation was assessed by immunohistochemistry and quantitative polymerase chain reaction. Cultured porcine cells were serially passaged and transduced with a lentiviral vector. Whereas ENR medium supported murine enteroid growth, it did not sustain porcine crypts beyond 5 days. Supplementation of Wnt3a-CM and GSK3i resulted in the formation of complex porcine enteroids with budding extensions. These enteroids contained a mixture of stem and differentiated cells and were successfully passaged in the presence of GSK3i. Crypts grown in media supplemented with porcine ISEMF-CM formed spheroids that were less well differentiated than enteroids. Enteroids and spheroids were transfected with a lentivirus with high efficiency. Thus, our method maintains juvenile and adult porcine crypt cells long-term in culture. Porcine enteroids and spheroids can be successfully passaged and transduced by using lentiviral vectors. C1 [Khalil, Hassan A.; Lei, Nan Ye; Scott, Andrew; Jabaji, Ziyad B.; Dunn, James C. Y.; Stelzner, Matthias G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Brinkley, Garrett; Wang, Jiafang; Kar, Upendra K.; Martin, Martin G.] Mattel Childrens Hosp, Dept Pediat, Div Gastroenterol & Nutr, Los Angeles, CA USA. [Brinkley, Garrett; Wang, Jiafang; Kar, Upendra K.; Martin, Martin G.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lewis, Michael] VA Greater Los Angeles Hlth Syst, Dept Pathol & Lab Med, Los Angeles, CA USA. [Stelzner, Matthias G.] VA Greater Los Angeles Hlth Syst, Dept Surg, Los Angeles, CA USA. RP Stelzner, MG (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA.; Stelzner, MG (reprint author), VA Greater Los Angeles Hlth Syst, Dept Surg, Los Angeles, CA USA. EM stelzner@ucla.edu OI Khalil, Hassan/0000-0002-3835-1290 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infections Diseases [DK085535-01, DK085535-02S2]; California Institute of Regenerative Medicine [RT2-01985]; [CURE/P30 DK041301] FX The UCLA Vectorcore is supported by CURE/P30 DK041301. This research was performed as a project of the Intestinal Stem Cell Consortium, a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infections Diseases (DK085535-01 and DK085535-02S2) and was supported in part by the California Institute of Regenerative Medicine (RT2-01985). NR 36 TC 2 Z9 2 U1 6 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X EI 1432-0878 J9 CELL TISSUE RES JI Cell Tissue Res. PD JUL PY 2016 VL 365 IS 1 BP 123 EP 134 DI 10.1007/s00441-016-2367-0 PG 12 WC Cell Biology SC Cell Biology GA DQ0GR UT WOS:000378877600011 PM 26928041 ER PT J AU Ananthakrishnan, AN Cagan, A Cai, TX Gainer, VS Shaw, SY Churchill, S Karlson, EW Murphy, SN Liao, KP Kohane, I AF Ananthakrishnan, Ashwin N. Cagan, Andrew Cai, Tianxi Gainer, Vivian S. Shaw, Stanley Y. Churchill, Susanne Karlson, Elizabeth W. Murphy, Shawn N. Liao, Katherine P. Kohane, Isaac TI Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Colon Cancer; CD; UC; HMG-CoA Reductase Inhibitors; Lipid-Lowering Drug; Crohn's Disease; Ulcerative Colitis; Statin; Colon Cancer ID PRIMARY SCLEROSING CHOLANGITIS; ULCERATIVE-COLITIS; 5-AMINOSALICYLIC ACID; URSODEOXYCHOLIC ACID; METAANALYSIS; NEOPLASIA; CARCINOMA; CHEMOPREVENTION; SURVEILLANCE; PREVENTION AB BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are associated with an increased risk of colorectal cancer (CRC). Chemopreventive strategies have produced weak or inconsistent results. Statins have been associated inversely with sporadic CRC. We examined their role as chemopreventive agents in patients with IBD. METHODS: We collected data from 11,001 patients with IBD receiving care at hospitals in the Greater Boston metropolitan area from 1998 through 2010. Diagnoses of CRC were determined using validated International Classification of Diseases, 9th revision, Clinical Modification codes. Statin use before diagnosis was assessed through analysis of electronic prescriptions. We performed multivariate logistic regression analyses, adjusting for potential confounders including primary sclerosing cholangitis, smoking, increased levels of inflammation markers, and CRC screening practices to identify an independent association between statin use and CRC. We performed sensitivity analyses using propensity score adjustment and variation in the definition of statin use. RESULTS: In our cohort, 1376 of the patients (12.5%) received 1 or more prescriptions for a statin. Patients using statins were more likely to be older, male, white, smokers, and have greater comorbidity than nonusers. Over a follow-up period of 9 years, 2% of statin users developed CRC compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24-0.53). On multivariate analysis, statin use remained independently and inversely associated with CRC (odds ratio, 0.42; 95% confidence interval, 0.28-0.62). Our findings were robust on a variety of sensitivity and subgroup analyses. CONCLUSIONS: Statin use was associated inversely with the risk of CRC in a large IBD cohort. Prospective studies on the role of statins as chemopreventive agents are warranted. C1 [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Shaw, Stanley Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Churchill, Susanne; Kohane, Isaac] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA USA. [Ananthakrishnan, Ashwin N.; Shaw, Stanley Y.; Karlson, Elizabeth W.; Murphy, Shawn N.; Liao, Katherine P.; Kohane, Isaac] Harvard Univ, Sch Med, Boston, MA USA. [Cagan, Andrew; Gainer, Vivian S.] Partners HealthCare, Res Informat Serv & Comp, Charlestown, MA USA. [Cai, Tianxi] Harvard Univ, Dept Biostat, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Karlson, Elizabeth W.; Liao, Katherine P.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. [Kohane, Isaac] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU National Institutes of Health [U54-LM008748, K08 AR060257, K24 AR052403, P60 AR047782, R01 AR049880]; US National Institutes of Health [K23 DK097142]; Harold and Duval Bowen Fund; American Gastroenterological Association FX Supported by National Institutes of Health (U54-LM008748 to I.K.); the American Gastroenterological Association and the US National Institutes of Health (K23 DK097142 to A.N.A.); National Institutes of Health grant K08 AR060257 and the Harold and Duval Bowen Fund (K.P.L.); and supported by grants from the National Institutes of Health (K24 AR052403, P60 AR047782, and R01 AR049880 to E.W.K.). NR 56 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JUL PY 2016 VL 14 IS 7 BP 973 EP 979 DI 10.1016/j.cgh.2016.02.017 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DP3KS UT WOS:000378392900015 PM 26905907 ER PT J AU Chen, SP Ayata, C AF Chen, Shih-Pin Ayata, Cenk TI Spreading Depression in Primary and Secondary Headache Disorders SO CURRENT PAIN AND HEADACHE REPORTS LA English DT Review DE Intracranial hemorrhage; Ischemic stroke; Migraine aura; Spreading depression; Spreading depolarization; Traumatic brain injury ID TRAUMATIC BRAIN-INJURY; HUMAN CEREBRAL-CORTEX; FAMILIAL HEMIPLEGIC MIGRAINE; SUBARACHNOID HEMORRHAGE; ISCHEMIC-STROKE; CLUSTER HEADACHE; INTRACEREBRAL HEMATOMAS; ONLINE MICRODIALYSIS; POSTICTAL HEADACHE; MALIGNANT STROKE AB Purpose of Review Spreading depression (SD) is a wave of simultaneous and near-complete depolarization of virtually all cells in brain tissue associated with a transient "depression" of all spontaneous or evoked electrical activity in the brain. SD is widely accepted as the pathophysiological event underlying migraine aura and may play a role in headache pathogenesis in secondary headache disorders such as ischemic stroke, subarachnoid or intracerebral hemorrhage, traumatic brain injury, and epilepsy. Here, we provide an overview of the pathogenic mechanisms and propose plausible hypotheses on the involvement of SD in primary and secondary headache disorders. Recent Findings SD can activate downstream trigeminovascular nociceptive pathways to explain the cephalgia in migraine, and possibly in secondary headache disorders as well. In healthy, well-nourished tissue (such as migraine), the intense transmembrane ionic shifts, the cell swelling, and the metabolic and hemodynamic responses associated with SD do not cause tissue injury; however, when SD occurs in metabolically compromised tissue (e.g., in ischemic stroke, intracranial hemorrhage, or traumatic brain injury), it can lead to irreversible depolarization, injury, and neuronal death. Recent non-invasive technologies to detect SDs in human brain injury may aid in the investigation of SD in headache disorders in which invasive recordings are not possible. Summary SD explains migraine aura and progression of neurological deficits associated with other neurological disorders. Studying the nature of SD in headache disorders might provide pathophysiological insights for disease and lead to targeted therapies in the era of precision medicine. C1 [Chen, Shih-Pin] Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan. [Chen, Shih-Pin] Natl Yang Ming Univ, Sch Med, Dept Neurol, Taipei 112, Taiwan. [Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurovasc Res Lab,Dept Radiol, Charlestown, MA 02129 USA. [Ayata, Cenk] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Stroke Serv, Boston, MA 02115 USA. [Ayata, Cenk] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Neurosci Intens Care Unit, Boston, MA 02115 USA. RP Ayata, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurovasc Res Lab,Dept Radiol, Charlestown, MA 02129 USA.; Ayata, C (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Stroke Serv, Boston, MA 02115 USA.; Ayata, C (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Neurosci Intens Care Unit, Boston, MA 02115 USA. EM cayata@mgh.harvard.edu NR 99 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1531-3433 EI 1534-3081 J9 CURR PAIN HEADACHE R JI Curr. Pain Headache Rep. PD JUL PY 2016 VL 20 IS 7 AR 44 DI 10.1007/s11916-016-0574-8 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DP7UL UT WOS:000378704600001 PM 27215627 ER PT J AU Tanigaki, K Chambliss, KL Yuhanna, IS Sacharidou, A Ahmed, M Atochin, DN Huang, PL Shaul, PW Mineo, C AF Tanigaki, Keiji Chambliss, Ken L. Yuhanna, Ivan S. Sacharidou, Anastasia Ahmed, Mohamed Atochin, Dmitriy N. Huang, Paul L. Shaul, Philip W. Mineo, Chieko TI Endothelial Fc gamma Receptor IIB Activation Blunts Insulin Delivery to Skeletal Muscle to Cause Insulin Resistance in Mice SO DIABETES LA English DT Article ID C-REACTIVE PROTEIN; NITRIC-OXIDE SYNTHASE; PHENOTYPIC HETEROGENEITY; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; GLUCOSE DISPOSAL; IN-VIVO; CELLS; TRANSPORT; DYSFUNCTION AB Modest elevations in C-reactive protein (CRP) are associated with type 2 diabetes. We previously revealed in mice that increased CRP causes insulin resistance and mice globally deficient in the CRP receptor Fc gamma receptor IIB (Fc gamma RIIB) were protected from the disorder. Fc gamma RIIB is expressed in numerous cell types including endothelium and B lymphocytes. Here we investigated how endothelial Fc gamma RIIB influences glucose homeostasis, using mice with elevated CRP expressing or lacking endothelial Fc gamma RIIB. Whereas increased CRP caused insulin resistance in mice expressing endothelial Fc gamma RIIB, mice deficient in the endothelial receptor were protected. The insulin resistance with endothelial Fc gamma RIIB activation was due to impaired skeletal muscle glucose uptake caused by attenuated insulin delivery, and it was associated with blunted endothelial nitric oxide synthase (eNOS) activation in skeletal muscle. In culture, CRP suppressed endothelial cell insulin transcytosis via Fc gamma RIIB activation and eNOS antagonism. Furthermore, in knock-in mice harboring constitutively active eNOS, elevated CRP did not invoke insulin resistance. Collectively these findings reveal that by inhibiting eNOS, endothelial Fc gamma RIIB activation by CRP blunts insulin delivery to skeletal muscle to cause insulin resistance. Thus, a series of mechanisms in endothelium that impairs insulin movement has been identified that may contribute to type 2 diabetes pathogenesis. C1 [Tanigaki, Keiji; Chambliss, Ken L.; Yuhanna, Ivan S.; Sacharidou, Anastasia; Ahmed, Mohamed; Shaul, Philip W.; Mineo, Chieko] Univ Texas SW Med Ctr Dallas, Dept Pediat, Ctr Pulm & Vasc Biol, Dallas, TX 75390 USA. [Atochin, Dmitriy N.; Huang, Paul L.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Atochin, Dmitriy N.; Huang, Paul L.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Atochin, Dmitriy N.; Huang, Paul L.] Harvard Univ, Sch Med, Boston, MA USA. RP Shaul, PW; Mineo, C (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, Ctr Pulm & Vasc Biol, Dallas, TX 75390 USA. EM philip.shaul@utsouthwestern.edu; chieko.mineo@utsouthwestern.edu RI Atochin, Dmitriy/Q-3150-2016 FU National Institutes of Health, National Heart, Lung, and Blood Institute [R01-HL115122]; American Diabetes Association [1-10-BS-124]; American Heart Association [13GRNT16080003] FX This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute, grant R01-HL115122 (to P.W.S.); American Diabetes Association grant 1-10-BS-124 (to C.M.); and American Heart Association grant 13GRNT16080003 (to C.M.). NR 42 TC 0 Z9 0 U1 2 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD JUL PY 2016 VL 65 IS 7 BP 1996 EP 2005 DI 10.2337/db15-1605 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP4JU UT WOS:000378463000026 PM 27207525 ER PT J AU Boffetta, P Hayes, RB Sartori, S Lee, YCA Muscat, J Olshan, A Winn, DM Castellsague, X Zhang, ZF Morgenstern, H Chen, C Schwartz, SM Vaughan, TL Wunsch, V Purdue, M Koifman, S Curado, MP Vilensky, M Gillison, M Fernandez, L Menezes, A Daudt, AW Schantz, S Yu, GP D'Souza, G Haddad, RI La Vecchia, C Hashibe, M AF Boffetta, Paolo Hayes, Richard B. Sartori, Samantha Lee, Yuan-Chin A. Muscat, Joshua Olshan, Andrew Winn, Deborah M. Castellsague, Xavier Zhang, Zuo-Feng Morgenstern, Hal Chen, Chu Schwartz, Stephen M. Vaughan, Thomas L. Wunsch-Filho, Victor Purdue, Mark Koifman, Sergio Curado, Maria P. Vilensky, Marta Gillison, Maura Fernandez, Leticia Menezes, Ana Daudt, Alexander W. Schantz, Stimson Yu, Guopei D'Souza, Gypsyamber Haddad, Robert I. La Vecchia, Carlo Hashibe, Mia TI Mouthwash use and cancer of the head and neck: a pooled analysis from the International Head and Neck Cancer Epidemiology Consortium SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE alcohol; head and neck cancer; laryngeal cancer; mouthwash; oral cancer; pharyngeal cancer ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; ORAL-CANCER; HUMAN-PAPILLOMAVIRUS; RISK-FACTORS; OROPHARYNX; ESOPHAGUS; HEALTH AB Most mouthwashes contain alcohol, a known cause of head and neck cancer (oral cavity, pharynx, larynx), likely through the carcinogenic activity of acetaldehyde, formed in the oral cavity from alcohol. We carried out a pooled analysis of 8981 cases of head and neck cancer and 10090 controls from 12 case-control studies with comparable information on mouthwash use in the International Head and Neck Cancer Epidemiology Consortium. Logistic regression was used to assess the association of mouthwash use with cancers of the oral cavity, oropharynx, hypopharynx, and larynx, adjusting for study, age, sex, pack-years of tobacco smoking, number of alcoholic drinks/day, and education. Compared with never users of mouthwash, the odds ratio (OR) of all head and neck cancers was 1.01 [95% confidence interval (CI): 0.94-1.08] for ever users, based on 12 studies. The corresponding ORs of cancer of the oral cavity and oropharynx were 1.11 (95% CI: 1.00-1.23) and 1.28 (95% CI: 1.06-1.56), respectively. OR for all head and neck cancer was 1.15 (95% CI: 1.01-1.30) for use for more than 35 years, based on seven studies (P for linear trend=0.01), and OR 1.31 (95% CI: 1.09-1.58) for use more than one per day, based on five studies (P for linear trend <0.001). Although limited by the retrospective nature of the study and the limited ability to assess risks of mouthwash use in nonusers of tobacco and alcohol, this large investigation shows potential risks for head and neck cancer subsites and in long-term and frequent users of mouthwash. This pooled analysis provides the most precise estimate of the association between mouthwash use and head and neck cancer. C1 [Boffetta, Paolo; Sartori, Samantha] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo; Sartori, Samantha] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, Dept Populat Hlth, New York, NY USA. [Schantz, Stimson] New York Eye & Ear Infirm, New York, NY USA. [Lee, Yuan-Chin A.; Hashibe, Mia] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Family & Prevent Med,Div Publ Hlth, Salt Lake City, UT USA. [Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Olshan, Andrew] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Winn, Deborah M.; Purdue, Mark] NCI, Bethesda, MD 20892 USA. [Gillison, Maura] Johns Hopkins Med Inst, Baltimore, MD USA. [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol & Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Chen, Chu; Schwartz, Stephen M.; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Haddad, Robert I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Castellsague, Xavier] Hosp Llobregat, Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Castellsague, Xavier] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Barcelona, Spain. [Wunsch-Filho, Victor] Univ Sao Paulo, Sao Paulo, Brazil. [Koifman, Sergio] Fundacao Oswaldo Cruz, Natl Sch Publ Hlth, Rio De Janeiro, Brazil. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Curado, Maria P.] Int Prevent Res Inst, Lyon, France. [Vilensky, Marta] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Yu, Guopei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. RP Boffetta, P (reprint author), Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. EM paolo.boffetta@mssm.edu RI Castellsague Pique, Xavier/N-5795-2014; Kowalski, Luiz/D-1701-2012; Menezes, Ana/G-7266-2012; Curado, Maria Paula/M-6200-2013; OI Castellsague Pique, Xavier/0000-0002-0802-3595; Kowalski, Luiz/0000-0001-5865-9308; Curado, Maria Paula/0000-0001-8172-2483; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X FU NIH [NCI R03CA113157, NIDCR R03DE016611, P01CA068384 K07CA104231, R01CA048996, R01DE012609, R01CA061188, P50CA090388, R01DA011386, R03CA077954, T32CA 009142, U01CA096134, R21ES011667, R01CA051845, DE016631]; National Institute of Environmental Health Sciences [P30ES010126]; Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; National Institutes of Health (NCI) US; NIDCR; Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina; IMIM (Barcelona); Fundaco de Amparo a' Pesquisa no Estado de Sao Paulo (FAPESP) [01/01768-2]; European Commission [IC18-CT97-0222]; Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; International Union Against Cancer (UICC); Yamagiwa-Yoshida Memorial International Cancer Study Grant; NCI, NIH, United States; Johns Hopkins Richard Gelb Cancer Prevention Award FX The INHANCE Consortium was supported by NIH grants NCI R03CA113157 and NIDCR R03DE016611. Studies participating in the pooled analysis were supported by grants: New York multicenter: NIH [P01CA068384 K07CA104231]; Seattle (1985-1995): NIH [R01CA048996, R01DE012609]; North Carolina (1994-1997): NIH [R01CA061188], and in part by a grant from the National Institute of Environmental Health Sciences [P30ES010126]; Los Angeles: NIH [P50CA090388, R01DA011386, R03CA077954, T32CA 009142, U01CA096134, R21ES011667] and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Puerto Rico: jointly funded by National Institutes of Health (NCI) US and NIDCR intramural programs; Latin America: Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), Fundaco de Amparo a' Pesquisa no Estado de Sao Paulo (FAPESP) [No 01/01768-2], and European Commission [IC18-CT97-0222]; IARC Multicenter: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013], International Union Against Cancer (UICC), and Yamagiwa-Yoshida Memorial International Cancer Study Grant; US multicenter: The Intramural Program of the NCI, NIH, United States; MSKCC: NIH [R01CA051845]; Baltimore: NIH [DE016631]; Hotspot: Johns Hopkins Richard Gelb Cancer Prevention Award. NR 21 TC 0 Z9 1 U1 6 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-8278 EI 1473-5709 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUL PY 2016 VL 25 IS 4 BP 344 EP 348 DI 10.1097/CEJ.0000000000000179 PG 5 WC Oncology SC Oncology GA DP6RK UT WOS:000378625900013 PM 26275006 ER PT J AU Jimenez, MC Curhan, GC Choi, HK Forman, JP Rexrode, KM AF Jimenez, M. C. Curhan, G. C. Choi, H. K. Forman, J. P. Rexrode, K. M. TI Plasma uric acid concentrations and risk of ischaemic stroke in women SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE hyperuricemia; ischaemic stroke; uric acid; women ID INCIDENT HYPERTENSION; ALL-CAUSE; HYPERURICEMIA; METAANALYSIS; MORTALITY; COHORT; LEVEL; DEATH; GOUT AB Background and purposeElevated plasma uric acid has been inconsistently associated with an increased risk of total stroke; however, data are sparse amongst women. The association between plasma uric acid concentrations and ischaemic stroke amongst women was examined and the effect modification by key cardiovascular risk factors was evaluated. MethodsA nested case-control design with matching by age, race/ethnicity, smoking status, menopausal status, postmenopausal hormone therapy use, date of blood draw and fasting status was utilized amongst female participants of the Nurses' Health Study who provided blood samples between 1989 and 1990. Plasma uric acid was measured on stored blood samples. The National Survey of Stroke criteria were utilized to confirm 460 incident cases of ischaemic stroke by medical records from 1990 to 2006. Multivariable conditional logistic regression models were estimated. ResultsIn matched analysis, risk of ischaemic stroke increased by 15% for each 1 mg/dl increase in plasma uric acid [95% confidence interval (CI) 3%-28%], but was no longer significant after adjustment for cardiovascular risk factors, particularly history of hypertension. The highest quartile of uric acid was significantly associated with greater risk of ischaemic stroke (relative risk 1.56; 95% CI 1.06-2.29, extreme quartiles) in matched analysis, but estimates were no longer significant after adjustment for cardiovascular risk factors (relative risk 1.43; 95% CI 0.93-2.18). Significant effect modification by key cardiovascular risk factors was not observed. ConclusionsPlasma uric acid levels were not independently associated with increased risk of ischaemic stroke in this cohort of women. Whilst plasma uric acid was associated with stroke risk factors, it was not independently associated with stroke risk. C1 [Jimenez, M. C.; Rexrode, K. M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Jimenez, M. C.; Curhan, G. C.; Choi, H. K.; Forman, J. P.; Rexrode, K. M.] Harvard Univ, Sch Med, Boston, MA USA. [Curhan, G. C.; Forman, J. P.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Choi, H. K.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Rexrode, KM (reprint author), 900 Commonwealth Ave,3rd Floor, Boston, MA 02215 USA. EM krexrode@partners.org FU National Heart, Lung and Blood Institute of the National Institutes of Health [HL088521, HL088521-S1, HL34594]; National Cancer Institute [CA186107, CA87969, CA49449]; National Heart, Lung, and Blood Institute [K01HL124391]; Brigham and Women's Hospital Faculty Career Development Award; Minority Faculty Career Development Award; National Institute of Diabetes and Digestive and Kidney Diseases [DK91417] FX We acknowledge HL088521, HL088521-S1 and HL34594 from the National Heart, Lung and Blood Institute of the National Institutes of Health and CA186107, CA87969 and CA49449 from the National Cancer Institute. Dr Jimenez is supported by K01HL124391 from the National Heart, Lung, and Blood Institute and the Brigham and Women's Hospital Faculty Career Development Award and Minority Faculty Career Development Award. Dr Curhan is supported by DK91417 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 24 TC 2 Z9 2 U1 4 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 2016 VL 23 IS 7 BP 1158 EP 1164 DI 10.1111/ene.12998 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DP3YC UT WOS:000378431100011 PM 27061733 ER PT J AU Khera, AV Natarajan, P Kathiresan, S AF Khera, Amit V. Natarajan, Pradeep Kathiresan, Sekar TI The future of low-density lipoprotein cholesterol lowering therapy: An end to statin exceptionalism? SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Editorial Material ID CARDIOVASCULAR EVENTS; REDUCING LIPIDS; EFFICACY; SAFETY C1 Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Khera, AV (reprint author), 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM avkhera@mgh.harvard.edu OI Natarajan, Pradeep/0000-0001-8402-7435 FU NHLBI NIH HHS [T32 HL007208] NR 7 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD JUL PY 2016 VL 23 IS 10 BP 1062 EP 1064 DI 10.1177/2047487315600818 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP8RD UT WOS:000378764500007 PM 26268264 ER PT J AU Jiang, L Chen, HD Pinello, L Yuan, GC AF Jiang, Lan Chen, Huidong Pinello, Luca Yuan, Guo-Cheng TI GiniClust: detecting rare cell types from single-cell gene expression data with Gini index SO GENOME BIOLOGY LA English DT Article DE Clustering; Single-cell analysis; RNA-seq; qPCR; Gini index; Rare cell type ID RNA-SEQ; CHARACTERIZING HETEROGENEITY; TRANSCRIPTOMICS AB High-throughput single-cell technologies have great potential to discover new cell types; however, it remains challenging to detect rare cell types that are distinct from a large population. We present a novel computational method, called GiniClust, to overcome this challenge. Validation against a benchmark dataset indicates that GiniClust achieves high sensitivity and specificity. Application of GiniClust to public single-cell RNA-seq datasets uncovers previously unrecognized rare cell types, including Zscan4-expressing cells within mouse embryonic stem cells and hemoglobin-expressing cells in the mouse cortex and hippocampus. GiniClust also correctly detects a small number of normal cells that are mixed in a cancer cell population. C1 [Jiang, Lan; Chen, Huidong; Pinello, Luca; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Jiang, Lan; Chen, Huidong; Pinello, Luca; Yuan, Guo-Cheng] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Jiang, Lan] Boston Childrens Hosp, Boston, MA 02115 USA. [Chen, Huidong] Tongji Univ, Dept Comp Sci & Technol, Shanghai, Peoples R China. [Yuan, Guo-Cheng] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Yuan, GC (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.; Yuan, GC (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM gcyuan@jimmy.harvard.edu FU Claudia Barr Award; NIH [R01HL119099]; NHGRI Career Development Award [K99HG008399] FX This work was supported by a Claudia Barr Award and NIH grant R01HL119099 to GCY and by an NHGRI Career Development Award K99HG008399 to LP. NR 28 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JUL 1 PY 2016 VL 17 AR 144 DI 10.1186/s13059-016-1010-4 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DQ0PL UT WOS:000378902100001 PM 27368803 ER PT J AU Basler, G Nikoloski, Z Larhlimi, A Barabasi, AL Liu, YY AF Basler, Georg Nikoloski, Zoran Larhlimi, Abdelhalim Barabasi, Albert-Laszlo Liu, Yang-Yu TI Control of fluxes in metabolic networks SO GENOME RESEARCH LA English DT Article ID S-ADENOSYLHOMOCYSTEINE HYDROLASE; DIACYLGLYCEROL KINASE; ESCHERICHIA-COLI; IN-VITRO; DEOXYGUANOSINE KINASE; DNA HYPOMETHYLATION; IMP DEHYDROGENASE; COUPLING ANALYSIS; PLANT-METABOLISM; CANCER GENES AB Understanding the control of large-scale metabolic networks is central to biology and medicine. However, existing approaches either require specifying a cellular objective or can only be used for small networks. We introduce new coupling types describing the relations between reaction activities, and develop an efficient computational framework, which does not require any cellular objective for systematic studies of large-scale metabolism. We identify the driver reactions facilitating control of 23 metabolic networks from all kingdoms of life. We find that unicellular organisms require a smaller degree of control than multicellular organisms. Driver reactions are under complex cellular regulation in Escherichia coil, indicating their preeminent role in facilitating cellular control. In human cancer cells, driver reactions play pivotal roles in malignancy and represent potential therapeutic targets. The developed framework helps us gain insights into regulatory principles of diseases and facilitates design of engineering strategies at the interface of gene regulation, signaling, and metabolism. C1 [Basler, Georg] Univ Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA. [Basler, Georg] CSIC, Estn Expt Zaidin, Dept Environm Protect, E-18008 Granada, Spain. [Nikoloski, Zoran] Max Planck Inst Mol Plant Physiol, Syst Biol & Math Modeling, D-14476 Potsdam, Germany. [Larhlimi, Abdelhalim] Univ Nantes, Lab Informat Nantes Atlantique, F-44322 Nantes, France. [Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys Comp Sci & Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo; Liu, Yang-Yu] Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Dept Med,Med Sch, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo; Liu, Yang-Yu] Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Sch Med, Boston, MA 02115 USA. RP Liu, YY (reprint author), Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Dept Med,Med Sch, Boston, MA 02115 USA.; Liu, YY (reprint author), Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Sch Med, Boston, MA 02115 USA. EM yyl@channing.harvard.edu FU Marie Curie Intra European Fellowship within the European Union's Seventh Framework Programme (FP7); Max Kade Foundation; National Institutes of Health (NIH) Grants: Centers of Excellence of Genomic Science (CEGS) [1P50HG004233, 1R01HL118455-01A1]; John Templeton Foundation [PFI-777, 51977]; European Commission (ERC) grant [329682] FX We thank Alisdair Femie, Tino Krell, Jan Lisec, and Clemens A. Schmitt for critical comments on the manuscript, and Francesco Gatto and Jens Nielsen for kindly providing the cancer networks. This work was supported by a Marie Curie Intra European Fellowship within the European Union's Seventh Framework Programme (FP7/2007-2013), European Commission (ERC) grant agreement number 329682, the Max Kade Foundation, the National Institutes of Health (NIH) Grants: Centers of Excellence of Genomic Science (CEGS) 1P50HG004233 and 1R01HL118455-01A1, and the John Templeton Foundation Awards PFI-777 and 51977. NR 77 TC 2 Z9 2 U1 5 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUL PY 2016 VL 26 IS 7 BP 956 EP 968 DI 10.1101/gr.202648.115 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DQ1UN UT WOS:000378986000009 PM 27197218 ER PT J AU Breithardt, G Baumgartner, H Berkowitz, SD Hellkamp, AS Piccini, JP Lokhnygina, Y Halperin, JL Singer, DE Hankey, GJ Hacke, W Becker, RC Nessel, CC Mahaffey, KW Califf, RM Fox, KAA Patel, MR AF Breithardt, Guenter Baumgartner, Helmut Berkowitz, Scott D. Hellkamp, Anne S. Piccini, Jonathan P. Lokhnygina, Yuliya Halperin, Jonathan L. Singer, Daniel E. Hankey, Graeme J. Hacke, Werner Becker, Richard C. Nessel, Christopher C. Mahaffey, Kenneth W. Califf, Robert M. Fox, Keith A. A. Patel, Manesh R. CA ROCKET AF Steering Comm TI Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban SO HEART LA English DT Article ID VALVULAR HEART-DISEASE; VON-WILLEBRAND-FACTOR; BLEEDING GASTROINTESTINAL ANGIODYSPLASIA; AORTIC-STENOSIS; MITRAL REGURGITATION; THROMBOEMBOLIC EVENTS; HEYDES-SYNDROME; ROCKET AF; ASSOCIATION; STROKE AB Objective To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD). Methods Using 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) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis. Results Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p<0.05) and MR or AR (HR 1.30, 1.07 to 1.57, p<0.01) than in no SVD, but there was no difference between AS and MR or AR (HR 1.24, 0.78 to 1.97). The relative efficacy of rivaroxaban versus warfarin was consistent among patients with and without valvular disease. Rivaroxaban was associated with higher rates of major bleeding than warfarin in patients with MR or AR (HR 1.63, 1.15 to 2.31). Conclusions We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD. C1 [Breithardt, Guenter] Univ Hosp Munster, Dept Cardiovasc Med, Div Electrophysiol, Munster, Germany. [Baumgartner, Helmut] Univ Hosp Munster, Dept Cardiovasc Med, Div Adult Congenital & Valvular Heart Dis, Munster, Germany. [Berkowitz, Scott D.] Bayer Healthcare Pharmaceut LP, Whippany, NJ USA. [Hellkamp, Anne S.; Piccini, Jonathan P.; Lokhnygina, Yuliya; Patel, Manesh R.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Div Gen Internal Med, Clin Epidemiol Unit, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Becker, Richard C.] Univ Cincinnati, Coll Med, Dept Med, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA. [Nessel, Christopher C.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Breithardt, G (reprint author), Univ Hosp Munster, Dept Cardiovasc Med, Div Electrophysiol, Munster, Germany. EM g.breithardt@uni-muenster.de RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Janssen Research & Development (Raritan, New Jersey, USA); Bayer HealthCare AG (Leverkusen, Germany) FX The ROCKET AF trial was supported by research grants from Janssen Research & Development (Raritan, New Jersey, USA) and Bayer HealthCare AG (Leverkusen, Germany). NR 46 TC 6 Z9 6 U1 2 U2 3 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 PY 2016 VL 102 IS 13 BP 1036 EP 1043 DI 10.1136/heartjnl-2015-308120 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP7YZ UT WOS:000378716400012 PM 26888572 ER PT J AU Choi, AJ Thomas, SS Singh, JP AF Choi, Anthony J. Thomas, Sunu S. Singh, Jagmeet P. TI Cardiac Resynchronization Therapy and Implantable Cardioverter Defibrillator Therapy in Advanced Heart Failure SO HEART FAILURE CLINICS LA English DT Article DE Heart failure; CIED; Defibrillator; Cardiac resynchronization therapy; Arrhythmia ID VENTRICULAR ASSIST DEVICE; MECHANICAL CIRCULATORY SUPPORT; ANTIARRHYTHMIC-DRUG THERAPY; INTERMACS ANNUAL-REPORT; BUNDLE-BRANCH BLOCK; LONG-TERM SURVIVAL; CONTINUOUS-FLOW; PRIMARY PREVENTION; INTERNATIONAL SOCIETY; ELECTRICAL DELAY AB Patients with advanced heart failure are at high risk for progression of their disease and sudden cardiac death. The role of device therapy in this patient population continues to evolve and is directed toward improving cardiac pump function and/or reducing sudden arrhythmic death. C1 [Choi, Anthony J.; Singh, Jagmeet P.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med,Electrophysiol Lab,Cardiac Arrhythmia Se, 55 Fruit St, Boston, MA 02114 USA. [Thomas, Sunu S.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Heart Failure & Transplant Serv,Dept Med, 55 Fruit St, Boston, MA 02114 USA. RP Singh, JP (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med,Electrophysiol Lab,Cardiac Arrhythmia Se, 55 Fruit St, Boston, MA 02114 USA. EM JSINGH@mgh.harvard.edu NR 69 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 1551-7136 J9 HEART FAIL CLIN JI Heart Fail. Clin. PD JUL PY 2016 VL 12 IS 3 BP 423 EP + DI 10.1016/j.hfc.2016.03.010 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ0QM UT WOS:000378905000010 PM 27371518 ER PT J AU Kadokura, A Frydenlund, N Leone, DA Yang, S Hoang, MP Deng, A Hernandez-Perez, M Biswas, A Singh, R Yaar, R Mahalingam, M AF Kadokura, Alexander Frydenlund, Noah Leone, Dominick A. Yang, Shi Hoang, Mai P. Deng, April Hernandez-Perez, Mader Biswas, Asok Singh, Rajendra Yaar, Ron Mahalingam, Meera TI Neurofibromin protein loss in desmoplastic melanoma subtypes: implicating NF1 allelic loss as a distinct genetic driver? SO HUMAN PATHOLOGY LA English DT Article DE Desmoplastic melanoma subtypes; Pure variant; Mixed variant; Neurofibromin; RETp ID CUTANEOUS MALIGNANT-MELANOMA; OF-THE-LITERATURE; PERINEURAL INVASION; TYPE-1; MUTATIONS; TUMORS; ASSOCIATION; DISEASE; PATIENT; PURE AB Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the protooncogene RET (RETp) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET, perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included chi(2) test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P = .02). In DM, significant differences in neurofibromin loss were noted in the following: non head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp, BRAF status, or PNI. RETp was marginally associated with PNI-positive DM versus PNI-negative DM (36 versus 18%; P = .08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers. Published by Elsevier Inc. C1 [Kadokura, Alexander] Boston Univ, Sch Med, Div Grad Med Sci, Boston, MA 02118 USA. [Frydenlund, Noah] Univ Iowa, Carver Coll Med, Iowa City, IA 52240 USA. [Leone, Dominick A.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Yang, Shi] Boston Univ Med, Dept Pathol, Boston, MA 02118 USA. [Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02118 USA. [Deng, April] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01601 USA. [Hernandez-Perez, Mader] Miraca Life Sci, Newton Upper Falls, MA 02458 USA. [Biswas, Asok] Western Gen Hosp, Dept Pathol, Edinburgh EH13 9QW, Midlothian, Scotland. [Singh, Rajendra] Icahn Sch Med Mt Sinai, Dept Pathol & Dermatol, New York, NY 10001 USA. [Yaar, Ron] Aurora Diagnost GPA Labs, Greensboro, NC 27401 USA. [Mahalingam, Meera] VA Consolidated Labs, Dept Pathol & Lab Med, Dermatopathol Sect, 1400 VFW PKWY, West Roxbury, MA 02132 USA. RP Mahalingam, M (reprint author), VA Consolidated Labs, Dept Pathol & Lab Med 113, Dermatopathol Sect, 1400 VFW PKWY, West Roxbury, MA 02132 USA. EM me@meeramahalingam.com NR 45 TC 2 Z9 2 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD JUL PY 2016 VL 53 BP 82 EP 90 DI 10.1016/j.humpath.2016.02.012 PG 9 WC Pathology SC Pathology GA DP7GW UT WOS:000378668200011 PM 26980030 ER PT J AU Mendes, RT Nguyen, D Stephens, D Pamuk, F Fernandes, D Van Dyke, TE Kantarci, A AF Mendes, Reila Taina Nguyen, Daniel Stephens, Danielle Pamuk, Ferda Fernandes, Daniel Van Dyke, Thomas E. Kantarci, Alpdogan TI Endothelial Cell Response to Fusobacterium nucleatum SO INFECTION AND IMMUNITY LA English DT Article ID PORPHYROMONAS-GINGIVALIS; GROWTH-FACTOR; IN-VITRO; DISEASE; ANGIOGENESIS; EXPRESSION; ADHESION; VEGF; CD31; PERIODONTITIS AB Vascular response is an essential aspect of an effective immune response to periodontal disease pathogens, as new blood vessel formation contributes to wound healing and inflammation. Gaining a greater understanding of the factors that affect vascular response may then contribute to future breakthroughs in dental medicine. In this study, we have characterized the endothelial cell response to the common bacterium Fusobacterium nucleatum, an important bridging species that facilitates the activity of late colonizers of the dental biofilm. Endothelial cells were infected with Fusobacterium nucleatum (strain 25586) for periods of 4, 12, 24, or 48 h. Cell proliferation and tube formation were analyzed, and expression of adhesion molecules (CD31 and CD34) and vascular endothelial growth factor (VEGF) receptors 1 and 2 was measured by fluorescence-activated cell sorter (FACS) analysis. Data indicate that F. nucleatum impaired endothelial cell proliferation and tube formation. The findings suggest that the modified endothelial cell response acts as a mechanism promoting the pathogenic progression of periodontal diseases and may potentially suggest the involvement of periodontopathogens in systemic diseases associated with periodontal inflammation. C1 [Mendes, Reila Taina; Nguyen, Daniel; Stephens, Danielle; Pamuk, Ferda; Van Dyke, Thomas E.; Kantarci, Alpdogan] Forsyth Inst, Cambridge, MA USA. [Mendes, Reila Taina; Fernandes, Daniel] Univ Estadual Ponta Grossa, Ponta Grossa, PR, Brazil. [Pamuk, Ferda] Istanbul Aydin Univ, Istanbul, Turkey. RP Kantarci, A (reprint author), Forsyth Inst, Cambridge, MA USA. EM akantarci@forsyth.org FU NIH/NIDCR [DE020906, DE15566]; Capes/Brazil [2100/13-4] FX This work, including the efforts of Alpdogan Kantarci, was funded by NIH/NIDCR (DE020906 and DE15566). This work, including the efforts of Reila Taina Mendes, was funded by Capes/Brazil - Science without borders (2100/13-4). NR 50 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2016 VL 84 IS 7 BP 2141 EP 2148 DI 10.1128/IAI.01305-15 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DP5IO UT WOS:000378529700022 PM 27185790 ER PT J AU O'Neill, AF Adil, EA Irace, AL Neff, L Davis, IJ Perez-Atayde, AR Voss, SD Weinberg, O Rahbar, R AF O'Neill, Allison F. Adil, Eelam A. Irace, Alexandria L. Neff, Laura Davis, Ian J. Perez-Atayde, Antonio R. Voss, Stephan D. Weinberg, Olga Rahbar, Reza TI Post-transplant lymphoproliferative disorder of the pediatric airway: Presentation and management SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Review DE Post-transplant lymphoproliferative disorder; Airway obstruction; Epstein-Barr virus; Rituximab ID EPSTEIN-BARR-VIRUS; ORGAN TRANSPLANT RECIPIENTS; LIVER-TRANSPLANTATION; DISEASE PTLD; IMMUNOSUPPRESSION; RITUXIMAB; CHEMOTHERAPY; LYMPHOCYTES; CHILDREN; LOADS AB Objective: Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of immunosuppression with little consensus on its evaluation and management. The purpose of this contemporary review is to describe a pediatric patient with PTLD of the airway and review the literature to provide multidisciplinary recommendations regarding management. Data Sources: Retrospective chart and literature review. Review Methods: A pediatric patient with PTLD of the airway is described. An extensive literature search to review the existing data on pediatric PTLD of the upper airway was also performed. Results: A pediatric patient with mixed fetal/embryonal hepatoblastoma developed laryngo-tracheal PTLD following liver transplantation. Diagnostic positron emission tomography (PET) scan demonstrated multiple sites of abnormal fluorodeoxyglucose (FDG) uptake within the larynx, distal esophagus, cervical lymph nodes, and abdomen concerning for PTLD. Laryngeal biopsy demonstrated Epstein Barr virus (EBV) positive cells confirming the diagnosis. Rituximab therapy and reduction of immunosuppression resulted in resolution of his laryngeal disease in 3 months. An extensive literature search to review the existing data on pediatric PTLD of the larynx and trachea revealed 14 reported cases. Conclusions: PTLD of the pediatric airway is an EBV-associated disease that requires a high index of suspicion as patients can often present with non-specific signs and symptoms but progress to have significant airway compromise. Evaluation consists of peripheral blood polymerase chain reaction (PCR) assays, biopsy, and PET/CT imaging. Management options include reduction of immunosuppression and/or systemic therapies. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [O'Neill, Allison F.] Harvard Univ, Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol,Med Sch, 300 Longwood Ave, Boston, MA 02115 USA. [Adil, Eelam A.; Irace, Alexandria L.; Rahbar, Reza] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, 300 Longwood Ave, Boston, MA 02115 USA. [Adil, Eelam A.; Rahbar, Reza] Harvard Univ, Dept Otolaryngol, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. [Neff, Laura] Childrens Mercy Hosp, Dept Otolaryngol, 2401 Gillham Rd, Kansas City, MO 64108 USA. [Davis, Ian J.] Univ N Carolina, Dept Pediat & Genet, Chapel Hill, NC 27599 USA. [Davis, Ian J.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Perez-Atayde, Antonio R.; Weinberg, Olga] Boston Childrens Hosp, Dept Pathol, 300 Longwood Ave, Boston, MA 02115 USA. [Voss, Stephan D.] Boston Childrens Hosp, Dept Radiol, 300 Longwood Ave, Boston, MA 02115 USA. RP O'Neill, AF (reprint author), Harvard Univ, Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol,Med Sch, 300 Longwood Ave, Boston, MA 02115 USA. EM allison_oneill@dfci.harvard.edu NR 39 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD JUL PY 2016 VL 86 BP 218 EP 223 DI 10.1016/j.ijpor1.2016.04.035 PG 6 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DP4EM UT WOS:000378449000042 PM 27260610 ER PT J AU Strychowsky, JE Albert, D Chan, K Cheng, A Daniel, SJ De Alarcon, A Garabedian, N Hart, C Hartnick, C Inglis, A Jacobs, I Kleinman, ME Mehta, NM Nicollas, R Nuss, R Pransky, S Russell, J Rutter, M Schilder, A Thompson, D Triglia, JM Volk, M Ward, B Watters, K Wyatt, M Zalzal, G Zur, K Rahbar, R AF Strychowsky, Julie E. Albert, David Chan, Kenny Cheng, Alan Daniel, Sam J. De Alarcon, Alessandro Garabedian, Noel Hart, Catherine Hartnick, Christopher Inglis, Andy Jacobs, Ian Kleinman, Monica E. Mehta, Nilesh M. Nicollas, Richard Nuss, Roger Pransky, Seth Russell, John Rutter, Mike Schilder, Anne Thompson, Dana Triglia, Jean-Michel Volk, Mark Ward, Bob Watters, Karen Wyatt, Michelle Zalzal, George Zur, Karen Rahbar, Reza TI International Pediatric Otolaryngology Group (IPOG) consensus recommendations: Routine peri-operative pediatric tracheotomy care SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Tracheotomy; Tracheostomy; Pediatric AB Objectives: To develop consensus recommendations for pen-operative tracheotomy care in pediatric patients. Methods: Expert opinion by the members of the International Pediatric Otolaryngology Group (IPOG). The mission of the IPOG is to develop expertise-based consensus recommendations for the management of pediatric otolaryngologic disorders with the goal of improving patient care. The consensus recommendations herein represent the first publication by the group. Results: Consensus recommendations including pre-operative, intra-operative, and post-operative considerations, as well as sedation and nutrition management are described. These recommendations are based on the collective opinion of the IPOG members and are targeted to (i) otolaryngologists who perform tracheotomies on pediatric patients, (ii) intensivists who are involved in the shared-care of these patients, and (iii) allied health professionals. Conclusion: Pediatric pen-operative tracheotomy care consensus recommendations are aimed at improving patient-centered care in this patient population. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Strychowsky, Julie E.; Nuss, Roger; Volk, Mark; Watters, Karen; Rahbar, Reza] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA USA. [Strychowsky, Julie E.] Univ Western Ontario, Childrens Hosp, London Hlth Sci Ctr, Dept Otolaryngol Head & Neck Surg, London, ON, Canada. [Albert, David; Wyatt, Michelle] Great Ormond St Hosp Sick Children, Great Ormond St, London WC1N 3JH, England. [Chan, Kenny] Childrens Hosp Colorado, Aurora, CO USA. [Cheng, Alan] Univ Sydney, Dept Pediat Otolaryngol, Sydney Childrens Hosp Network, Westmead Campus, Sydney, NSW 2006, Australia. [Daniel, Sam J.] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Montreal, PQ H3H 1P3, Canada. [De Alarcon, Alessandro; Hart, Catherine; Rutter, Mike] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Garabedian, Noel] Univ Paris 05, Hop Necker Enfants Malad, AP HP, Pediat ENT Dept, Paris, France. [Hartnick, Christopher] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. [Inglis, Andy] Seattle Childrens Hosp, Seattle, WA USA. [Jacobs, Ian; Zur, Karen] Childrens Hosp Philadelphia, Div Otolaryngol, Philadelphia, PA 19104 USA. [Kleinman, Monica E.; Mehta, Nilesh M.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Div Crit Care Med, Boston, MA USA. [Nicollas, Richard; Triglia, Jean-Michel] Aix Marseille Univ, La Timone Childrens Hosp, Dept Pediat Otolaryngol, Marseille, France. [Nuss, Roger; Volk, Mark; Watters, Karen; Rahbar, Reza] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Pransky, Seth] Rady Childrens Hosp, San Diego, CA USA. [Russell, John] Our Ladys Childrens Hosp, Dublin, Ireland. [Schilder, Anne] Royal Natl Throat Nose & Ear Hosp, UCL Ear Inst, EvidENT, Grays Inn Rd, London WC1X 8DA, England. [Thompson, Dana] Ann & Robert H Lurie Childrens Hosp Chicago, Div Otolaryngol Head & Neck Surg, Chicago, IL 60611 USA. [Ward, Bob] NYU, Dept Otolaryngol Head & Neck Surg, Langone Med Ctr, New York, NY USA. [Zalzal, George] Natl Childrens Hosp, Dept Otolaryngol, Washington, DC USA. RP Strychowsky, JE (reprint author), Univ Western Ontario, Dept Otolaryngol Head & Neck Surg, VH B3-444 800 Commissioners Rd East, London, ON N6A 5W9, Canada. EM julie.strychowsky@lhsc.on.ca RI Mehta, Nilesh/G-7073-2016 FU Department of Health [NIHR-RP-011-045]; NCATS NIH HHS [UL1 TR001425] NR 1 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD JUL PY 2016 VL 86 BP 250 EP 255 DI 10.1016/j.ijpor1.2016.03.029 PG 6 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DP4EM UT WOS:000378449000049 PM 27132195 ER PT J AU Carter, J Rahbar, R Brigger, M Chan, K Cheng, A Daniel, SJ De Alarcon, A Garabedian, N Hart, C Hartnick, C Jacobs, I Liming, B Nicollas, R Pransky, S Richter, G Russell, J Rutter, MJ Schilder, A Smith, RJH Strychowsky, J Ward, R Watters, K Wyatt, M Zalzal, G Zur, K Thompson, D AF Carter, John Rahbar, Reza Brigger, Matthew Chan, Kenny Cheng, Alan Daniel, Sam J. De Alarcon, Alessandro Garabedian, Noel Hart, Catherine Hartnick, Christopher Jacobs, Ian Liming, Bryan Nicollas, Richard Pransky, Seth Richter, Gresham Russell, John Rutter, Michael J. Schilder, Anne Smith, Richard J. H. Strychowsky, Julie Ward, Robert Watters, Karen Wyatt, Michelle Zalzal, George Zur, Karen Thompson, Dana TI International Pediatric ORL Group (IPOG) laryngomalacia consensus recommendations SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Laryngomalacia; Infant; Stridor; Pediatric AB Objective: To provide recommendations for the comprehensive management of young infants who present with signs or symptoms concerning for laryngomalacia. Methods: Expert opinion by the members of the International Pediatric Otolaryngology Group (IPOG). Results: Consensus recommendations include initial care and triage recommendations for health care providers who commonly evaluate young infants with noisy breathing. The consensus statement also provides comprehensive care recommendations for otolaryngologists who manage young infants with laryngomalacia including: evaluation and treatment considerations for commonly debated issues in laryngomalacia, initial work-up of infants presenting with inspiratory stridor, treatment recommendations based on disease severity, management of the infant with feeding difficulties, post-surgical treatment management recommendations, and suggestions for acid suppression therapy. Conclusion: Laryngomalacia care consensus recommendations are aimed at improving patient centered care in infants with laryngomalacia. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Carter, John; Thompson, Dana] Ann & Robert H Lurie Childrens Hosp Chicago, Div Otolaryngol Head & Neck Surg, 225 Chicago Ave, Chicago, IL 60611 USA. [Rahbar, Reza; Watters, Karen] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA USA. [Brigger, Matthew; Pransky, Seth] Rady Childrens Hosp, San Diego, CA USA. [Chan, Kenny] Childrens Hosp Colorado, Aurora, CO USA. [Cheng, Alan] Univ Sydney, Sydney Childrens Hosp Network, Dept Pediat Otolaryngol, Westmead Campus, Sydney, NSW 2006, Australia. [Daniel, Sam J.] McGill Univ, Montreal Childrens Hosp, Dept Otolaryngol Head & Neck Surg, Ctr Hlth, Montreal, PQ H3H 1P3, Canada. [De Alarcon, Alessandro; Hart, Catherine; Rutter, Michael J.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Garabedian, Noel] Univ Paris 05, Hop Necker Enfants Malad, AP HP, Pediat ENT Dept, Paris, France. [Hartnick, Christopher] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. [Jacobs, Ian; Zur, Karen] Childrens Hosp Philadelphia, Div Otolaryngol, Philadelphia, PA 19104 USA. [Liming, Bryan; Smith, Richard J. H.] Univ Iowa Hosp & Clin, Dept Otolaryngol, Iowa City, IA 52242 USA. [Nicollas, Richard] Aix Marseille Univ, La Timone Childrens Hosp, Dept Pediat Otolaryngol, Marseille, France. [Richter, Gresham] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Russell, John] Our Ladys Childrens Hosp, Dublin, Ireland. [Schilder, Anne] Royal Natl Throat Nose & Ear Hosp, UCL Ear Inst, EvidENT, Grays Inn Rd, London WC1X 8DA, England. [Strychowsky, Julie] Univ Western Ontario, Dept Otolaryngol Head & Neck Surg, Childrens Hosp, London Hlth Sci Ctr, London, ON, Canada. [Ward, Robert] NYU, Dept Otolaryngol Head & Neck Surg, Langone Med Ctr, New York, NY USA. [Wyatt, Michelle] Great Ormond St Hosp Sick Children, Great Ormond St, London WC1N 3JH, England. [Zalzal, George] Natl Childrens Hosp, Dept Otolaryngol, Washington, DC USA. RP Carter, J (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, Div Otolaryngol Head & Neck Surg, 225 Chicago Ave, Chicago, IL 60611 USA. EM jmcarter@luriechildrens.org FU Department of Health [NIHR-RP-011-045]; NCATS NIH HHS [UL1 TR001425] NR 0 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 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD JUL PY 2016 VL 86 BP 256 EP 261 DI 10.1016/j.ijpor1.2016.04.007 PG 6 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DP4EM UT WOS:000378449000050 PM 27107728 ER PT J AU Morrison, K Winter, L Gitlin, LN AF Morrison, Karen Winter, Laraine Gitlin, Laura N. TI Recruiting Community-Based Dementia Patients and Caregivers in a Nonpharmacologic Randomized Trial: What Works and How Much Does It Cost? SO JOURNAL OF APPLIED GERONTOLOGY LA English DT Article DE caregiving; dementia care; home care; clinical trials ID ALZHEIMER-DISEASE RESEARCH; OLDER-ADULTS; INTERVENTION RESEARCH; AFRICAN-AMERICAN; AGING RESEARCH; RETENTION; MANAGEMENT; PARTICIPATION; PREVENTION; ATTITUDES AB Objectives: The aim of this study was to evaluate the yield and cost of three recruitment strategiesdirect mail, newspaper advertisements, and community outreachfor identifying and enrolling dementia caregivers into a randomized trial testing a nonpharmacologic approach to enhancing quality of life of patients and caregivers (dyads). Method: Enrollment occurred between 2006 and 2008. The number of recruitment inquiries, number and race of enrollees, and costs for each recruitment strategy were recorded. Results: Of 284 inquiries, 237 (83%) dyads enrolled. Total cost for recruitment across methodologies was US$154 per dyad. Direct mailings resulted in the most enrollees (n = 135, 57%) and was the least costly method (US$63 per dyad) compared with newspaper ads (US$224 per dyad) and community outreach (US$350 per dyad). Although enrollees were predominately White, mailings yielded the highest number of non-Whites (n = 37). Discussion: Direct mailings was the most effective and least costly method for enrolling dyads in a nonpharmacologic dementia trial. C1 [Morrison, Karen] Bayada Home Hlth Care, 190 N Independence Mall West,Suite 700, Philadelphia, PA 19106 USA. [Winter, Laraine] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Gitlin, Laura N.] Johns Hopkins Univ, Ctr Innovat Care Aging, Baltimore, MD USA. RP Morrison, K (reprint author), Bayada Home Hlth Care, 190 N Independence Mall West,Suite 700, Philadelphia, PA 19106 USA. EM morrisonkk49@gmail.com FU National Institute on Aging; National Institute on Nursing Research [RO1 AG22254]; PA Department of Health, Tobacco Settlement [SAP 100027298] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research reported in this article was supported by funds from the National Institute on Aging and the National Institute on Nursing Research (Grant RO1 AG22254) and the PA Department of Health, Tobacco Settlement (SAP 100027298). NR 40 TC 3 Z9 3 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0733-4648 EI 1552-4523 J9 J APPL GERONTOL JI J. Appl. Gerontol. PD JUL PY 2016 VL 35 IS 7 BP 788 EP 800 DI 10.1177/0733464814532012 PG 13 WC Gerontology SC Geriatrics & Gerontology GA DP7PM UT WOS:000378691300006 PM 24799354 ER PT J AU Dy, ME Chang, FCF De Jesus, S Anselm, I Mahant, N Zeilman, P Rodan, LH Foote, KD Tan, WH Eskandar, E Sharma, N Okun, MS Fung, VSC Waugh, JL AF Dy, Marisela E. Chang, Florence C. F. De Jesus, Sol Anselm, Irina Mahant, Neil Zeilman, Pamela Rodan, Lance H. Foote, Kelly D. Tan, Wen-Hann Eskandar, Emad Sharma, Nutan Okun, Michael S. Fung, Victor S. C. Waugh, Jeff L. TI Treatment of ADCY5-Associated Dystonia, Chorea, and Hyperkinetic Disorders With Deep Brain Stimulation: A Multicenter Case Series SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE chorea; ADCY5; deep brain stimulation; whole-exome sequencing; hyperkinetic movements ID FACIAL MYOKYMIA FDFM; FAMILIAL DYSKINESIA; ADCY5 MUTATIONS; EXPRESSION; GENE AB ADCY5 mutations have been reported as a cause of early onset hyperkinetic movements associated with delayed motor milestones, hypotonia, and exacerbation during sleep. The movement disorder may be continuous or episodic, and can vary considerably in severity within families and in individuals. The authors report a case series of 3 patients with ADCY5 mutations treated with deep brain stimulation after unsuccessful medication trials. All had extensive imaging, metabolic, and genetic testing prior to confirmation of their ADCY5 mutation. Two of the patients had the c.1252C>T; p.R418W mutation, while the youngest and most severely affected had a de novo c.2080_2088del; p.K694_M696 mutation. All had variable and incomplete, but positive responses to deep brain stimulation. The authors conclude that deep brain stimulation may provide benefit in ADCY5-related movement disorders. Long-term efficacy remains to be confirmed by longitudinal observation. ADCY5 should be considered in the differential diagnosis of early onset hyperkinetic movement disorders, and may respond to deep brain stimulation. C1 [Dy, Marisela E.; Anselm, Irina; Sharma, Nutan; Waugh, Jeff L.] Boston Childrens Hosp, Dept Neurol, 333 Longwood Ave,Fegan 11, Boston, MA 02115 USA. [Dy, Marisela E.; Sharma, Nutan; Waugh, Jeff L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dy, Marisela E.; Anselm, Irina; Rodan, Lance H.; Tan, Wen-Hann; Eskandar, Emad; Sharma, Nutan; Waugh, Jeff L.] Harvard Med Sch, Boston, MA USA. [Chang, Florence C. F.; Mahant, Neil; Fung, Victor S. C.] Westmead Hosp, Dept Neurol, Movement Disorders Unit, Westmead, NSW, Australia. [Chang, Florence C. F.; Mahant, Neil; Fung, Victor S. C.] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia. [De Jesus, Sol; Zeilman, Pamela; Okun, Michael S.] Univ Florida, Dept Neurol, Ctr Movement Disorders & Neurorestorat, Gainesville, FL USA. [Rodan, Lance H.; Tan, Wen-Hann] Boston Childrens Hosp, Div Genet & Genom, 333 Longwood Ave,Fegan 11, Boston, MA 02115 USA. [Foote, Kelly D.; Okun, Michael S.] Univ Florida, Dept Neurosurg, Ctr Movement Disorders & Neurorestorat, Gainesville, FL USA. [Eskandar, Emad] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Dy, ME (reprint author), Boston Childrens Hosp, Dept Neurol, 333 Longwood Ave,Fegan 11, Boston, MA 02115 USA. EM marisela.dy@childrens.harvard.edu NR 18 TC 2 Z9 2 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD JUL PY 2016 VL 31 IS 8 BP 1027 EP 1035 DI 10.1177/0883073816635749 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DQ0GL UT WOS:000378876900011 PM 27052971 ER PT J AU Bevers, MB McGuone, D Jerath, NU Musolino, PL AF Bevers, Matthew B. McGuone, Declan Jerath, Nivedita U. Musolino, Patricia L. TI Leptomeningeal transthyretin-type amyloidosis presenting as acute hydrocephalus and subarachnoid hemorrhage SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Amyloidosis; Subarachnoid hemorrhage; Transthyretin ID MENINGOCEREBROVASCULAR AMYLOIDOSIS; POLYNEUROPATHY; TAFAMIDIS AB We present a report of a 47-year-old woman with developmental delay who presented with subarachnoid hemorrhage and acute hydrocephalus. She did not have an aneurysm, but there was symmetric calcification and gadolinium-enhancement of the meninges within the Sylvian fissure. Biopsy and genetic testing confirmed transthyretin-type amyloidosis. It is important to consider such rare causes in atypical presentations of non-aneurysmal subarachnoid hemorrhage. (c) 2016 Elsevier Ltd. All rights reserved. C1 [Bevers, Matthew B.; Jerath, Nivedita U.; Musolino, Patricia L.] Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,WACC 835, Boston, MA 02118 USA. [McGuone, Declan] Massachusetts Gen Hosp, Dept Neuropathol, Boston, MA 02118 USA. [McGuone, Declan] Off Chief Med Examiner, New York, NY USA. [Jerath, Nivedita U.] Univ Iowa Hosp & Clin, Dept Neurol, Iowa City, IA 52242 USA. RP Bevers, MB (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,WACC 835, Boston, MA 02118 USA. EM mbevers@partners.org NR 9 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 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD JUL PY 2016 VL 29 BP 203 EP 205 DI 10.1016/j.jocn.2015.12.017 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DP4EU UT WOS:000378449800047 PM 26896372 ER PT J AU Song, Y Chou, EL Baecker, A You, NCY Song, YQ Sun, Q Liu, SM AF Song, Yan Chou, Elizabeth L. Baecker, Aileen You, Nai-Chieh Y. Song, Yiqing Sun, Qi Liu, Simin TI Endocrine-disrupting chemicals, risk of type 2 diabetes, and diabetes-related metabolic traits: A systematic review and meta-analysis SO JOURNAL OF DIABETES LA English DT Article DE bisphenol A; diabetes; endocrine-disrupting chemical; phthalate; meta-analysis ID PERSISTENT ORGANIC POLLUTANTS; NUTRITION EXAMINATION SURVEY; BISPHENOL-A CONCENTRATION; POLYCHLORINATED BIPHENYL EXPOSURE; CAPACITOR MANUFACTURING PLANT; INSULIN-RESISTANCE; PHTHALATE METABOLITES; SERUM CONCENTRATIONS; NATIONAL-HEALTH; ORGANOCHLORINE PESTICIDES AB BackgroundElevated blood or urinary concentrations of endocrine-disrupting chemicals (EDCs) may be related to increased risk of type 2 diabetes (T2D). The aim of the present study was to assess the role of EDCs in affecting risk of T2D and related metabolic traits. MethodsMEDLINE was searched for cross-sectional and prospective studies published before 8 March 2014 into the association between EDCs (dioxin, polychlorinated biphenyl [PCB], chlorinated pesticide, bisphenol A [BPA], phthalate) and T2D and related metabolic traits. Three investigators independently extracted information on study design, participant characteristics, EDC types and concentrations, and association measures. ResultsForty-one cross-sectional and eight prospective studies from ethnically diverse populations were included in the analysis. Serum concentrations of dioxins, PCBs, and chlorinated pesticides were significantly associated with T2D risk; comparing the highest to lowest concentration category, the pooled relative risks (RR) were 1.91 (95% confidence interval [CI] 1.44-2.54) for dioxins, 2.39 (95% CI 1.86-3.08) for total PCBs, and 2.30 (95% CI 1.81-2.93) for chlorinated pesticides. Urinary concentrations of BPA and phthalates were also associated with T2D risk; comparing the highest to lowest concentration categories, the pooled RR were 1.45 (95% CI 1.13-1.87) for BPA and 1.48 (95% CI 0.98-2.25) for phthalates. Further, EDC concentrations were associated with indicators of impaired fasting glucose and insulin resistance. ConclusionsPersistent and non-persistent EDCs may affect the risk of T2D. There is an urgent need for further investigation of EDCs, especially non-persistent ones, and T2D risk in large prospective studies. C1 [Song, Yan; Baecker, Aileen; You, Nai-Chieh Y.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA. [Song, Yan; Liu, Simin] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Song, Yiqing] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA. [Sun, Qi] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Sun, Qi] Harvard Med Sch, Boston, MA USA. [Sun, Qi] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Chou, Elizabeth L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Liu, SM (reprint author), Brown Univ, Box G-S121-2,121 South Main St, Providence, RI 02912 USA. EM simin_liu@brown.edu FU Burroughs Wellcome Fund FX This research was funded by the Burroughs Wellcome Fund. NR 74 TC 9 Z9 10 U1 15 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1753-0393 EI 1753-0407 J9 J DIABETES JI J. Diabetes PD JUL PY 2016 VL 8 IS 4 BP 516 EP 532 DI 10.1111/1753-0407.12325 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP8DE UT WOS:000378727300009 PM 26119400 ER PT J AU Ziegler, A Walker, R Varvares, M AF Ziegler, Andrea Walker, Ronald Varvares, Mark TI Oncologic Outcomes of Invasive Squamous Cell Carcinoma of the Scalp Requiring Resection of Cranial Bone SO JOURNAL OF NEUROLOGICAL SURGERY PART A-CENTRAL EUROPEAN NEUROSURGERY LA English DT Article DE squamous cell carcinoma; scalp cancer; head and neck cancer; survival outcomes; periosteal invasion ID CLINICAL PERINEURAL INVASION; RISK-FACTORS; HEAD; NECK; METASTASIS; SKIN; RECURRENCE; CANCER AB ObjectivesTo identify the recurrence rates and survival outcomes of patients with invasive squamous cell carcinoma of the scalp. MethodsThis study was a retrospective chart review of eight patients that had squamous cell carcinoma of the scalp with either periosteal or skull invasion on clinical and/or radiographic evaluation. ResultsThe disease-free survival was 62.5% (5/8 patients) with a local control rate of 75% (6/8 patients) for the entire group. The two patients with full-thickness craniectomy had a local control rate of 100% (2/2 patients); the patients with outer cortex removal had a local control rate of 66.7% (4/6 patients). The disease-free survival of the full-thickness group was 50% (1/2 patients ), and the disease-free survival of the outer cortex removal patients was 66.7% (4/6 patients). ConclusionDespite the invasive nature of this disease, a high degree of local control can be achieved in this high-risk group with multiple comorbidities using outer cortex drilldown, and, in properly selected patients, full-thickness calvarial resection. We conclude that for patients without evidence of medullary involvement that outer table drilldown offers a well-tolerated approach with reasonable oncologic control. C1 [Ziegler, Andrea] Loyola Univ, Stritch Sch Med, Dept Otolaryngol, 2160 S 1st Ave, Maywood, IL 60153 USA. [Walker, Ronald] St Louis Univ, Sch Med, Dept Otolaryngol, St Louis, MO USA. [Varvares, Mark] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. RP Varvares, M (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, 243 Charter St, Boston, MA 02114 USA. EM mark_varvares@meei.harvard.edu NR 14 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2193-6315 EI 2193-6323 J9 J NEUROL SURG PART A JI J. Neurol. Surg. Part A PD JUL PY 2016 VL 77 IS 4 BP 308 EP 311 DI 10.1055/s-0035-1567859 PG 4 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DP6MC UT WOS:000378610200005 PM 26807618 ER PT J AU Costine, B Smith, C Price, G McGuone, D Duhaime, AC AF Costine, Beth Smith, Colin Price, George McGuone, Declan Duhaime, Ann-Christine TI NEUROBLASTS DIFFERENTIATE AT THE WHITE MATTER LESION AFTER TBI IN THE GYRENCEPHALIC BRAIN SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE cortical impact; gyrencephalic; doublecortin; white matter C1 [Costine, Beth; Smith, Colin; Price, George; McGuone, Declan; Duhaime, Ann-Christine] Massachusetts Gen Hosp, Neurosurg, 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 JUL 1 PY 2016 VL 33 IS 13 MA PSA-153 BP A66 EP A67 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200181 ER PT J AU Dixon, CE Carlson, SW AF Dixon, C. Edward Carlson, Shaun W. TI FUNCTIONAL DEFICITS ARE ATTENUATED IN HUMAN ALPHA SYNUCLEIN TRANSGENIC RATS AFTER TBI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE alpha synuclein; transgenic; CCI; function C1 [Dixon, C. Edward; Carlson, Shaun W.] Univ Pittsburgh, Neurosurg, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Neurosurg, Pittsburgh, PA 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-190 BP A80 EP A81 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200219 ER PT J AU Duhaime, AC Murphy, S Rincon, S Young, J Adapa, P Caruso, P AF Duhaime, Ann-Christine Murphy, Sarah Rincon, Sandra Young, Joseph Adapa, Pavani Caruso, Paul TI MRI-CENTRIC ASSESSMENT AND MANAGEMENT IN ACUTE PEDIATRIC TBI: UTILITY AND RELIABILITY COMPARED TO CT SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE MRI; CT; neuroimaging; management; emergency department; intensive care unit C1 [Duhaime, Ann-Christine; Murphy, Sarah; Rincon, Sandra; Young, Joseph; Adapa, Pavani; Caruso, Paul] 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-271 BP A110 EP A110 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200300 ER PT J AU Edlow, B Chatelle, C Spencer, C Chu, C O'Connor, K Hirschberg, R Hochberg, L Giacino, J Rosenthal, E Wu, O AF Edlow, Brian Chatelle, Camille Spencer, Camille Chu, Catherine O'Connor, Kathryn Hirschberg, Ronald Hochberg, Leigh Giacino, Joseph Rosenthal, Eric Wu, Ona TI DETECTING CONSCIOUSNESS AND PREDICTING RECOVERY IN ACUTE SEVERE TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE coma; consciousness C1 [Edlow, Brian; Chatelle, Camille; Spencer, Camille; Chu, Catherine; O'Connor, Kathryn; Hochberg, Leigh; Rosenthal, Eric] Harvard Univ, Massachusetts Gen Hosp, Neurol, Boston, MA 02115 USA. [Wu, Ona] Harvard Univ, Massachusetts Gen Hosp, Radiol, Boston, MA 02115 USA. [Hirschberg, Ronald; Giacino, Joseph] Spaulding Rehabil Hosp, PM&R, Charlestown, 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 JUL 1 PY 2016 VL 33 IS 13 MA PSA-094 BP A46 EP A47 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200123 ER PT J AU Grovola, M Harris, JP Brown, DP Wolf, JA Cullen, DK AF Grovola, Michael Harris, James P. Brown, Daniel P. Wolf, John A. Cullen, D. Kacy TI NEUROPATHOLOGICAL ALTERATIONS IN THE HILUS AFTER DIFFUSE BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE large animal models; mossy cell; diffuse brain injury; synaptic changes C1 [Grovola, Michael; Harris, James P.; Brown, Daniel P.; Wolf, John A.; Cullen, D. Kacy] Univ Penn, Neurosurg, Philadelphia, PA 19104 USA. [Grovola, Michael; Harris, James P.; Brown, Daniel P.; Wolf, John A.; Cullen, D. Kacy] Philadelphia VA Med Ctr, Neurosurg, Philadelphia, PA 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-247 BP A101 EP A101 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200276 ER PT J AU Gupta, R Ahmadi, E Namati, J Blair, P Padole, A Chico-Calero, I Lev, M Lee, J Hamblin, M Vakoc, B AF Gupta, Rajiv Ahmadi, Emad Namati, Jacqueline Blair, Parry Padole, Atul Chico-Calero, Isabel Lev, Michael Lee, Jarone Hamblin, Michael Vakoc, Benjamin TI LOW-LEVEL LIGHT THERAPY FOR TRAUMATIC BRAIN INJURY (TBI) SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE low-level light therapy; advanced MRI imaging; diffusion tensor imaging; resting-state fMRI; hypercapnia; cerbrovascular reserve C1 [Gupta, Rajiv; Ahmadi, Emad; Namati, Jacqueline; Blair, Parry; Padole, Atul; Chico-Calero, Isabel; Lev, Michael; Lee, Jarone; Hamblin, Michael; Vakoc, Benjamin] Massachusetts Gen Hosp, Neuroradiol, Boston, MA 02114 USA. [Gupta, Rajiv; Ahmadi, Emad; Namati, Jacqueline; Padole, Atul; Chico-Calero, Isabel; Lev, Michael; Lee, Jarone; Hamblin, Michael; Vakoc, Benjamin] Harvard Univ, Sch Med, Radiol, 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 JUL 1 PY 2016 VL 33 IS 13 MA AANS02-03 BP A2 EP A3 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200004 ER PT J AU Haghighi, F Carr, W LoPresti, M Yarnell, A Karmakar, M Mendelev, N Umali, M McCarron, R Elder, G Ahlers, S AF Haghighi, Fatemeh Carr, Walter LoPresti, Matthew Yarnell, Angela Karmakar, Moumita Mendelev, Natalia Umali, Michelle McCarron, Richard Elder, Gregory Ahlers, Stephen TI EPIGENETIC AND TRANSCRIPTIONAL SIGNATURES OF BLAST EXPOSURE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE epigenetics; methylation; blast C1 [Haghighi, Fatemeh; Karmakar, Moumita; Mendelev, Natalia] Icahn Sch Med Mt Sinai, Neurosci, New York, NY 10029 USA. [Haghighi, Fatemeh; Umali, Michelle; Elder, Gregory] James J Peters VA Med Ctr, Med Epigen, New York, NY USA. [Carr, Walter; LoPresti, Matthew; Yarnell, Angela] Walter Reed Army Inst Res, Rockville, MD USA. [McCarron, Richard; Ahlers, Stephen] Naval Med Res Ctr, Silver Spring, MD 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-183 BP A78 EP A78 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200212 ER PT J AU Harel, N Yung, L Romero, A Santiago, T Guber, K Kastuar, S Nguyen, N Wu, YK Carmel, J Spungen, A Bauman, W AF Harel, Noam Yung, Lok Romero, Angelica Santiago, Tiffany Guber, Kenneth Kastuar, Shivani Nhuquynh Nguyen Wu, Yu-Kuang Carmel, Jason Spungen, Ann Bauman, William TI PAIRED MAGNETIC AND ELECTRICAL STIMULATION FOR CERVICAL SCI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE non-invasive brain stimulation; TMS; cervical electrical stimulation; spike timing-dependent plasticity C1 [Harel, Noam; Yung, Lok; Romero, Angelica; Santiago, Tiffany; Guber, Kenneth; Nhuquynh Nguyen; Wu, Yu-Kuang; Spungen, Ann; Bauman, William] James J Peters VA Med Ctr, Neurol, Spinal Cord Injury, Bronx, NY USA. [Harel, Noam; Kastuar, Shivani; Spungen, Ann; Bauman, William] Icahn Sch Med Mt Sinai, Neurol, Rehabil Med, New York, NY 10029 USA. [Carmel, Jason] Cornell Univ, Coll Med, Burke Med Res Inst, Neurol, White Plains, NY 10605 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 JUL 1 PY 2016 VL 33 IS 13 MA AANS03-02 BP A3 EP A3 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200006 ER PT J AU Padole, A Ahmadi, E He, J Vablus, M Chan, P Namati, J Vakoc, B Tan, C Hayman, A Gupta, R AF Padole, Atul Ahmadi, Emad He, Julian Vablus, Mark Chan, Phoebe Namati, Jacqueline Vakoc, Benjamin Tan, Can Hayman, Anne Gupta, Rajiv TI ASSESSMENT OF WHITE MATTER TRACTS IN ACUTE HEAD TRAUMA USING ANATOM-E SOFTWARE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE acute head trauma; white matter tracts systems; software with deformable anatomic template C1 [Padole, Atul; Ahmadi, Emad; He, Julian; Chan, Phoebe; Namati, Jacqueline; Vakoc, Benjamin; Tan, Can; Hayman, Anne; Gupta, Rajiv] Massachusetts Gen Hosp, Neuroradiol, Boston, MA 02114 USA. [Vablus, Mark] Anatom E Syst, Houston, TX 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 JUL 1 PY 2016 VL 33 IS 13 MA PSA-175 BP A75 EP A75 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200203 ER PT J AU Spencer, C Chatelle, C Chu, C Wu, O Giacino, J Rosenthal, E Edlow, B AF Spencer, Camille Chatelle, Camille Chu, Catherine Wu, Ona Giacino, Joseph Rosenthal, Eric Edlow, Brian TI LONGITUDINAL CHANGES IN CORTICAL NETWORK CONNECTIVITY AFTER RECOVERY FROM TRAUMATIC COMA SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE consciousness; coma; EEG; networks C1 [Spencer, Camille; Chatelle, Camille; Chu, Catherine; Rosenthal, Eric; Edlow, Brian] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. [Wu, Ona] Massachusetts Gen Hosp, Radiol, Boston, MA 02114 USA. [Giacino, Joseph] Spaulding Rehabil Hosp, PM&R, Charlestown, 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-255 BP A104 EP A104 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200284 ER PT J AU Tan, CO Hu, RL Padole, A Besheli, LD Lev, M Forghani, R Young, J Romero, J Gupta, R AF Tan, Can Ozan Hu, Ranliang Padole, Atul Besheli, Laleh Daftari Lev, Michael Forghani, Reza Young, Joseph Romero, Javier Gupta, Rajiv TI DUAL ENERGY CT SPOT SIGN FOR ASSESSMENT OF ACUTE INTRACRANIAL HEMORRHAGE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE intracranial hemorrhage; dual energy computed tomography; hematoma expansion; spot sign C1 [Hu, Ranliang; Padole, Atul; Besheli, Laleh Daftari; Lev, Michael; Young, Joseph; Romero, Javier; Gupta, Rajiv] Massachusetts Gen Hosp, Neuroradiol, Boston, MA 02114 USA. [Tan, Can Ozan] Spaulding Rehabil Hosp, Phys Med & Rehabil, Boston, MA USA. [Forghani, Reza] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. [Tan, Can Ozan; Hu, Ranliang; Padole, Atul; Besheli, Laleh Daftari; Lev, Michael; Young, Joseph; Romero, Javier; Gupta, Rajiv] Harvard Univ, Sch Med, Boston, MA USA. [Forghani, Reza] McGill Univ, Montreal, PQ, Canada. 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-265 BP A108 EP A108 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200294 ER PT J AU Wofford, KL Browne, K Harris, JP Mietus, C Brown, DP Grovola, M Kuo, E Wolf, JA Duda, JE Spiller, KL Cullen, DK AF Wofford, Kathryn L. Browne, Kevin Harris, James P. Mietus, Constance Brown, Daniel P. Grovola, Michael Kuo, Emory Wolf, John A. Duda, John E. Spiller, Kara L. Cullen, D. Kacy TI RAPID MICROGLIAL ACTIVATION NEAR INJURED NEURONS FOLLOWING DIFFUSE BRAIN INJURY IN SWINE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 34th Annual National Neurotrauma Symposium CY JUN 26-29, 2016 CL Lexington, KY DE diffuse brain injury; plasmalemmal disruption; glial reactivity C1 [Wofford, Kathryn L.; Browne, Kevin; Harris, James P.; Brown, Daniel P.; Grovola, Michael; Kuo, Emory; Wolf, John A.; Duda, John E.; Cullen, D. Kacy] Vet Affairs Med Ctr, Philadelphia, PA USA. [Wofford, Kathryn L.; Browne, Kevin; Harris, James P.; Mietus, Constance; Brown, Daniel P.; Grovola, Michael; Kuo, Emory; Wolf, John A.; Cullen, D. Kacy] Univ Penn, Neurosurg, Ctr Brain Injury & Repair, Philadelphia, PA 19104 USA. [Wofford, Kathryn L.; Spiller, Kara L.] Drexel Univ, Biomed Engn, 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 JUL 1 PY 2016 VL 33 IS 13 MA PSB-295 BP A118 EP A119 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DP2QY UT WOS:000378336200324 ER PT J AU Renapurkar, S Pasternack, MS Nielsen, GP Kaban, LB AF Renapurkar, Shravan Pasternack, Mark S. Nielsen, G. Petur Kaban, Leonard B. TI Juvenile Mandibular Chronic Osteomyelitis: Role of Surgical Debridement and Antibiotics SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID DIFFUSE SCLEROSING OSTEOMYELITIS; RECURRENT MULTIFOCAL OSTEOMYELITIS; OSTEITIS SAPHO SYNDROME; OF-THE-LITERATURE; RETROSPECTIVE ANALYSIS; HYPEROSTOSIS; PUSTULOSIS; SYNOVITIS; ACNE; CLASSIFICATION AB Purpose: To document outcomes of management of juvenile mandibular chronic osteomyelitis (JMCO) using a standardized treatment protocol including open biopsy, decortication, microbial culture, and long-term antibiotic therapy. Materials and Methods: This was a retrospective case study of pediatric patients with JMCO treated at Massachusetts General Hospital for Children from 1996 through 2014. Inclusion criteria included age younger than 18 years, diagnosis of JMCO, management by the protocol, adequate clinical and radiographic data in the record, and follow-up of at least 1 year after initial treatment. Inpatient and outpatient records were reviewed for demographics, clinical and radiographic findings, and histologic and laboratory evaluations. The predictor variable was the standardized treatment protocol and the primary outcome variables were disease status at end of treatment and complications of treatment. Results: Twenty patients (mean age at onset, 10.7 yr; range, 3 to 14 yr) were treated, 12 (11 girls) of whom met the inclusion criteria. Management of all patients consisted of biopsy (extraoral when feasible, n = 9; intraoral, n = 3), decortication, cultures, and long-term antibiotic therapy. Nonsteroidal antiinflammatory drugs (NSAIDs) were administered only as needed for pain control. There was complete resolution of osteomyelitis with no recurrence in 7 of 12 patients (mean follow-up, 4.3 yr; range, 1 to 11 yr). Five patients had partial responses, with decreased frequency and severity of disease recurrence. These were well controlled with short courses of antibiotics (4 to 12 weeks) with NSAIDs only as needed for pain control (mean follow-up, 1.4 yr; range, 1 to 3 yr). There were no major complications related to antibiotic therapy. Minor complications included rash (n = 2), nausea and vomiting (n = 1), and vaginal candidiasis (n = 1). Conclusion: The results of this study indicate that 58.3% of patients were cured and had no recurrent symptoms (mean follow-up, 4.3 yr). The remaining patients continue on intermittent treatment with antibiotics for recurrent episodes of swelling and pain. Favorable responses to antibiotic therapy support the hypothesis that JMCO is an infectious disease and that negative cultures might represent a failure of standard culture techniques to isolate the responsible organisms. (C) 2016 American Association of Oral and Maxillofacial Surgeons. C1 [Renapurkar, Shravan] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp, 188 Longwood Ave, Boston, MA 02115 USA. [Pasternack, Mark S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Infect Dis, Boston, MA USA. [Nielsen, G. Petur] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kaban, Leonard B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp,Massachusetts Gen Hosp Chi, 188 Longwood Ave, Boston, MA 02115 USA. RP Kaban, LB (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM Kaban.leonard@mgh.harvard.edu FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; MGH/AO Pediatric CMF fellowship FX This study was funded by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund and MGH/AO Pediatric CMF fellowship. NR 31 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUL PY 2016 VL 74 IS 7 BP 1368 EP 1382 DI 10.1016/j.joms.2016.01.027 PG 15 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DP5ZH UT WOS:000378576200015 PM 26921614 ER PT J AU Partridge, JC Cipriani, N Faquin, WC Chuang, SK Keith, DA Lahey, ET AF Partridge, Justin C. Cipriani, Nicole Faquin, William C. Chuang, Sung K. Keith, David A. Lahey, Edward Thomas TI Periarticular Cysts of the Temporomandibular Joint Are More Frequently Synovial Than Ganglion SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article AB Purpose: Differentiating between ganglion and synovial cysts by standard histology is difficult, leading to inaccurate statements on frequency for each of these periarticular lesions. The purpose of this study was to use immunohistochemical (IHC) analysis to 1) calculate the accuracy of the histologic diagnoses, 2) determine the frequency of ganglion and synovial cysts of the temporomandibular joint (TMJ), and 3) compare the frequency of these lesions in the TMJ compared with the extracranial skeleton in patients treated at Massachusetts General Hospital (MGH). Materials and Methods: This is a retrospective cohort study of all patients undergoing treatment of TMJ cysts at MGH from 2001 through 2013. IHC analysis of tissue samples for each patient was completed and compared with the original histologic diagnoses. Categorical variables, including age, gender, and sidedness, were recorded. A natural language search of the MGH Department of Pathology database determined the frequency of extracranial periarticular cysts during the same period. Results: Thirteen patients met the inclusion criteria. Eleven cysts were synovial and 2 were ganglion based on histology. IHC analysis identified 2 false-positive synovial cyst diagnoses, resulting in 100% sensitivity and 50% specificity for the original histologic assessment and a percentage error of 22%. Of the periarticular TMJ lesions, 69% were synovial cysts and 31% were ganglion cysts. The frequency of TMJ versus extracranial ganglion cysts was 0.24%, and the frequency of TMJ versus extracranial synovial cysts was 0.60% based on 3,176 extracranial cysts (1,506 synovial; 1,670 ganglion). Conclusion: This study represents the largest single-institution experience with periarticular cysts of the TMJ, and contrary to previous reports, TMJ cysts appear to be more frequently synovial than ganglion. IHC can be used to overcome the relatively poor specificity of histologic diagnosis of synovial cysts. (C) 2016 American Association of Oral and Maxillofacial Surgeons C1 [Partridge, Justin C.; Chuang, Sung K.; Keith, David A.; Lahey, Edward Thomas] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Partridge, Justin C.; Chuang, Sung K.; Keith, David A.; Lahey, Edward Thomas] Harvard Univ, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. [Cipriani, Nicole] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cipriani, Nicole; Faquin, William C.] Harvard Univ, Sch Med, Boston, MA USA. [Cipriani, Nicole] Univ Chicago Med & Biol Sci, Pathol, Chicago, IL USA. [Faquin, William C.] Massachusetts Gen Hosp, Head & Neck Pathol, Boston, MA 02114 USA. [Faquin, William C.] Massachusetts Gen Hosp, Pathol, Boston, MA 02114 USA. RP Lahey, ET (reprint author), Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp, 188 Longwood Ave, Boston, MA 02115 USA. EM elahey@post.harvard.edu FU Education and Research Fund; Department of Oral and Maxillofacial Surgery; Massachusetts General Hospital; Harvard Medical School Scholars in Medicine Office FX This study was funded by the Education and Research Fund, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and the Harvard Medical School Scholars in Medicine Office. NR 18 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUL PY 2016 VL 74 IS 7 BP 1396 EP 1402 DI 10.1016/j.joms.2016.01.036 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DP5ZH UT WOS:000378576200018 PM 26902711 ER PT J AU Glass, HC Shellhaas, RA Wusthoff, CJ Chang, T Abend, NS Chu, CJ Cilio, MR Glidden, DV Bonifacio, SL Massey, S Tsuchida, TN Silverstein, FS Soul, JS AF Glass, Hannah C. Shellhaas, Renee A. Wusthoff, Courtney J. Chang, Taeun Abend, Nicholas S. Chu, Catherine J. Cilio, M. Roberta Glidden, David V. Bonifacio, Sonia L. Massey, Shavonne Tsuchida, Tammy N. Silverstein, Faye S. Soul, Janet S. CA Neonatal Seizure Registry Study TI Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study SO JOURNAL OF PEDIATRICS LA English DT Article ID THERAPEUTIC HYPOTHERMIA; RISK-FACTORS; NEWBORNS AB Objective To determine the contemporary etiology, burden, and short-term outcomes of seizures in neonates monitored with continuous video-electroencephalogram (cEEG). Study design We prospectively collected data from 426 consecutive neonates (56% male, 88% term) <= 44 weeks' postmenstrual age with clinically suspected seizures and/or electrographic seizures. Subjects were assessed between January 2013 and April 2015 at 7 US tertiary care pediatric centers following the guidelines of the American Clinical Neurophysiology Society for cEEG for at-risk neonates. Seizure etiology, burden, management, and outcome were determined by chart review by the use of a case report form designed at study onset. Results The most common seizure etiologieswere hypoxic-ischemic encephalopathy (38%), ischemic stroke (18%), and intracranial hemorrhage (11%). Seizure burden was high, with 59% having >= 7 electrographic seizures and 16% having status epilepticus; 52% received >= 2 antiseizure medications. During the neonatal admission, 17% died; 49% of survivors had abnormal neurologic examination at hospital discharge. In an adjusted analysis, high seizure burden was a significant risk factor for mortality, length of hospital stay, and abnormal neurological examination at discharge. Conclusions In this large contemporary profile of consecutively enrolled newborns with seizures treated at centers that use cEEG per the guidelines of the American Clinical Neurophysiology Society, about one-half had high seizure burden, received >= 2 antiseizure medications, and/or died or had abnormal examination at discharge. Greater seizure burden was associated with increased morbidity and mortality. These findings underscore the importance of accurate determination of neonatal seizure frequency and etiology and a potential for improved outcome if seizure burden is reduced. C1 [Glass, Hannah C.; Cilio, M. Roberta] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Neurol, San Francisco, CA 94143 USA. [Glass, Hannah C.; Cilio, M. Roberta] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA. [Glass, Hannah C.; Glidden, David V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shellhaas, Renee A.; Silverstein, Faye S.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Wusthoff, Courtney J.] Stanford Univ, Dept Neurol, Palo Alto, CA 94304 USA. [Wusthoff, Courtney J.] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Chang, Taeun; Tsuchida, Tammy N.] George Washington Univ, Sch Med, Dept Neurol, Childrens Natl Hlth Syst, Washington, DC USA. [Abend, Nicholas S.; Massey, Shavonne] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. [Abend, Nicholas S.; Massey, Shavonne] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Abend, Nicholas S.; Massey, Shavonne] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chu, Catherine J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bonifacio, Sonia L.] Stanford Univ, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Soul, Janet S.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. RP Glass, HC (reprint author), Univ Calif San Francisco, Benioff Childrens Hosp, Dept Neurol, San Francisco, CA 94143 USA.; Glass, HC (reprint author), Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA.; Glass, HC (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. OI Chang, Taeun/0000-0002-1797-8449; Shellhaas, Renee/0000-0002-3175-3908 FU Pediatric Epilepsy Research Foundation (Multi-center Neonatal Seizure Registry) [A120625]; National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke [K23NS066137]; Neonatal Brain Research Institute at University of California, San Francisco; Boston Children's Hospital Intellectual and Developmental Disabilities Research Center [P30 HD18655]; University of California, San Francisco FX Supported by the Pediatric Epilepsy Research Foundation (Multi-center Neonatal Seizure Registry/A120625). H.G. is supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (K23NS066137) and the Neonatal Brain Research Institute at University of California, San Francisco. J.S. is supported by Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (P30 HD18655). REDCap (Research Electronic Data Capture) tools is supported by University of California, San Francisco. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors declare no conflicts of interest. NR 20 TC 5 Z9 5 U1 5 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2016 VL 174 BP 98 EP + DI 10.1016/j.jpeds.2016.03.035 PG 7 WC Pediatrics SC Pediatrics GA DP6PX UT WOS:000378620800021 PM 27106855 ER PT J AU Sabino, CP Deana, AM Yoshimura, TM da Silva, DFT Franca, CM Hamblin, MR Ribeiro, MS AF Sabino, Caetano P. Deana, Alessandro M. Yoshimura, Tania M. da Silva, Daniela F. T. Franca, Cristiane M. Hamblin, Michael R. Ribeiro, Martha S. TI The optical properties of mouse skin in the visible and near infrared spectral regions SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Article DE Biophotonics; Tissue spectroscopy; Skin optics; Photodiagnosis; Phototherapy; Radiative transfer ID DIFFUSE-REFLECTANCE SPECTROSCOPY; BIOLOGICAL TISSUES; SCATTERING; MELANIN; RANGE; LIGHT; LASER; NM AB Visible and near-infrared radiation is now widely employed in health science and technology. Pre-clinical trials are still essential to allow appropriate translation of optical methods into clinical practice. Our results stress the importance of considering the mouse strain and gender when planning pre-clinical experiments that depend on light-skin interactions. Here, we evaluated the optical properties of depilated albino and pigmented mouse skin using reproducible methods to determine parameters that have wide applicability in biomedical optics. Light penetration depth (delta), absorption (mu(a)), reduced scattering (mu'(s)) and reduced attenuation (mu'(t)) coefficients were calculated using the Kubellca-Munk model of photon transport and spectrophotometric measurements. Within a broad wavelength coverage (400-1400 nm), the main optical tissue interactions of visible and near infrared radiation could be inferred. Histological analysis was performed to correlate the findings with tissue composition and structure. Disperse melanin granules present in depilated pigmented mouse skin were shown to be irrelevant for light absorption. Gender mostly affected optical properties in the visible range due to variations in blood and abundance of dense connective tissue. On the other hand, mouse strains could produce more variations in the hydration level of skin, leading to changes in absorption in the infrared spectral region. A spectral region of minimal light attenuation, commonly referred as the "optical window", was observed between 600 and 1350 nm. (C) 2016 Elsevier B.V. All rights reserved. C1 [Sabino, Caetano P.; Yoshimura, Tania M.; Ribeiro, Martha S.] IPEN CNEN SP, Nucl & Energy Res Inst, Ctr Lasers & Applicat, Sao Paulo, SP, Brazil. [Sabino, Caetano P.] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo, SP, Brazil. [Sabino, Caetano P.] Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo, SP, Brazil. [Deana, Alessandro M.; da Silva, Daniela F. T.; Franca, Cristiane M.] Univ Nove de Julho, Biophoton Postgrad Program, Sao Paulo, SP, Brazil. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Ribeiro, MS (reprint author), IPEN CNEN SP, Nucl & Energy Res Inst, Ctr Lasers & Applicat, Sao Paulo, SP, Brazil. EM marthasr@usp.br RI Ribeiro, Martha/G-3517-2012; Sabino, Caetano/D-4196-2016; Yoshimura, Tania/A-5509-2017 OI Ribeiro, Martha/0000-0002-4203-1134; Sabino, Caetano/0000-0002-2048-2823; Yoshimura, Tania/0000-0003-4099-9739 FU Brazilian funding agency FAPESP [2014/02564-1]; Brazilian funding agency CNPq [307091/2011-2]; US NIH [R01AI050875] FX Authors gratefully recognize the efforts made on histological processing by Cristiano de Loura Santana and Fabiana dos Santos from the Biophotonics Applied to Health Sciences Laboratory at Nove de Julho University (Uninove). The financial support was provided by the Brazilian funding agencies FAPESP (grant 2014/02564-1) and CNPq (307091/2011-2). MR Hamblin was supported by the US NIH grant R01AI050875. NR 32 TC 4 Z9 4 U1 8 U2 14 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD JUL PY 2016 VL 160 BP 72 EP 78 DI 10.1016/j.jphotobiol.2016.03.047 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DP4GD UT WOS:000378453500009 PM 27101274 ER PT J AU Janssen, SJ Kortlever, JTP Ready, JE Raskin, KA Ferrone, ML Hornicek, FJ Lozano-Calderon, SA Schwab, JH AF Janssen, Stein J. Kortlever, Joost T. P. Ready, John E. Raskin, Kevin A. Ferrone, Marco L. Hornicek, Francis J. Lozano-Calderon, Santiago A. Schwab, Joseph H. TI Complications After Surgical Management of Proximal Femoral Metastasis: A Retrospective Study of 417 Patients SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Article ID TOTAL HIP-REPLACEMENT; BONE METASTASES; COMORBIDITY INDEX; INTERNAL-FIXATION; FEMUR FRACTURES; NECK FRACTURES; SURVIVAL; DISEASE; PROGNOSTICATION; SURGERY AB Background: Proximal femoral fractures resulting from metastatic disease often require surgical management. Few studies have compared surgical techniques, and physicians' preferred strategies vary. This study compared revision and complication rates among surgical strategies. Methods: The study consisted of a retrospective review of electronic medical records of 417 consecutive patients with proximal femoral metastasis or multiple myeloma who underwent intramedullary nailing (n = 302), endoprosthetic reconstruction (n = 70), and open reduction and internal fixation (n = 45) between 1999 and 2014 at two orthopaedic oncology centers. Primary outcome measures were revisions and 30-day systemic complications. Secondary outcome measures were total estimated blood loss, anesthesia time, duration of hospital admission, and 30-day survival. Results: Revision rates did not differ between strategies (5.3% after intramedullary nailing, 11% after endoprosthetic reconstruction, and 13% after open reduction and internal fixation; P = 0.134). When reasons for revision were assessed separately, fixation failure was most common after open reduction and internal fixation (13% versus 3.0% after intramedullary nailing and none after endoprosthetic reconstruction; P < 0.001), whereas deep infection was most common after endoprosthetic reconstruction (8.6% versus 2.0% after intramedullary nailing and none after open reduction and internal fixation; P = 0.010). Overall systemic complication rates did not differ between strategies (8.3% after intramedullary nailing, 14% after endoprosthetic reconstruction, and 11% after open reduction and internal fixation; P = 0.268). Conclusion: Implant-specific complications and their timing should be considered in the choice of surgical strategy. Analysis of secondary outcomes and risk factors for systemic complications could aid in surgical decision making. C1 [Janssen, Stein J.; Kortlever, Joost T. P.; Ready, John E.; Raskin, Kevin A.; Ferrone, Marco L.; Hornicek, Francis J.; Lozano-Calderon, Santiago A.; Schwab, Joseph H.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Janssen, SJ (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. EM steinjanssen@gmail.com NR 26 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 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD JUL PY 2016 VL 24 IS 7 BP 483 EP 494 DI 10.5435/JAAOS-D-16-00043 PG 12 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DP7ET UT WOS:000378662700008 PM 27227983 ER PT J AU McCauley, JL Hyer, JM Ramakrishnan, VR Leite, R Melvin, CL Fillingim, RB Frick, C Brady, KT AF McCauley, Jenna L. Hyer, J. Madison Ramakrishnan, V. Ramesh Leite, Renata Melvin, Cathy L. Fillingim, Roger B. Frick, Christie Brady, Kathleen T. TI Dental opioid prescribing and multiple opioid prescriptions among dental patients Administrative data from the South Carolina prescription drug monitoring program SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE Oxycodone; patient education; prescriptions; drug ID UNITED-STATES; NONMEDICAL USE; OVERDOSE; PAIN; ABUSE; GUIDELINES; THERAPY; RISK; PHARMACOGENETICS; HYDROCODONE AB Background. Despite increased attention to dentists' roles in curbing opioid misuse, abuse, and diversion, information regarding prescribing practices and the frequency of multiple concurrent opioid prescriptions among dental patients is limited. Methods. The authors reviewed South Carolina prescription drug monitoring program data representing dispensed medication for patients prescribed at least 1 opioid by a dentist during the most recently available 2-year time frame (2012-2013). The authors used descriptive analyses to examine the types and frequency of dental opioid prescriptions and the frequency of existing multiple concurrent opioid prescriptions among dental patients. Results. Nearly all dispensed dental opioid prescriptions (99.9%; n = 653,650) were for immediate-release opioids and were initial prescription fills (96.2%). Hydrocodone (76.1%) and oxycodone (12.2%) combination products were the most frequently dispensed opioids prescribed by dentists. People younger than 21 years received 11.2% of dentist-prescribed opioids dispensed. Patients with multiple concurrent opioid prescriptions were identified within 30-day (n = 113,818), 90-day (n = 166,124), and 180-day (n = 205,576) time frames. Conclusions. Dentists prescribed a high volume of the immediate-release opioids dispensed in South Carolina. A notable minority of dental patients had incidents of multiple preexisting opioid prescriptions, a factor implicated in patient misuse, abuse, overdose, and diversion. Practical Implications. Use of a prescription drug monitoring program before prescribing provides a record of controlled substances dispensed to a patient and may inform prescribing, coordination of care, and addiction screening or referral. Patients should receive information regarding misuse behaviors and their risks, as well as the importance of secure storage and disposal of leftover opioid medications. C1 [McCauley, Jenna L.] Med Univ S Carolina, Addict Sci Div, Dept Psychiat & Behav Sci, 67 President St, Charleston, SC 29425 USA. [Hyer, J. Madison; Ramakrishnan, V. Ramesh; Melvin, Cathy L.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Leite, Renata] Med Univ S Carolina, Dept Periodont, Charleston, SC 29425 USA. [Fillingim, Roger B.] Univ Florida, Dept Community Dent & Behav Sci, Gainesville, FL USA. [Frick, Christie] S Carolina Dept Hlth & Environm Control, Prescript Drug Monitoring Program, Columbia, SC 29201 USA. [Brady, Kathleen T.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Brady, Kathleen T.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP McCauley, JL (reprint author), Med Univ S Carolina, Addict Sci Div, Dept Psychiat & Behav Sci, 67 President St, Charleston, SC 29425 USA. EM mccaule@musc.edu FU National Institute on Drug Abuse [K12-DA031794, K23-DA036566]; South Carolina Clinical and Translational Research Institute; National Institutes of Health [UL1-TR000062] FX This research was supported by grants K12-DA031794 and K23-DA036566 from the National Institute on Drug Abuse and by the South Carolina Clinical and Translational Research Institute, with an academic home at the Medical University of South Carolina, through grant UL1-TR000062 from the National Institutes of Health. NR 46 TC 1 Z9 1 U1 1 U2 1 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUL PY 2016 VL 147 IS 7 BP 537 EP 544 DI 10.1016/j.adaj.2016.02.017 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DP5ON UT WOS:000378547000007 PM 27055600 ER PT J AU Rodriguez, E Nifong, LW Bonatti, J Casula, R Falk, V Folliguet, TA Kiaii, BB Mack, MJ Mihaljevic, T Smith, JM Suri, RM Bavaria, JE MacGillivray, TE Chitwood, WR AF Rodriguez, Evelio Nifong, L. Wiley Bonatti, Johannes Casula, Roberto Falk, Volkmar Folliguet, Thierry A. Kiaii, Bob B. Mack, Michael J. Mihaljevic, Tomislav Smith, J. Michael Suri, Rakesh M. Bavaria, Joseph E. MacGillivray, Thomas E. Chitwood, W. Randolph, Jr. TI Pathway for surgeons and programs to establish and maintain a successful robot-assisted adult cardiac surgery program SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID MITRAL-VALVE REPAIRS; MULTICENTER TRIAL; BYPASS SURGERY; ARTERY; EXPERIENCE; SAFETY; GRAFT C1 [Rodriguez, Evelio] St Thomas Heart Hosp, 4230 Harding Rd,Ste 430, Nashville, TN 37205 USA. [Nifong, L. Wiley] East Carolina Heart Inst, Dept Cardiovasc Sci, Greenville, NC USA. [Bonatti, Johannes] Cleveland Clin, Abu Dhabi Heart & Vasc Inst, Cleveland, Qld, Australia. [Casula, Roberto] St Marys Hosp, Imperial Coll Healthcare NHS Trust, London, England. [Casula, Roberto] St Marys Hosp, Dept Cardiothorac Surg, London, England. [Falk, Volkmar] Charite, Deutsch Herzzentrum Berlin, Berlin, Germany. [Folliguet, Thierry A.] Ctr Hosp Univ Brabois ILCV, Vandoeuvre Les Nancy, France. [Kiaii, Bob B.] London Hlth Sci Ctr, Dept Cardiovasc & Thorac Surg, London, ON, Canada. [Mack, Michael J.] Heart Hosp, Baylor Hlth Care Syst, Plano, TX USA. [Mihaljevic, Tomislav] Cleveland Clin Abu Dhabi, Cleveland, OH USA. [Smith, J. Michael] Good Samaritan Hosp, Cincinnati, OH USA. [Suri, Rakesh M.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Bavaria, Joseph E.] Hosp Univ Penn, Div Cardiovasc Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. [MacGillivray, Thomas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chitwood, W. Randolph, Jr.] Vidant Med Ctr, Greenville, NC USA. [Chitwood, W. Randolph, Jr.] E Carolina Univ, Greenville, NC USA. RP Rodriguez, E (reprint author), St Thomas Heart Hosp, 4230 Harding Rd,Ste 430, Nashville, TN 37205 USA. EM evelio.rodriguez@sth.org NR 14 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUL PY 2016 VL 152 IS 1 BP 9 EP 13 DI 10.1016/j.jtcvs.2016.05.018 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DQ0AG UT WOS:000378858800021 PM 27343904 ER PT J AU Kenagy, RD Civelek, M Kikuchi, S Chen, LH Grieff, A Sobel, M Lusis, AJ Clowes, AW AF Kenagy, Richard D. Civelek, Mete Kikuchi, Shinsuke Chen, Lihua Grieff, Anthony Sobel, Michael Lusis, Aldons J. Clowes, Alexander W. TI Scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN) are hub genes of coexpression network modules associated with peripheral vein graft patency SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID SMOOTH-MUSCLE-CELLS; INTERMEDIATE-LAYER PROTEIN; EPIDERMAL-GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; NUCLEOTIDE EXCHANGE FACTOR; EX-VIVO EXPANSION; SAPHENOUS-VEIN; FACTOR-XA; ENDOTHELIAL-CELLS; SELENOPROTEIN P AB Objective: Approximately 30% of autogenous vein grafts develop luminal narrowing and fail because of intimal hyperplasia or negative remodeling. We previously found that vein graft cells from patients who later develop stenosis proliferate more in vitro in response to growth factors than cells from patients who maintain patent grafts. To discover novel determinants of vein graft outcome, we have analyzed gene expression profiles of these cells using a systems biology approach to cluster the genes into modules by their coexpression patterns and to correlate the results with growth data from our prior study and with new studies of migration and matrix remodeling. Methods: RNA from 4-hour serum-or platelet-derived growth factor (PDGF)-BB-stimulated human saphenous vein cells obtained from the outer vein wall (20 cell lines) was used for microarray analysis of gene expression, followed by weighted gene coexpression network analysis. Cell migration in microchemotaxis chambers in response to PDGF-BB and cell-mediated collagen gel contraction in response to serum were also determined. Gene function was determined using short-interfering RNA to inhibit gene expression before subjecting cells to growth or collagen gel contraction assays. These cells were derived from samples of the vein grafts obtained at surgery, and the long-term fate of these bypass grafts was known. Results: Neither migration nor cell-mediated collagen gel contraction showed a correlation with graft outcome. Although 1188 and 1340 genes were differentially expressed in response to treatment with serum and PDGF, respectively, no single gene was differentially expressed in cells isolated from patients whose grafts stenosed compared with those that remained patent. Network analysis revealed four unique groups of genes, which we term modules, associated with PDGF responses, and 20 unique modules associated with serum responses. The "yellow" and "skyblue" modules, from PDGF and serum analyses, respectively, correlated with later graft stenosis (P=.005 and P=.02, respectively). In response to PDGF, yellow was also associated with increased cell growth. For serum, skyblue was also associated with inhibition of collagen gel contraction. The hub genes for yellow and skyblue (ie, the gene most connected to other genes in the module), scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN), respectively, were tested for effects on proliferation and collagen contraction. Knockdown of SCARA5 increased proliferation by 29.9% +/- 7.8% (P<.01), whereas knockdown of SBSN had no effect. Knockdown of SBSN increased collagen gel contraction by 24.2% +/- 8.6% (P<.05), whereas knockdown of SCARA5 had no effect. Conclusions: Using weighted gene coexpression network analysis of cultured vein graft cell gene expression, we have discovered two small gene modules, which comprise 42 genes, that are associated with vein graft failure. Further experiments are needed to delineate the venous cells that express these genes in vivo and the roles these genes play in vein graft healing, starting with the module hub genes SCARA5 and SBSN, which have been shown to have modest effects on cell proliferation or collagen gel contraction. C1 [Kenagy, Richard D.; Kikuchi, Shinsuke; Chen, Lihua; Grieff, Anthony; Sobel, Michael; Clowes, Alexander W.] Univ Washington, Dept Surg, Seattle, WA 98109 USA. [Civelek, Mete; Lusis, Aldons J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Kikuchi, Shinsuke] Asahikawa Med Univ, Dept Vasc Surg, Asahikawa, Hokkaido, Japan. [Sobel, Michael] VA Puget Sound Hlth Care Syst, Div Vasc Surg, Seattle, WA USA. [Sobel, Michael] Univ Washington, Seattle, WA 98109 USA. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Immunol & Mol Genet, Los Angeles, CA USA. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. RP Kenagy, RD (reprint author), Univ Washington, Ctr Cardiovasc Biol, POB 358050,850 Republican St, Seattle, WA 98109 USA. EM rkenagy@u.washington.edu OI Civelek, Mete/0000-0002-8141-0284 FU CSRD VA [I01 CX000712]; NHLBI NIH HHS [K99 HL121172, P01 HL030568, R01 HL030946, T32 HL069766] NR 111 TC 0 Z9 0 U1 5 U2 5 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 2016 VL 64 IS 1 BP 202 EP + DI 10.1016/j.jvs.2014.12.052 PG 14 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DP5UI UT WOS:000378562900028 PM 25935274 ER PT J AU Nou, E Lo, J Hadigan, C Grinspoon, SK AF Nou, Eric Lo, Janet Hadigan, Colleen Grinspoon, Steven K. TI Pathophysiology and management of cardiovascular disease in patients with HIV SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; T-CELL-ACTIVATION; INTIMA-MEDIA THICKNESS; C-REACTIVE PROTEIN; EPICARDIAL ADIPOSE-TISSUE; RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; MULTICENTER AIDS COHORT AB Results from several studies have suggested that people with HIV have an increased risk of cardiovascular disease, especially coronary heart disease, compared with people not infected with HIV. People living with HIV have an increased prevalence of traditional cardiovascular disease risk factors, and HIV-specific mechanisms such as immune activation. Although older, more metabolically harmful antiretroviral regimens probably contributed to the risk of cardiovascular disease, new data suggest that early and continuous use of modern regimens, which might have fewer metabolic effects, minimises the risk of myocardial infarction by maintaining viral suppression and decreasing immune activation. Even with antiretroviral therapy, however, immune activation persists in people with HIV and could contribute to accelerated atherosclerosis, especially of coronary lesions that are susceptible to rupture. Therefore, treatments that safely reduce inflammation in people with HIV could provide additional cardiovascular protection alongside treatment of both traditional and non-traditional risk factors. C1 [Nou, Eric; Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Hadigan, Colleen] NIAID, NIH, Bethesda, MD USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU US National Institute of Allergies and Infectious Diseases Intramural Program FX This work was partly supported by the US National Institute of Allergies and Infectious Diseases Intramural Program. NR 137 TC 5 Z9 5 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUL PY 2016 VL 4 IS 7 BP 598 EP 610 DI 10.1016/S2213-8587(15)00388-5 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ0CD UT WOS:000378864700022 PM 26873066 ER PT J AU Pivonello, R Isidori, AM De Martino, MC Newell-Price, J Biller, BMK Colao, A AF Pivonello, Rosario Isidori, Andrea M. De Martino, Maria Cristina Newell-Price, John Biller, Beverly M. K. Colao, Annamaria TI Complications of Cushing's syndrome: state of the art SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Review ID BONE-MINERAL DENSITY; POLYCYSTIC OVARIAN SYNDROME; GLUCOCORTICOID-INDUCED OSTEOPOROSIS; AUTOIMMUNE THYROID-DYSFUNCTION; CARDIOVASCULAR RISK-FACTORS; CLINICAL-PRACTICE GUIDELINE; ECTOPIC ACTH-SECRETION; LONG-TERM CURE; ENDOGENOUS HYPERCORTISOLISM; DIABETES-MELLITUS AB Cushing's syndrome is a serious endocrine disease caused by chronic, autonomous, and excessive secretion of cortisol. The syndrome is associated with increased mortality and impaired quality of life because of the occurrence of comorbidities. These clinical complications include metabolic syndrome, consisting of systemic arterial hypertension, visceral obesity, impairment of glucose metabolism, and dyslipidaemia; musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures; neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania; impairment of reproductive and sexual function; and dermatological manifestations, mainly represented by acne, hirsutism, and alopecia. Hypertension in patients with Cushing's syndrome has a multifactorial pathogenesis and contributes to the increased risk for myocardial infarction, cardiac failure, or stroke, which are the most common causes of death; risks of these outcomes are exacerbated by a prothrombotic diathesis and hypokalaemia. Neuropsychiatric disorders can be responsible for suicide. Immune disorders are common; immunosuppression during active disease causes susceptibility to infections, possibly complicated by sepsis, an important cause of death, whereas immune rebound after disease remission can exacerbate underlying autoimmune diseases. Prompt treatment of cortisol excess and specific treatments of comorbidities are crucial to prevent serious clinical complications and reduce the mortality associated with Cushing's syndrome. C1 [Pivonello, Rosario; De Martino, Maria Cristina; Colao, Annamaria] Univ Naples Federico II, Sez Endocrinol, Dipartimento Med Clin & Chirurg, I-80131 Naples, Italy. [Isidori, Andrea M.] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy. [Newell-Price, John] Univ Sheffield, Sch Med, Dept Oncol & Metab, Sheffield, S Yorkshire, England. [Newell-Price, John] Sheffield Teaching Hosp NHS Fdn Trust, Royal Hallamshire Hosp, Endocrine Unit, Sheffield, S Yorkshire, England. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Harvard Med Sch, Neuroendocrine Unit, Dept Med, Boston, MA 02114 USA. RP Pivonello, R (reprint author), Univ Naples Federico II, Sez Endocrinol, Dipartimento Med Clin & Chirurg, I-80131 Naples, Italy. EM rosario.pivonello@unina.it RI Isidori, Andrea/F-3062-2010; De Martino, Maria Cristina/K-7090-2016 OI Isidori, Andrea/0000-0002-9037-5417; FU Novartis; Pfizer; HRA Pharma; ViroPharma-Shire; Italfarmaco; Ipsen; Ferring; Menarini; Otsuka; Cortendo; Lilly; Novo Nordisk FX RP reports grants, personal fees, and other from Novartis; grants and personal fees from Pfizer; grants from HRA Pharma; grants and personal fees from ViroPharma-Shire; personal fees from Italfarmaco; personal fees from Ipsen; and personal fees from Ferring, outside the submitted work. AMI reports personal fees from Menarini, personal fees from Otsuka, grants and personal fees from Viropharma-Shire, and personal fees from Novartis, outside the submitted work. JN-P reports grants and personal fees from HRA Pharma, grants and personal fees from Novartis, and grants and personal fees from Ipsen, outside the submitted work. BMKB reports grants and personal fees from Cortendo, grants and personal fees from Novartis, personal fees from HRA Pharma, and personal fees from Ipsen, outside the submitted work. AC reports grants, personal fees, and other from Novartis; grants and personal fees from Pfizer; grants from HRA Pharma; grants and personal fees from Italfarmaco; grants, personal fees, and other from Ipsen; and grants from Ferring, Lilly, and Novo Nordisk, outside the submitted work. MCDM declares no competing interests. NR 155 TC 6 Z9 6 U1 12 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUL PY 2016 VL 4 IS 7 BP 611 EP 629 DI 10.1016/S2213-8587(16)00086-3 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ0CD UT WOS:000378864700023 PM 27177728 ER PT J AU Baldini, EH AF Baldini, Elizabeth H. TI Defining the role of radiotherapy for retroperitoneal sarcoma SO LANCET ONCOLOGY LA English DT Editorial Material ID PREOPERATIVE RADIATION-THERAPY; RECURRENCE; RPS C1 [Baldini, Elizabeth H.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Baldini, Elizabeth H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Baldini, EH (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; Baldini, EH (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ebaldini@lroc.harvard.edu NR 9 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2016 VL 17 IS 7 BP 857 EP 859 DI 10.1016/S1470-2045(16)30103-6 PG 4 WC Oncology SC Oncology GA DQ1FO UT WOS:000378947100038 PM 27210905 ER PT J AU Antonia, SJ Lopez-Martin, JA Bendell, J Ott, PA Taylor, M Eder, JP Jager, D Pietanza, MC Le, DT de Braud, F Morse, MA Ascierto, PA Horn, L Amin, A Pillai, RN Evans, J Chau, I Bono, P Atmaca, A Sharma, P Harbison, CT Lin, CS Christensen, O Calvo, E AF Antonia, Scott J. Lopez-Martin, Jose A. Bendell, Johanna Ott, Patrick A. Taylor, Matthew Eder, Joseph Paul Jaeger, Dirk Pietanza, M. Catherine Le, Dung T. de Braud, Filippo Morse, Michael A. Ascierto, Paolo A. Horn, Leora Amin, Asim Pillai, Rathi N. Evans, Jeffry Chau, Ian Bono, Petri Atmaca, Akin Sharma, Padmanee Harbison, Christopher T. Lin, Chen-Sheng Christensen, Olaf Calvo, Emiliano TI Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial SO LANCET ONCOLOGY LA English DT Article ID III TRIAL; METASTATIC MELANOMA; UNTREATED MELANOMA; MYASTHENIA-GRAVIS; EXTENSIVE-DISEASE; TREATMENT OPTIONS; COMBINATION; THERAPY; IRINOTECAN; DOCETAXEL AB Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198.5 days (IQR 163.0-464.0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361.0 days (273.0-470.0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260.5 days (248.0-288.0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. C1 [Antonia, Scott J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Lopez-Martin, Jose A.] Hosp Univ 12 Octubre, Madrid, Spain. [Bendell, Johanna] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. [Ott, Patrick A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Taylor, Matthew] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Eder, Joseph Paul] Yale Comprehens Canc Ctr, New Haven, CT USA. [Jaeger, Dirk] Univ Med Ctr, NCT, Heidelberg, Germany. [Pietanza, M. Catherine] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Le, Dung T.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [de Braud, Filippo] Fdn IRCCS Ist Nazl Tumori Milano, Milan, Italy. [Morse, Michael A.] Duke Univ, Med Ctr, Durham, NC USA. [Ascierto, Paolo A.] Ist Nazl Tumori Fdn Pascale, Naples, Italy. [Horn, Leora] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Amin, Asim] Carolinas Med Ctr, Levine Canc Inst, Charlotte, NC 28203 USA. [Pillai, Rathi N.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Evans, Jeffry] Univ Glasgow, Glasgow, Lanark, Scotland. [Chau, Ian] Royal Marsden Hosp, Sutton, Surrey, England. [Bono, Petri] Helsinki Univ Hosp, Ctr Comprehens Canc, Helsinki, Finland. [Bono, Petri] Univ Helsinki, Helsinki, Finland. [Atmaca, Akin] Krankenhaus Nordwest UCT Univ, Ctr Canc, Frankfurt, Germany. [Sharma, Padmanee] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Harbison, Christopher T.; Lin, Chen-Sheng; Christensen, Olaf] Bristol Myers Squibb Co, Princeton, NJ USA. [Calvo, Emiliano] START Madrid, Ctr Integral Oncol Clara Campal, Calle Ona 10, Madrid 28050, Spain. RP Calvo, E (reprint author), START Madrid, Ctr Integral Oncol Clara Campal, Calle Ona 10, Madrid 28050, Spain. EM emiliano.calvo@start.stoh.com RI de Braud, Filippo/B-9997-2017 OI de Braud, Filippo/0000-0003-0103-730X FU Bristol-Myers Squibb FX Bristol-Myers Squibb. NR 36 TC 38 Z9 39 U1 9 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2016 VL 17 IS 7 BP 883 EP 895 DI 10.1016/S1470-2045(16)30098-5 PG 13 WC Oncology SC Oncology GA DQ1FO UT WOS:000378947100054 PM 27269741 ER PT J AU Choueiri, TK Escudier, B Powles, T Tannir, NM Mainwaring, PN Rini, BI Hammers, HJ Donskov, F Roth, BJ Peltola, K Lee, JL Heng, DYC Schmidinger, M Agarwal, N Sternberg, CN McDermott, DF Aftab, DT Hessel, C Old, CS Schwab, G Hutson, TE Pal, S Motzer, RJ AF Choueiri, Toni K. Escudier, Bernard Powles, Thomas Tannir, Nizar M. Mainwaring, Paul N. Rini, Brian I. Hammers, Hans J. Donskov, Frede Roth, Bruce J. Peltola, Katriina Lee, Jae Lyun Heng, Daniel Y. C. Schmidinger, Manuela Agarwal, Neeraj Sternberg, Cora N. McDermott, David F. Aftab, Dana T. Hessel, Colin Old, Christian Scheff Schwab, Gisela Hutson, Thomas E. Pal, Sumanta Motzer, Robert J. CA METEOR Investigators TI Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID TARGETED THERAPY; PROGNOSTIC-FACTORS; EAU GUIDELINES; III TRIAL; CANCER; COMBINATION; METASTASIS; SORAFENIB; SURVIVAL; EFFICACY AB Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18.7 months (IQR 16.1-21.1) in the cabozantinib group and 18.8 months (16.0-21.2) in the everolimus group. Median overall survival was 21.4 months (95% CI 18.7-not estimable) with cabozantinib and 16.5 months (14.7-18.8) with everolimus (hazard ratio [HR] 0.66 [95% CI 0.53-0.83]; p=0.00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0.51 [95% CI 0.41-0.62]; p<0.0001) and objective response (17% [13-22] with cabozantinib vs 3% [2-6] with everolimus; p<0.0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. C1 [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Escudier, Bernard] Inst Gustave Roussy, Villejuif, France. [Powles, Thomas] Queen Mary Univ London, Royal Free NHS Trust, Canc Res UK Expt Canc Med Ctr, Barts Canc Inst, London, England. [Tannir, Nizar M.] Univ Texas MD Anderson Canc Ctr Hosp, Houston, TX USA. [Mainwaring, Paul N.] Icon Canc Care, Brisbane, Qld, Australia. [Rini, Brian I.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Hammers, Hans J.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Donskov, Frede] Aarhus Univ Hosp, Aarhus, Denmark. [Roth, Bruce J.] Washington Univ, St Louis, MO USA. [Peltola, Katriina] Univ Helsinki, Cent Hosp, Ctr Canc, Helsinki, Finland. [Lee, Jae Lyun] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Heng, Daniel Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Schmidinger, Manuela] Med Univ Vienna, Vienna, Austria. [Agarwal, Neeraj] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Sternberg, Cora N.] San Camillo Hosp, Rome, Italy. [Sternberg, Cora N.] Forlanini Hosp, Rome, Italy. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Aftab, Dana T.; Hessel, Colin; Old, Christian Scheff; Schwab, Gisela] Exelixis, San Francisco, CA USA. [Hutson, Thomas E.] Baylor Sammons Canc Ctr, Texas Oncol, Dallas, TX USA. [Pal, Sumanta] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM toni_choueiri@dfci.harvard.edu FU Exelixis Inc. FX Exelixis Inc. NR 30 TC 48 Z9 48 U1 5 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2016 VL 17 IS 7 BP 917 EP 927 DI 10.1016/S1470-2045(16)30107-3 PG 11 WC Oncology SC Oncology GA DQ1FO UT WOS:000378947100057 PM 27279544 ER PT J AU Weber, JS Gibney, G Sullivan, RJ Sosman, JA Slingluff, CL Lawrence, DP Logan, TF Schuchter, LM Nair, S Fecher, L Buchbinder, EI Berghorn, E Ruisi, M Kong, G Jiang, J Horak, C Hodi, FS AF Weber, Jeffrey S. Gibney, Geoff Sullivan, Ryan J. Sosman, Jeffrey A. Slingluff, Craig L., Jr. Lawrence, Donald P. Logan, Theodore F. Schuchter, Lynn M. Nair, Suresh Fecher, Leslie Buchbinder, Elizabeth I. Berghorn, Elmer Ruisi, Mary Kong, George Jiang, Joel Horak, Christine Hodi, F. Stephen TI Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID UNTREATED MELANOMA; CTLA-4; PD-1 AB Background Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged >= 18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1: 1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3-5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3-5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37.6-62.4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31.1-55.3] of 70 patients). The most common treatment-related grade 3-4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29.4-53.8] vs 14 [20%; 11.4-31.3]). Progression was reported in 26 (38%; 95% CI 26.7-50.8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49.0-72.8) patients in the reverse sequence group at week 13 and in 26 (38%; 26.7-50.8) and 42 (60%; 47.6-71.5) patients at week 25, respectively. After a median follow-up of 19.8 months (IQR 12.8-25.7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23.7-not reached), whereas over a median follow-up of 14.7 months (IQR 5.6-23.9) in the ipilimumab followed by nivolumab group, median overall survival was 16.9 months (95% CI 9.2-26.5; HR 0.48 [95% CI 0.29-0.80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64-85 vs 54%; 42-65). Interpretation Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. C1 [Weber, Jeffrey S.] NYU, Langone Med Ctr, New York, NY USA. [Weber, Jeffrey S.; Gibney, Geoff] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Gibney, Geoff] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Sullivan, Ryan J.; Lawrence, Donald P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sosman, Jeffrey A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Slingluff, Craig L., Jr.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Logan, Theodore F.; Fecher, Leslie] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Schuchter, Lynn M.] Univ Penn, Philadelphia, PA 19104 USA. [Nair, Suresh] Lehigh Valley Hlth Network, Allentown, PA USA. [Fecher, Leslie] Univ Michigan, Ann Arbor, MI 48109 USA. [Buchbinder, Elizabeth I.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Berghorn, Elmer; Ruisi, Mary; Kong, George; Jiang, Joel; Horak, Christine] Bristol Myers Squibb Co, Princeton, NJ USA. [Hodi, F. Stephen] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu FU Bristol-Myers Squibb FX Bristol-Myers Squibb. NR 22 TC 13 Z9 13 U1 5 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2016 VL 17 IS 7 BP 943 EP 955 DI 10.1016/S1470-2045(16)30126-7 PG 13 WC Oncology SC Oncology GA DQ1FO UT WOS:000378947100059 PM 27269740 ER PT J AU Planchard, D Besse, B Groen, HJM Souquet, PJ Quoix, E Baik, CS Barlesi, F Kim, TM Mazieres, J Novello, S Rigas, JR Upalawanna, A D'Amelio, AM Zhang, PK Mookerjee, B Johnson, BE AF Planchard, David Besse, Benjamin Groen, Harry J. M. Souquet, Pierre-Jean Quoix, Elisabeth Baik, Christina S. Barlesi, Fabrice Kim, Tae Min Mazieres, Julien Novello, Silvia Rigas, James R. Upalawanna, Allison D'Amelio, Anthony M., Jr. Zhang, Pingkuan Mookerjee, Bijoyesh Johnson, Bruce E. TI Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID HARBORING BRAF MUTATIONS; 1ST-LINE TREATMENT; V600 MUTATIONS; MELANOMA; CHEMOTHERAPY; CRIZOTINIB; EGFR; ADENOCARCINOMAS; INHIBITION; AMPLIFICATION AB Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAF(V600E)-mutant NSCLC. Methods In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged >= 18 years) with pretreated metastatic stage IV BRAF(V600E)-mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. Findings Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63.2% [95% CI 49.3-75.6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3-4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator). Interpretation Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF(V600E)-mutant NSCLC. C1 [Planchard, David; Besse, Benjamin] Gustave Roussy, Villejuif, France. [Besse, Benjamin] Univ Paris 11, Orsay, France. [Groen, Harry J. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Souquet, Pierre-Jean] Hop Lyon Sud, Pierre Benite, France. [Quoix, Elisabeth] Univ Hosp, Nouvel Hop Civil, Strasbourg, France. [Baik, Christina S.] Univ Washington, Seattle, WA 98195 USA. [Barlesi, Fabrice] Aix Marseille Univ, Hop Nord, Assistance Publ Hop Marseille, Multidisciplinary Oncol & Therapeut Innovat Dept, Marseille, France. [Kim, Tae Min] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Mazieres, Julien] Rangueil Larrey Hosp, Toulouse, France. [Mazieres, Julien] Univ Toulouse 3, F-31062 Toulouse, France. [Novello, Silvia] Univ Turin, Dept Oncol, Orbassano, Italy. [Rigas, James R.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Upalawanna, Allison] Novartis Pharma AG, Basel, Switzerland. [D'Amelio, Anthony M., Jr.; Zhang, Pingkuan; Mookerjee, Bijoyesh] Novartis Pharmaceut, E Hanover, NJ USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Bruce_Johnson@dfci.harvard.edu FU GlaxoSmithKline FX GlaxoSmithKline. NR 37 TC 17 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2016 VL 17 IS 7 BP 984 EP 993 DI 10.1016/S1470-2045(16)30146-2 PG 10 WC Oncology SC Oncology GA DQ1FO UT WOS:000378947100063 PM 27283860 ER PT J AU Capalonga, L Karsten, M Hentschke, VS Rossato, DD Dornelles, MP Sonza, A Bagnato, VS Ferraresi, C Parizotto, NA Dal Lago, P AF Capalonga, Lucas Karsten, Marlus Hentschke, Vitor Scotta Rossato, Douglas Dalcin Dornelles, Mauricio Pinto Sonza, Anelise Bagnato, Vanderlei Salvador Ferraresi, Cleber Parizotto, Nivaldo Antonio Dal Lago, Pedro TI Light-emitting diode therapy (LEDT) improves functional capacity in rats with heart failure SO LASERS IN MEDICAL SCIENCE LA English DT Article DE Phototherapy; Maximal oxygen uptake; Exercise test; Hemodynamic function ID LEVEL LASER THERAPY; NEUROMUSCULAR ELECTRICAL-STIMULATION; OBSTRUCTIVE PULMONARY-DISEASE; SKELETAL-MUSCLE PERFORMANCE; SUPER-PULSED LASER; EXERCISE; PHOTOTHERAPY; DAMAGE; ENDURANCE; FATIGUE AB The syndrome of heart failure (HF) promotes central and peripheral dysfunctions that result in functional capacity decrease, leading to fatigue, dyspnea, and exercise intolerance. The use of light-emitting diode therapy (LEDT) has shown good results reducing fatigue and exercise intolerance, when applied on skeletal muscles before or after exercises. Thereby, the aim of this study was to compare the effects of LEDT on functional capacity, aerobic power, and hemodynamic function in HF rats. Male Wistar rats (230-260 g) were randomly allocated into three experimental groups: Sham (n = 6), Control-HF (n = 4), and LEDT-HF (n = 6). The animals were subjected to an exercise performance test (ET) with gas analysis coupled in ametabolic chamber for rats performed two times (6 and 14 weeks after myocardial infarction). On the day after the baseline aerobic capacity test, the animals were submitted during 8 weeks to the phototherapy protocol, five times/week, 60 s of irradiation, 6 J delivered per muscle group. Statistical analysis was performed by one-and two-way ANOVAs with repeated measures and Student-Newman-Keuls post hoc tests (p <= 0.05). Comparing the percentage difference (Delta) between baseline and the final ET, there was no significant difference for the VO2max variable considering all groups. However, Sham and LEDT-HF groups showed higher relative values than the Control-HF group, respectively, for distance covered (27.7 and 32.5 %), time of exercise test (17.7 and 20.5 %), and speed (13.6 and 12.2 %). In conclusion, LEDT was able to increase the functional capacity evaluated by distance covered, time, and speed of exercise in rats with HF. C1 [Capalonga, Lucas; Karsten, Marlus; Hentschke, Vitor Scotta; Dornelles, Mauricio Pinto; Sonza, Anelise; Dal Lago, Pedro] UFCSPA, Lab Expt Physiol, Porto Alegre, RS, Brazil. [Capalonga, Lucas; Karsten, Marlus; Sonza, Anelise; Dal Lago, Pedro] UFCSPA, Postgrad Program Rehabil Sci, Porto Alegre, RS, Brazil. [Hentschke, Vitor Scotta; Dal Lago, Pedro] UFCSPA, Postgrad Program Hlth Sci, Porto Alegre, RS, Brazil. [Rossato, Douglas Dalcin] Ctr Univ Franciscano, Santa Maria, RS, Brazil. [Bagnato, Vanderlei Salvador; Ferraresi, Cleber] Univ Sao Paulo, Phys Inst Sao Carlos, BR-09500900 Sao Paulo, Brazil. [Ferraresi, Cleber; Parizotto, Nivaldo Antonio] Univ Fed Sao Carlos UFSCar, Dept Phys Therapy, Lab Electrothermophototherapy, Sao Paulo, Brazil. [Ferraresi, Cleber] Harvard Univ, Massachusetts Gen Hosp, Harvard Med Sch, Wellman Ctr Photomed, Boston, MA 02115 USA. [Dal Lago, Pedro] UFCSPA, PPG CR, Rua Sarmento Leite 245, BR-90050170 Porto Alegre, RS, Brazil. RP Dal Lago, P (reprint author), UFCSPA, Lab Expt Physiol, Porto Alegre, RS, Brazil.; Dal Lago, P (reprint author), UFCSPA, Postgrad Program Rehabil Sci, Porto Alegre, RS, Brazil.; Dal Lago, P (reprint author), UFCSPA, Postgrad Program Hlth Sci, Porto Alegre, RS, Brazil.; Dal Lago, P (reprint author), UFCSPA, PPG CR, Rua Sarmento Leite 245, BR-90050170 Porto Alegre, RS, Brazil. EM pdallago@ufcspa.edu.br RI Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; USP, CePOF/J-3608-2015; Dal Lago, Pedro/K-4414-2013 OI Dal Lago, Pedro/0000-0001-9907-7689 FU Fundacao de Amparo a Pesquisa do Rio Grande do Sul (FAPERGS, PRONEM-Programa de Nucleos Emergentes); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Chamada Universal); Programa Nacional de Pos-doutorado da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, PNPD Concessao Institucional) FX This research was supported by: Fundacao de Amparo a Pesquisa do Rio Grande do Sul (FAPERGS, PRONEM-Programa de Nucleos Emergentes, 2011), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Chamada Universal, 2012), and Programa Nacional de Pos-doutorado da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, PNPD Concessao Institucional, 2011). NR 41 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0268-8921 EI 1435-604X J9 LASER MED SCI JI Lasers Med. Sci. PD JUL PY 2016 VL 31 IS 5 BP 937 EP 944 DI 10.1007/s10103-016-1922-y PG 8 WC Engineering, Biomedical; Surgery SC Engineering; Surgery GA DP5NB UT WOS:000378543200016 PM 27059227 ER PT J AU Julius, A Longfellow, K AF Julius, Anthony Longfellow, Katelan TI Movement Disorders A Brief Guide in Medication Management SO MEDICAL CLINICS OF NORTH AMERICA LA English DT Article DE Movement disorders; Parkinson's disease; Nonmotor symptoms; Essential tremor; Restless leg syndrome ID RESTLESS LEGS SYNDROME; PLACEBO-CONTROLLED TRIAL; SLEEP BEHAVIOR DISORDER; AGONIST WITHDRAWAL SYNDROME; QUALITY STANDARDS SUBCOMMITTEE; EARLY PARKINSONS-DISEASE; DOUBLE-BLIND TRIAL; TOXIN TYPE-A; ESSENTIAL TREMOR; ORTHOSTATIC HYPOTENSION AB Movement disorders can be challenging to manage and often use a specific set of medications. Because it is a complex and broad field within neurology, many providers are unfamiliar with the classes of medications. This article details medications used for specific conditions, explains why these medications are helpful, and shares pearls and pitfalls related to each agent, focusing on parameters such as dose titration, side effect profiles, and specific drug-drug interactions and challenges. We focus on the most commonly encountered movement disorders, including essential tremor, Parkinson's disease, rapid eye movement sleep behavior disorder, and restless leg syndrome. C1 [Julius, Anthony; Longfellow, Katelan] Univ Washington, Med Ctr, VA Puget Sound, 1660 S Columbian Way, Seattle, WA 98108 USA. RP Longfellow, K (reprint author), Univ Washington, Med Ctr, VA Puget Sound, 1660 S Columbian Way, Seattle, WA 98108 USA. EM katelanlongfellow@catholichealth.net NR 137 TC 0 Z9 0 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 0025-7125 EI 1557-9859 J9 MED CLIN N AM JI Med. Clin. N. Am. PD JUL PY 2016 VL 100 IS 4 BP 733 EP + DI 10.1016/j.mcna.2016.03.002 PG 30 WC Medicine, General & Internal SC General & Internal Medicine GA DP6BK UT WOS:000378581700007 PM 27235613 ER PT J AU Allen, C Evans, G Sutton, EL AF Allen, Caitlin Evans, Ginger Sutton, Eliza L. TI Pharmacologic Therapies in Women's Health Contraception and Menopause Treatment SO MEDICAL CLINICS OF NORTH AMERICA LA English DT Article DE Long-acting reversible contraception; Combined hormonal contraception; Emergency contraception; Menopause transition; Genitourinary syndrome of menopause; Estrogen therapy ID ACTING REVERSIBLE CONTRACEPTION; RANDOMIZED CONTROLLED-TRIAL; EMERGENCY CONTRACEPTION; INTRAUTERINE-DEVICE; VASOMOTOR SYMPTOMS; ORAL-CONTRACEPTIVES; VENOUS THROMBOEMBOLISM; ULIPRISTAL ACETATE; CLINICAL-TRIAL; HORMONAL CONTRACEPTIVES AB Female hormones play a significant role in the etiology and treatment of many women's health conditions. This article focuses on the common uses of hormonal therapy. When prescribing estrogen-containing regimens throughout the span of a woman's life, the risks are similar (ie, cardiovascular risk and venous thromboembolism), but the degree of risk varies significantly depending on a woman's particular set of risk factors and the details of the hormone regimen. In addition to estrogens and progestogens, this article also touches on the use of selective steroid receptor modulators in emergency contraception and in treatment of menopause symptoms. C1 [Allen, Caitlin] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, MFCB 5120, 1685 Highland Ave, Madison, WI 53705 USA. [Evans, Ginger] Univ Washington, Dept Med, VA Puget Sound Hlth Care Syst, 1660 South Columbian Way,S-123 PCC, Seattle, WA 98108 USA. [Sutton, Eliza L.] Univ Washington, Dept Med, Womens Hlth Care Ctr, 4245 Roosevelt Way Northeast,Box 354765, Seattle, WA 98105 USA. RP Allen, C (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, MFCB 5120, 1685 Highland Ave, Madison, WI 53705 USA. EM callen@uwhealth.org NR 94 TC 0 Z9 0 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 0025-7125 EI 1557-9859 J9 MED CLIN N AM JI Med. Clin. N. Am. PD JUL PY 2016 VL 100 IS 4 BP 763 EP + DI 10.1016/j.mcna.2016.03.008 PG 28 WC Medicine, General & Internal SC General & Internal Medicine GA DP6BK UT WOS:000378581700008 PM 27235614 ER PT J AU Joo, MS Kim, WD Lee, KY Kim, JH Koo, JH Kim, SG AF Joo, Min Sung Kim, Won Dong Lee, Ki Young Kim, Ji Hyun Koo, Ja Hyun Kim, Sang Geon TI AMPK Facilitates Nuclear Accumulation of Nrf2 by Phosphorylating at Serine 550 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; GLYCOGEN-SYNTHASE KINASE-3-BETA; TRANSCRIPTION FACTOR NRF2; VEIN ENDOTHELIAL-CELLS; OXIDATIVE STRESS; ANTIOXIDANT RESPONSE; GENE-EXPRESSION; ENERGY SENSOR; INDUCED APOPTOSIS; EXPORT SIGNALS AB Nrf2 (nuclear factor erythroid 2-related factor 2) is an antioxidant transcription factor. AMP-activated protein kinase (AMPK) functions as a central regulator of cell survival in response to stressful stimuli. Nrf2 should be coordinated with the cell survival pathway controlled by AMPK, but so far the mechanistic connections remain undefined. This study investigated the role of AMPK in Nrf2 trafficking and its activity regulation. A subnetwork integrating neighbor molecules suggested direct interaction between AMPK and Nrf2. In cells, AMPK activation caused nuclear accumulation of Nrf2. In the in vitro kinase and peptide competition assays, AMPK phosphorylated Nrf2 at the Ser558 residue (Ser550 in mouse) located in the canonical nuclear export signal. Nrf2 with an S550A mutation failed to be accumulated in the nucleus after AMPK activation. Leptomycin B, a nuclear export inhibitor, did not enhance nuclear accumulation of wild-type Nrf2 (WT-Nrf2) activated by AMPK or a phospho-Ser550-mimetic Nrf2 mutant, corroborating the finding that AMPK facilitated nuclear accumulation of Nrf2, probably by inhibiting nuclear export. Activated glycogen synthase kinase 3 beta (GSK3 beta) diminished the basal nuclear level of Myc-S550A-Nrf2. Taking the data collectively, AMPK phosphorylates Nrf2 at the Ser550 residue, which, in conjunction with AMPK-mediated GSK3 beta inhibition, promotes nuclear accumulation of Nrf2 for antioxidant response element (ARE)-driven gene transactivation. C1 [Joo, Min Sung; Kim, Won Dong; Koo, Ja Hyun; Kim, Sang Geon] Seoul Natl Univ, Coll Pharm, Seoul, South Korea. [Joo, Min Sung; Kim, Won Dong; Koo, Ja Hyun; Kim, Sang Geon] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul, South Korea. [Lee, Ki Young; Kim, Ji Hyun] Ajou Univ, Sch Med, Dept Biomed Informat, Suwon, South Korea. [Kim, Won Dong] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Kim, Won Dong] Harvard Med Sch, Boston, MA USA. RP Kim, SG (reprint author), Seoul Natl Univ, Coll Pharm, Seoul, South Korea.; Kim, SG (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul, South Korea. EM sgk@snu.ac.kr OI Koo, Ja Hyun/0000-0001-5738-1105 FU Ministry of Science, ICT and Future Planning (MSIP) [2013R1A2A2A04013317, 2007-0056817, NRF-2014M1A3A3A02034698] FX This work, including the efforts of Min Sung Joo, Won Dong Kim, Ki-Young Lee, Ji Hyun Kim, Ja Hyun Koo, and Sang Geon Kim, was funded by Ministry of Science, ICT and Future Planning (MSIP) (2013R1A2A2A04013317, 2007-0056817, NRF-2014M1A3A3A02034698). NR 52 TC 1 Z9 1 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2016 VL 36 IS 14 BP 1931 EP 1942 DI 10.1128/MCB.00118-16 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DQ0XG UT WOS:000378924500004 PM 27161318 ER PT J AU Wu, C Arora, P Agha, O Hurst, LA Allen, K Nathan, DI Hu, DJ Jiramongkolchai, P Smith, JG Melander, O Trenson, S Janssens, SP Domian, I Wang, TJ Bloch, KD Buys, ES Bloch, DB Newton-Cheh, C AF Wu, Connie Arora, Pankaj Agha, Obiajulu Hurst, Liam A. Allen, Kaitlin Nathan, Daniel I. Hu, Dongjian Jiramongkolchai, Pawina Smith, J. Gustav Melander, Olle Trenson, Sander Janssens, Stefan P. Domian, Ibrahim Wang, Thomas J. Bloch, Kenneth D. Buys, Emmanuel S. Bloch, Donald B. Newton-Cheh, Christopher TI Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL-DERIVED CARDIOMYOCYTE; PLURIPOTENT STEM-CELLS; CARDIAC-HYPERTROPHY; MESSENGER-RNA; HEART-TISSUE; EXPRESSION; DIFFERENTIATION; FAILURE; TARGETS AB Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure. C1 [Wu, Connie; Hu, Dongjian; Smith, J. Gustav; Domian, Ibrahim; Bloch, Kenneth D.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Harvard Med Sch, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Wu, Connie; Agha, Obiajulu; Hurst, Liam A.; Allen, Kaitlin; Nathan, Daniel I.; Jiramongkolchai, Pawina; Bloch, Kenneth D.; Buys, Emmanuel S.; Bloch, Donald B.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Wu, Connie; Smith, J. Gustav; Newton-Cheh, Christopher] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Arora, Pankaj] Univ Alabama Birmingham, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. [Hu, Dongjian] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Smith, J. Gustav; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Human Genet Res, Boston, MA 02114 USA. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden. [Smith, J. Gustav] Skane Univ Hosp, Dept Heart Failure & Valvular Dis, Lund, Sweden. [Melander, Olle] Lund Univ, Dept Internal Med, Clin Sci, Malmo, Sweden. [Melander, Olle] Skane Univ Hosp, Malmo, Sweden. [Trenson, Sander; Janssens, Stefan P.] Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium. [Domian, Ibrahim] Harvard Stem Cell Inst, Cambridge, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Harvard Med Sch, Boston, MA 02114 USA. RP Buys, ES; Bloch, DB (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA.; Bloch, DB (reprint author), Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Harvard Med Sch, Boston, MA 02114 USA. EM EBUYS@mgh.harvard.edu; dbloch@partners.org FU HHS \ National Institutes of Health (NIH) [R01HL098283, R01HL113933, R01HL124262]; Howard Hughes Medical Institute (HHMI); HHS \ NIH \ National Heart, Lung, and Blood Institute (NHLBI) [T32HL007208]; Fondation Leducq FX This work, including the efforts of Thomas J. Wang and Christopher Newton-Cheh, was funded by HHS vertical bar National Institutes of Health (NIH) (R01HL098283). This work, including the efforts of Christopher Newton-Cheh, was funded by HHS vertical bar National Institutes of Health (NIH) (R01HL113933). This work, including the efforts of Christopher Newton-Cheh, was funded by HHS vertical bar National Institutes of Health (NIH) (R01HL124262). This work, including the efforts of Pawina Jiramongkolchai, was funded by Howard Hughes Medical Institute (HHMI). This work, including the efforts of Connie Wu, was funded by HHS vertical bar NIH vertical bar National Heart, Lung, and Blood Institute (NHLBI) (T32HL007208). This work, including the efforts of Connie Wu, Kenneth D Bloch, and Donald B. Bloch, was funded by Fondation Leducq. NR 36 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2016 VL 36 IS 14 BP 1977 EP 1987 DI 10.1128/MCB.01114-15 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DQ0XG UT WOS:000378924500007 PM 27185878 ER PT J AU Rich, SS Wang, ZY Sturcke, A Ziyabari, L Feolo, M O'Donnell, CJ Rice, K Bis, JC Psaty, BM AF Rich, Stephen S. Wang, Zeng Y. Sturcke, Anne Ziyabari, Lora Feolo, Mike O'Donnell, Christopher J. Rice, Ken Bis, Joshua C. Psaty, Bruce M. TI Rapid evaluation of phenotypes, SNPs and results through the dbGaP CHARGE Summary Results site SO NATURE GENETICS LA English DT Letter ID GENOME-WIDE ASSOCIATION; DESIGN C1 [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Wang, Zeng Y.; Sturcke, Anne; Ziyabari, Lora; Feolo, Mike] US Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Div Intramural Res, Framingham, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Rich, SS (reprint author), Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. EM ssr4n@virginia.edu NR 8 TC 2 Z9 2 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2016 VL 48 IS 7 BP 702 EP 703 DI 10.1038/ng.3582 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DP9TK UT WOS:000378840100002 PM 27350599 ER PT J AU Li, B Li, TW Pignon, JC Wang, BB Wang, JZ Shukla, SA Dou, RX Chen, QM Hodi, FS Choueiri, TK Wu, C Hacohen, N Signoretti, S Liu, JS Liu, XS AF Li, Bo Li, Taiwen Pignon, Jean-Christophe Wang, Binbin Wang, Jinzeng Shukla, Sachet A. Dou, Ruoxu Chen, Qianming Hodi, F. Stephen Choueiri, Toni K. Wu, Catherine Hacohen, Nir Signoretti, Sabina Liu, Jun S. Liu, X. Shirley TI Landscape of tumor-infiltrating T cell repertoire of human cancers SO NATURE GENETICS LA English DT Article ID RNA-SEQ READS; SEQUENCING DATA; ANTIGEN; IMMUNOTHERAPY; RECOGNITION; RECEPTORS; BLOCKADE; LYMPHOCYTES; RESPONSES; LEUKEMIA AB We developed a computational method to infer the complementarity-determining region 3 (CDR3) sequences of tumor-infiltrating T cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600,000 CDR3 sequences, including 15% that were full length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage, for infiltrating T cells in many tumors, except in brain and kidney cancers, resembled those for peripheral blood cells from healthy donors. We observed a strong association between T cell diversity and tumor mutation load, and we predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified three potential immunogenic somatic mutations on the basis of their co-occurrence with CDR3 sequences. One of them, a PRAMEF4 mutation encoding p. Phe300Val, was predicted to result in peptide binding strongly to both MHC class I and class II molecules, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigens and tumor-reactive T cell clonotypes. C1 [Li, Bo; Li, Taiwen; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Bo; Liu, Jun S.; Liu, X. Shirley] Harvard Univ, Dept Stat, Boston, MA 02115 USA. [Li, Taiwen; Chen, Qianming] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610064, Peoples R China. [Pignon, Jean-Christophe; Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Wang, Binbin; Wang, Jinzeng] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China. [Shukla, Sachet A.; Wu, Catherine] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dou, Ruoxu] Sun Yat Sen Univ, Dept Colorectal Surg, Affiliated Hosp 6, Guangzhou 510275, Guangdong, Peoples R China. [Hodi, F. Stephen] Harvard Univ, Sch Med, Ctr ImmunoOncol, Boston, MA USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Kidney Canc Ctr, Boston, MA 02115 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Canc Immunotherapy, Boston, MA 02114 USA. RP Liu, XS (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Liu, JS; Liu, XS (reprint author), Harvard Univ, Dept Stat, Boston, MA 02115 USA. EM jliu@stat.harvard.edu; xsliu@jimmy.harvard.edu FU NCI [1U01 CA180980]; National Natural Science Foundation of China [31329003]; Chinese Scholarship Council; NIH/NCI DF/HCC Kidney Cancer SPORE [P50 CA101942] FX We thank G. Freeman for helpful discussion during manuscript preparation. We also acknowledge the following funding sources for supporting our work: NCI grant 1U01 CA180980, National Natural Science Foundation of China grant 31329003 and a Chinese Scholarship Council Fellowship. This work was supported in part by NIH/NCI DF/HCC Kidney Cancer SPORE P50 CA101942 to S.S. and T.K.C. NR 45 TC 11 Z9 11 U1 6 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2016 VL 48 IS 7 BP 725 EP + DI 10.1038/ng.3581 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DP9TK UT WOS:000378840100009 PM 27240091 ER PT J AU McPherson, A Roth, A Laks, E Masud, T Bashashati, A Zhang, AW Ha, G Biele, J Yap, D Wan, A Prentice, LM Khattra, J Smith, MA Nielsen, CB Mullaly, SC Kalloger, S Karnezis, A Shumansky, K Siu, C Rosner, J Chan, HL Ho, J Melnyk, N Senz, J Yang, W Moore, R Mungall, AJ Marra, MA Bouchard-Cote, A Gilks, CB Huntsman, DG McAlpine, JN Aparicio, S Shah, SP AF McPherson, Andrew Roth, Andrew Laks, Emma Masud, Tehmina Bashashati, Ali Zhang, Allen W. Ha, Gavin Biele, Justina Yap, Damian Wan, Adrian Prentice, Leah M. Khattra, Jaswinder Smith, Maia A. Nielsen, Cydney B. Mullaly, Sarah C. Kalloger, Steve Karnezis, Anthony Shumansky, Karey Siu, Celia Rosner, Jamie Chan, Hector Li Ho, Julie Melnyk, Nataliya Senz, Janine Yang, Winnie Moore, Richard Mungall, Andrew J. Marra, Marco A. Bouchard-Cote, Alexandre Gilks, C. Blake Huntsman, David G. McAlpine, Jessica N. Aparicio, Samuel Shah, Sohrab P. TI Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer SO NATURE GENETICS LA English DT Article ID BRCA2 MUTATIONS; EVOLUTION; CARCINOMA; INFERENCE; DYNAMICS; DOLLO; TP53 AB We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers. C1 [McPherson, Andrew; Roth, Andrew; Laks, Emma; Masud, Tehmina; Bashashati, Ali; Zhang, Allen W.; Ha, Gavin; Biele, Justina; Yap, Damian; Wan, Adrian; Khattra, Jaswinder; Smith, Maia A.; Mullaly, Sarah C.; Kalloger, Steve; Shumansky, Karey; Siu, Celia; Rosner, Jamie; Huntsman, David G.; Aparicio, Samuel; Shah, Sohrab P.] BC Canc Agcy, Dept Mol Oncol, Vancouver, BC, Canada. [McPherson, Andrew] Simon Fraser Univ, Sch Comp Sci, Burnaby, BC V5A 1S6, Canada. [McPherson, Andrew; Roth, Andrew; Zhang, Allen W.; Ha, Gavin; Smith, Maia A.] Univ British Columbia, Grad Bioinformat Training Program, Vancouver, BC V5Z 1M9, Canada. [McPherson, Andrew; Masud, Tehmina; Nielsen, Cydney B.; Huntsman, David G.; Aparicio, Samuel; Shah, Sohrab P.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Zhang, Allen W.] Child & Family Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada. [Ha, Gavin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ha, Gavin] Broad Inst MIT & Harvard, Cambridge, MA USA. [Prentice, Leah M.; Karnezis, Anthony; Chan, Hector Li; Ho, Julie; Melnyk, Nataliya; Senz, Janine; Yang, Winnie; Huntsman, David G.] BC Canc Agcy, Ctr Translat & Appl Gen, Vancouver, BC, Canada. [Moore, Richard; Mungall, Andrew J.; Marra, Marco A.; Shah, Sohrab P.] BC Canc Agcy, Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Bouchard-Cote, Alexandre] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1W5, Canada. [Gilks, C. Blake] Vancouver Gen Hosp, Dept Pathol, 855 W 12Th Ave, Vancouver, BC V5Z 1M9, Canada. [McAlpine, Jessica N.] Univ British Columbia, Dept Gynecol & Obstet, Vancouver, BC V5Z 1M9, Canada. RP Aparicio, S; Shah, SP (reprint author), BC Canc Agcy, Dept Mol Oncol, Vancouver, BC, Canada.; Aparicio, S; Shah, SP (reprint author), Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada.; Shah, SP (reprint author), BC Canc Agcy, Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. EM saparicio@bccrc.ca; sshah@bccrc.ca RI Marra, Marco/B-5987-2008; OI Yap, Damian/0000-0002-5370-4592 FU BC Cancer Foundation; Canadian Breast Cancer Foundation; Canadian Cancer Society Research Institute [701584]; Terry Fox Research Institute; Genome Canada/Genome BC [173-CIC, 177-EVO]; Canadian Institutes for Health Research (CIHR) [MOP-115170, MOP-126119, FDN-143246]; TFRI; Canada Research Chairs; NSERC CGS scholarship; CIHR CGS scholarship; Canadian Breast Cancer Foundation British Columbia/Yukon Postdoctoral Fellowship; [MSH-261515] FX We thank V. Earle for the artwork depicting anatomical sites sampled in the study. We acknowledge generous long-term funding support provided by the BC Cancer Foundation. In addition, the groups of S.P.S. and S.A. receive operating funds from the Canadian Breast Cancer Foundation, the Canadian Cancer Society Research Institute (grant 701584), the Terry Fox Research Institute, Genome Canada/Genome BC (173-CIC and 177-EVO), the Canadian Institutes for Health Research (CIHR) (MOP-115170, MOP-126119, and FDN-143246), a new investigator grant to J.N.M. (MSH-261515), and a TFRI new investigator award to S.P.S. S.P.S. and S.A. are supported by Canada Research Chairs. S.P.S. is a Michael Smith Foundation for Health Research scholar. A.M. is supported by a NSERC CGS scholarship. A.R. is supported by a CIHR CGS scholarship. T.M. is supported by a Canadian Breast Cancer Foundation British Columbia/Yukon Postdoctoral Fellowship. NR 27 TC 10 Z9 10 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2016 VL 48 IS 7 BP 758 EP + DI 10.1038/ng.3573 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DP9TK UT WOS:000378840100013 PM 27182968 ER PT J AU Engblom, C Pfirschke, C Pittet, MJ AF Engblom, Camilla Pfirschke, Christina Pittet, Mikael J. TI The role of myeloid cells in cancer therapies SO NATURE REVIEWS CANCER LA English DT Review ID TUMOR-ASSOCIATED MACROPHAGES; COLONY-STIMULATING FACTOR; CD8(+) T-CELLS; INDEPENDENT PROGNOSTIC-FACTOR; DEPENDENT ANTITUMOR IMMUNITY; PLASMACYTOID DENDRITIC CELLS; ANTIGEN-PRESENTING CELLS; BREAST-CANCER; SUPPRESSOR-CELLS; MAST-CELLS AB Recent clinical trials have demonstrated the ability to durably control cancer in some patients by manipulating T lymphocytes. These immunotherapies are revolutionizing cancer treatment but benefit only a minority of patients. It is thus a crucial time for clinicians, cancer scientists and immunologists to determine the next steps in shifting cancer treatment towards better cancer control. This Review describes recent advances in our understanding of tumour-associated myeloid cells. These cells remain less studied than T lymphocytes but have attracted particular attention because their presence in tumours is often linked to altered patient survival. Also, experimental studies indicate that myeloid cells modulate key cancer-associated activities, including immune evasion, and affect virtually all types of cancer therapy. Consequently, targeting myeloid cells could overcome limitations of current treatment options. C1 [Engblom, Camilla; Pfirschke, Christina; Pittet, Mikael J.] Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA. [Engblom, Camilla; Pfirschke, Christina; Pittet, Mikael J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Engblom, Camilla] Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA 02115 USA. RP Pittet, MJ (reprint author), Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA.; Pittet, MJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu FU Samana Cay MGH Research Scholar Fund; National Institutes of Health (NIH) [P50-CA86355, R21 CA190344, R01-AI084880]; Boehringer Ingelheim Fonds; Deutsche Forschungsgemeinschaft (DFG) [PF809/1-1] FX The authors thank members of the Pittet laboratory and of the Massachusetts General Hospital (MGH) Center for Systems Biology for critical discussions and acknowledge all contributors to the field whose work we could not cite owing to space limitations. This work was supported in part by the Samana Cay MGH Research Scholar Fund, National Institutes of Health (NIH) grants P50-CA86355, R21 CA190344 and R01-AI084880 (to M.J.P.), the Boehringer Ingelheim Fonds (to C.E.) and the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1 (to C.P.). NR 242 TC 9 Z9 9 U1 11 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD JUL PY 2016 VL 16 IS 7 BP 447 EP 462 DI 10.1038/nrc.2016.54 PG 16 WC Oncology SC Oncology GA DP9TA UT WOS:000378838900007 PM 27339708 ER PT J AU Malakhov, A Wen, J Zhang, BX Wang, H Geng, H Chen, XD Sun, Y Yeh, CK AF Malakhov, A. Wen, J. Zhang, B-X Wang, H. Geng, H. Chen, X-D Sun, Y. Yeh, C-K TI Rechargeable anticandidal denture material with sustained release in saliva SO ORAL DISEASES LA English DT Article DE Candida-associated denture stomatitis; antifungal treatment; drug delivery; rechargeable biomaterial ID CANDIDA-ALBICANS; BIOFILM FORMATION; IN-VITRO; TISSUE CONDITIONERS; ANTIFUNGAL ACTIVITY; SILVER-ZEOLITE; DRUG-RELEASE; STOMATITIS; MICONAZOLE; RESISTANCE AB ObjectiveCandida-induced denture stomatitis is a common debilitating problem among denture wearers. Previously, we described the fabrication of a new denture material that released antifungal drugs when immersed in phosphate buffered saline. Here, we use more clinically relevant immersion conditions (human saliva; 37 degrees C) and measure miconazole release and bioactivity. Materials and MethodsDisks were prepared by grafting PNVP [poly(N-vinyl-2-pyrrolidinone)] onto PMMA [poly(methylmethacrylate)] using plasma initiation (PMMA-g-PNVP) and then loaded with miconazole. Drug-loaded disks were immersed in 10-100% human saliva (1-30days). Miconazole release was measured and then tested for bioactivity vs miconazole-sensitive and miconazole-resistant Candida isolates. ResultsHPLC was used to quantify miconazole levels in saliva. Miconazole-loaded disks released antifungal drug for up to 30days. Higher drug release was found with higher concentrations of saliva, and, interestingly, miconazole solubility was increased with higher saliva concentrations. The released miconazole retained its anticandidal activity. After immersion, the residual miconazole could be quenched and the disks recharged. Freshly recharged disks displayed the same release kinetics and bioactivity as the original disks. Quenched disks could also be charged with chlorhexidine that displayed anticandidal activity. ConclusionsThese results suggest that PMMA-g-PNVP is a promising new denture material for long-term management of denture stomatitis. C1 [Malakhov, A.; Zhang, B-X; Wang, H.; Chen, X-D; Yeh, C-K] South Texas Vet Hlth Care Syst, Educ & Clin Ctr, Geriatr Res, San Antonio, TX 78229 USA. [Malakhov, A.; Zhang, B-X; Wang, H.; Chen, X-D; Yeh, C-K] South Texas Vet Hlth Care Syst, Res Serv, Audie L Murphy Div, San Antonio, TX 78229 USA. [Malakhov, A.; Zhang, B-X; Wang, H.; Chen, X-D; Yeh, C-K] Univ Texas Hlth Sci Ctr San Antonio, Dept Comprehens Dent, San Antonio, TX 78229 USA. [Wen, J.; Sun, Y.] Univ Massachusetts, Dept Chem, Lowell, MA USA. [Geng, H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Yeh, CK (reprint author), South Texas Vet Hlth Care Syst, Educ & Clin Ctr, Geriatr Res, San Antonio, TX 78229 USA.; Yeh, CK (reprint author), South Texas Vet Hlth Care Syst, Res Serv, Audie L Murphy Div, San Antonio, TX 78229 USA. EM yeh@uthscsa.edu FU NIH; NIDCR T-32 [DE021084, DE014318]; COSTAR Program; VA Merit Review [1I01BX001103] FX This study was supported by NIH and NIDCR T-32 grants DE021084, DE014318, the COSTAR Program, and a VA Merit Review (1I01BX001103). We are grateful to Dr. Nathan Wiederhold, Director of the Fungal Testing Laboratory (UTHSCSA), for kindly providing the Candida isolates used in this study and to Dr. David Dean (Professor, Comprehensive Dentistry, UTHSCSA) for his scientific input and careful editing of the manuscript. The authors declared no potential conflict of interests with respect to the authorship and/or publication of this article. NR 33 TC 0 Z9 0 U1 5 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD JUL PY 2016 VL 22 IS 5 BP 391 EP 398 DI 10.1111/odi.12456 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DP6WA UT WOS:000378638800007 PM 26855200 ER PT J AU Poston, CJ Pierce, TC Li, Y Brinson, CW Lu, Z Lauer, AW Leite, RS Huang, Y AF Poston, C. J. Pierce, T. C. Li, Y. Brinson, C. W. Lu, Z. Lauer, A. W. Leite, R. S. Huang, Y. TI Statin intake is associated with MMP-1 level in gingival crevicular fluid of patients with periodontitis SO ORAL DISEASES LA English DT Article DE statin; periodontitis; diabetes mellitus; matrix metalloproteinase-1 ID MATRIX METALLOPROTEINASE-1 EXPRESSION; U937 MONONUCLEAR-CELLS; ALVEOLAR BONE LOSS; HIGH GLUCOSE; CARDIOVASCULAR-DISEASE; INFLAMMATORY RESPONSES; INTERFERON-GAMMA; LIPOPOLYSACCHARIDE; THERAPY; ROSUVASTATIN AB BackgroundThis study was conducted to assess whether statin intake is associated with clinical parameters of periodontitis and matrix metalloproteinase (MMP) levels in gingival crevicular fluid (GCF) of non-diabetic and diabetic patients. MethodsWe first determined the effect of simvastatin on MMP expression in mononuclear cells. We then recruited 117 non-diabetic and diabetic patients, who all had periodontitis and took or did not take statin, and measured periodontal probing depth (PPD) and clinical attachment level (CAL), and collected gingival crevicular fluid (GCF) to quantify MMPs. ResultsThe invitro studies showed that simvastatin potently inhibited the expression of MMP-1, MMP-8, and MMP-9 upregulated by lipopolysaccharide (LPS) and high glucose in mononuclear cells. The patient study showed that, after adjusting for age and smoking status, PPD in diabetic patients on statin was significantly less than that in diabetic patients not on statin. MMP-1 level in GCF of non-diabetic and diabetic patients on statin was lower than that of non-diabetic and diabetic patients not on statin, respectively. No difference was found for MMP-8 and -9 levels in GCF. ConclusionStatin intake is associated with reduced PPD in diabetic patients and MMP-1 level in GCF in either non-diabetic or diabetic patients. C1 [Poston, C. J.; Pierce, T. C.; Leite, R. S.] Med Univ S Carolina, Coll Dent Med, Div Periodont, Dept Stomatol, Charleston, SC 29425 USA. [Li, Y.; Brinson, C. W.; Huang, Y.] Med Univ S Carolina, Coll Med, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. [Lu, Z.; Huang, Y.] Ralph H Johnson Vet Affairs Med Ctr, 114 Doughty St, Charleston, SC 29425 USA. [Lauer, A. W.] Med Univ S Carolina, Coll Med, Dept Publ Hlth Sci, Div Biostat, Charleston, SC 29425 USA. RP Huang, Y (reprint author), Ralph H Johnson Vet Affairs Med Ctr, 114 Doughty St, Charleston, SC 29425 USA.; Huang, Y (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, 114 Doughty St, Charleston, SC 29425 USA. EM huangyan@musc.edu FU NIH [DE016353]; Merit Review Grant from Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs FX This work was supported by NIH grant DE016353 and Merit Review Grant from the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs (to Y.H.). NR 45 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD JUL PY 2016 VL 22 IS 5 BP 438 EP 444 DI 10.1111/odi.12474 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DP6WA UT WOS:000378638800013 PM 26988924 ER PT J AU Hasegawa, K Linnemann, RW Mansbach, JM Ajami, NJ Espinola, JA Petrosino, JF Piedra, PA Stevenson, MD Sullivan, AF Thompson, AD Camargo, CA AF Hasegawa, Kohei Linnemann, Rachel W. Mansbach, Jonathan M. Ajami, Nadim J. Espinola, Janice A. Petrosino, Joseph F. Piedra, Pedro A. Stevenson, Michelle D. Sullivan, Ashley F. Thompson, Amy D. Camargo, Carlos A., Jr. TI The Fecal Microbiota Profile and Bronchiolitis in Infants SO PEDIATRICS LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; PROBIOTIC SUPPLEMENTATION; IMMUNE-RESPONSES; INFECTION; RHINOVIRUS; CHILDREN; MUCOSAL; DEFENSE; ASTHMA AB BACKGROUND: Little is known about the association of gut microbiota, a potentially modifiable factor, with bronchiolitis in infants. We aimed to determine the association of fecal microbiota with bronchiolitis in infants. METHODS: We conducted a case-control study. As a part of multicenter prospective study, we collected stool samples from 40 infants hospitalized with bronchiolitis. We concurrently enrolled 115 age-matched healthy controls. By applying 16S rRNA gene sequencing and an unbiased clustering approach to these 155 fecal samples, we identified microbiota profiles and determined the association of microbiota profiles with likelihood of bronchiolitis. RESULTS: Overall, the median age was 3 months, 55% were male, and 54% were non-Hispanic white. Unbiased clustering of fecal microbiota identified 4 distinct profiles: Escherichiadominant profile (30%), Bifidobacterium-dominant profile (21%), Enterobacter/Veillonelladominant profile (22%), and Bacteroides-dominant profile (28%). The proportion of bronchiolitis was lowest in infants with the Enterobacter/Veillonella-dominant profile (15%) and highest in the Bacteroides-dominant profile (44%), corresponding to an odds ratio of 4.59 (95% confidence interval, 1.58-15.5; P =.008). In the multivariable model, the significant association between the Bacteroides-dominant profile and a greater likelihood of bronchiolitis persisted (odds ratio for comparison with the Enterobacter/Veillonella-dominant profile, 4.24; 95% confidence interval, 1.56-12.0; P =.005). In contrast, the likelihood of bronchiolitis in infants with the Escherichia-dominant or Bifidobacterium-dominant profile was not significantly different compared with those with the Enterobacter/Veillonella-dominant profile. CONCLUSIONS: In this case-control study, we identified 4 distinct fecal microbiota profiles in infants. The Bacteroides-dominant profile was associated with a higher likelihood of bronchiolitis. C1 [Hasegawa, Kohei; Espinola, Janice A.; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Emergency Med, Boston, MA 02114 USA. [Linnemann, Rachel W.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Mansbach, Jonathan M.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Ajami, Nadim J.; Petrosino, Joseph F.] Baylor Coll Med, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol & Pediat, Houston, TX 77030 USA. [Stevenson, Michelle D.] Kosair Childrens Hosp, Louisville, KY USA. [Thompson, Amy D.] Alfred I duPont Hosp Children, Delaware, OH USA. RP Hasegawa, K (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 920, Boston, MA 02114 USA. EM khasegawa1@partners.org FU National Institutes of Health (Bethesda, MD) [U01 AI-087881, R01 AI-114552, R01 AI-108588, R21 HL-129909]; National Institutes of Health (NIH) FX Supported by grants U01 AI-087881, R01 AI-114552, R01 AI-108588, and R21 HL-129909 from the National Institutes of Health (Bethesda, MD). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funded by the National Institutes of Health (NIH). NR 40 TC 2 Z9 2 U1 3 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUL PY 2016 VL 138 IS 1 AR e20160218 DI 10.1542/peds.2016-0218 PG 9 WC Pediatrics SC Pediatrics GA DP9YD UT WOS:000378853100042 ER PT J AU Lee, J Greenspan, PT Israel, E Katz, A Fasano, A Kaafarani, HMA Linov, PL Raja, AS Rao, SK AF Lee, Jarone Greenspan, Peter T. Israel, Esther Katz, Aubrey Fasano, Alessio Kaafarani, Haytham M. A. Linov, Pamela L. Raja, Ali S. Rao, Sandhya K. TI Emergency Department Utilization Report to Decrease Visits by Pediatric Gastroenterology Patients SO PEDIATRICS LA English DT Article ID CENTERED MEDICAL HOME; ASSOCIATION; CARE; CHILDREN AB BACKGROUND AND OBJECTIVES: Emergency department (ED) utilization is a major driver of health care costs. Specialist physicians have an important role in addressing ED utilization, especially at highly specialized, academic medical centers. We sought to investigate whether reporting of ED utilization to specialist physicians can decrease ED visits. METHODS: This study analyzed an intervention to reduce ED utilization among ED patients who were followed by pediatric gastroenterologists. In May 2013, each pediatric gastroenterologist began receiving reports with rates of ED use by their patients. The reports generated discussion that resulted in a cultural and process change in which patients with urgent gastrointestinal (GI)-related complaints were preferentially seen in the office. Using control charts, we examined GI-related and all-diagnoses ED use over a 2-year period. RESULTS: The rate of GI-related ED visits decreased by 60% after the intervention, from 4.89 to 1.95 per 1000 office visits (P < .001). Similarly, rates of GI-related ED visits during office hours decreased by 59% from 2.19 to 0.89 per 1000 (P < .001). Rates of all-diagnoses ED visits did not change. CONCLUSIONS: Physician-level reporting of ED utilization to pediatric gastroenterologists was associated with physician engagement and a cultural and process change to preferentially treat patients with urgent issues in the office. C1 [Lee, Jarone; Raja, Ali S.] Massachusetts Gen Hosp, Dept Emergency Med, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. [Lee, Jarone; Kaafarani, Haytham M. A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Rao, Sandhya K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lee, Jarone; Greenspan, Peter T.; Linov, Pamela L.; Rao, Sandhya K.] Massachusetts Gen Phys Org, Boston, MA USA. [Greenspan, Peter T.; Israel, Esther; Katz, Aubrey; Fasano, Alessio] MassGen Hosp Children, Boston, MA USA. RP Lee, J (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM lee.jarone@mgh.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUL PY 2016 VL 138 IS 1 AR e20153586 DI 10.1542/peds.2015-3586 PG 7 WC Pediatrics SC Pediatrics GA DP9YD UT WOS:000378853100010 ER PT J AU Perrin, JM Houtrow, A Kelleher, K Hoagwood, K Stein, REK Zima, B AF Perrin, James M. Houtrow, Amy Kelleher, Kelly Hoagwood, Kimberly Stein, Ruth E. K. Zima, Bonnie TI Supplemental Security Income Benefits for Mental Disorders SO PEDIATRICS LA English DT Article ID CHILD HEALTH; DISABILITY AB The Supplemental Security Income Program (SSI) provides financial support to low-income households with children and youth with severe disabilities. The program included children when it began in the early 1970s. The numbers of children receiving SSI benefits increased substantially in the early 1990s, in part through an expansion of the listings of mental health conditions with which children could become eligible. Over the past 20 years, larger numbers of children have received SSI benefits for mental disorders, and these increases have led to questions from the press and Congress regarding these numbers. Do they indicate more of an increase in mental disorders among SSI children than in the general population? The National Academy of Medicine (NAM; formerly the Institute of Medicine) convened a study panel to examine what is known about mental disorders among the child SSI population and how that compares with evidence about mental disorders in children in general. The NAM report provides detailed information about how SSI works, about the changing numbers of children receiving SSI for mental disorders, and some comparisons with other evidence about rising rates of mental disorders in the general population and especially among children living in poverty. The report indicates that increasing numbers of children with mental disorders in SSI mirror similar increases in the population in general. This article summarizes key evidence from the NAM report and suggests the implications for pediatricians. C1 [Perrin, James M.] MassGen Hosp Children, 125 Nashua St,860, Boston, MA 02114 USA. [Perrin, James M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Houtrow, Amy] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Houtrow, Amy] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Kelleher, Kelly] Nationwide Childrens Hosp, Columbus, OH USA. [Kelleher, Kelly] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Hoagwood, Kimberly] NYU, Sch Med, Dept Child Psychiat, New York, NY USA. [Stein, Ruth E. K.] Childrens Hosp Montefiore, Bronx, NY USA. [Stein, Ruth E. K.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Zima, Bonnie] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Zima, Bonnie] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. RP Perrin, JM (reprint author), MassGen Hosp Children, 125 Nashua St,860, Boston, MA 02114 USA. EM jperrin@mgh.harvard.edu NR 25 TC 1 Z9 1 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUL PY 2016 VL 138 IS 1 AR e20160354 DI 10.1542/peds.2016-0354 PG 8 WC Pediatrics SC Pediatrics GA DP9YD UT WOS:000378853100047 ER PT J AU Mazzoni, M Bombardi, C Vallorani, C Sirri, F De Giorgio, R Caio, G Grandis, A Sternini, C Clavenzani, P AF Mazzoni, M. Bombardi, C. Vallorani, C. Sirri, F. De Giorgio, R. Caio, G. Grandis, A. Sternini, C. Clavenzani, P. TI Distribution of alpha-transducin and alpha-gustducin immunoreactive cells in the chicken (Gallus domesticus) gastrointestinal tract SO POULTRY SCIENCE LA English DT Article DE chemosensing; alpha-transducin; alpha-gustducin; gastrointestinal tract; chicken ID BITTER TASTE RECEPTORS; SMALL-INTESTINE; SIGNALING MECHANISMS; CHROMOGRANIN-A; EXPRESSION; GUT; ENDOCRINE; COLOCALIZATION; NUTRIENTS; ONTOGENY AB The expression and distribution patterns of the taste signaling molecules, alpha-gustducin (G(alpha gust)) and alpha-transducin (G(alpha tran)) G-protein subunits, were studied in the gastrointestinal tract of the chicken (Gallus domesticus) using the immunohistochemical method. G(alpha gust) and G(alpha tran) immunoreactive (-IR) cells were observed in the mucosal layer of all examined segments, except the esophagus, crop, and the saccus cranialis of the gizzard. The highest numbers of G(alpha gus)t and G(alpha tran)-IR cells were found in the proventriculus glands and along the villi of the pyloric, duodenum, and rectal mucosa. G(alpha gust) and G(alpha tran)-IR cells located in the villi of the jejunum, ileum, and cloaca were much less numerous, while only a few G(alpha gus)t and G(alpha tran)-IR cells were detected in the mucosa of the proventriculus and cecum. In the crypts, IR cells were observed in the small and large intestine as well as in the cloaca. G(alpha gust) and G(alpha tran)-IR cells displayed elongated ("bottle-" or "pearlike") or rounded shape. The demonstration of G(alpha gust) and G(alpha tran) expression provides evidence for taste receptor mediated mucosal chemosensitivity in the chicken gastrointestinal tract. C1 [Mazzoni, M.; Bombardi, C.; Vallorani, C.; Grandis, A.; Clavenzani, P.] Univ Bologna, Dept Vet Med Sci, Ozzano Dell Emilia, BO, Italy. [Sirri, F.] Univ Bologna, Dept Agr & Food Sci, Ozzano Dell Emilia, BO, Italy. [De Giorgio, R.; Caio, G.] Univ Bologna, Dept Med & Surg Sci, Ozzano Dell Emilia, BO, Italy. [Sternini, C.] Univ Calif Los Angeles, David Geffen Sch Med, CURE DDRC, Div Digest Dis,Dept Med, Los Angeles, CA 90095 USA. [Sternini, C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Sternini, C.] Vet Adm Greater Los Angeles Hlth Syst, Los Angeles, CA USA. RP Mazzoni, M (reprint author), Univ Bologna, Dept Vet Med Sci, Ozzano Dell Emilia, BO, Italy. EM m.mazzoni@unibo.it RI Mazzoni, Maurizio/J-1918-2016 OI Mazzoni, Maurizio/0000-0002-7384-5990 FU Department of Veterinary Medical Science, University of Bologna; National Institute of Health [P30DK41301, R01DK98447] FX This study was financed by the Department of Veterinary Medical Science, University of Bologna. CS is supported by the National Institute of Health grants, P30DK41301 and R01DK98447. NR 34 TC 1 Z9 1 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0032-5791 EI 1525-3171 J9 POULTRY SCI JI Poult. Sci. PD JUL PY 2016 VL 95 IS 7 BP 1624 EP 1630 DI 10.3382/ps/pew057 PG 7 WC Agriculture, Dairy & Animal Science SC Agriculture GA DP6PI UT WOS:000378619000018 PM 26957624 ER PT J AU Cabrera, AR Kirkpatrick, JP Fiveash, JB Shih, HA Koay, EJ Lutz, S Petit, J Chao, ST Brown, PD Vogelbaum, M Reardon, DA Chakravarti, A Wen, PY Chang, E AF Cabrera, Alvin R. Kirkpatrick, John P. Fiveash, John B. Shih, Helen A. Koay, Eugene J. Lutz, Stephen Petit, Joshua Chao, Samuel T. Brown, Paul D. Vogelbaum, Michael Reardon, David A. Chakravarti, Arnab Wen, Patrick Y. Chang, Eric TI Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline SO PRACTICAL RADIATION ONCOLOGY LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; QUALITY-OF-LIFE; RADIOTHERAPY PLUS CONCOMITANT; RANDOMIZED PHASE-III; ADJUVANT TEMOZOLOMIDE; MALIGNANT GLIOMA; STEREOTACTIC RADIOSURGERY; ELDERLY-PATIENTS; GRADE GLIOMAS; TRIAL AB Purpose: To present evidence-based guidelines for radiation therapy in treating glioblastoma not arising from the brainstem. Methods and materials: The American Society for Radiation Oncology (ASTRO) convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects? (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status? (3) What are ideal target volumes for curative-intent external beam radiation therapy of glioblastoma? (4) What is the role of reirradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. Results: Following biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiation therapy (eg, 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (>= 70 years of age) with reasonable performance status should receive hypofractionated radiation therapy (eg, 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving 2 phases (primary and boost volumes) or 1 phase (single volume). For recurrent glioblastoma, focal reirradiation can be considered in younger patients with good performance status. Conclusions: Radiation therapy occupies an integral role in treating glioblastoma. Whether and how radiation therapy should be applied depends on characteristics specific to tumor and patient, including age and performance status. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. C1 [Cabrera, Alvin R.] Grp Hlth Phys, Dept Radiat Oncol, Seattle, WA USA. [Kirkpatrick, John P.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. [Fiveash, John B.] Univ Alabama Birmingham, Dept Radiat Oncol, Birmingham, AL USA. [Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Koay, Eugene J.; Brown, Paul D.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Lutz, Stephen] Blanchard Valley Reg Hlth Ctr, Dept Radiat Oncol, Findlay, OH USA. [Petit, Joshua] Univ Colorado Hlth, Dept Radiat Oncol, Ft Collins, CO USA. [Chao, Samuel T.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Vogelbaum, Michael] Cleveland Clin, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44106 USA. [Reardon, David A.; Wen, Patrick Y.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Chakravarti, Arnab] Ohio State Univ, Dept Radiat Oncol, Columbus, OH 43210 USA. [Chang, Eric] Univ So Calif, Keck Sch Med, Dept Radiat Oncol, Los Angeles, CA 90033 USA. RP Cabrera, AR (reprint author), Grp Hlth Phys, Radiat Oncol CMB A Level,201 16th Ave East, Seattle, WA 98122 USA. EM acabrera@post.harvard.edu OI Kirkpatrick, John/0000-0002-4019-0350 NR 46 TC 1 Z9 1 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1879-8500 J9 PRACT RADIAT ONCOL JI Pract. Radiat. Oncol. PD JUL-AUG PY 2016 VL 6 IS 4 BP 217 EP 225 DI 10.1016/j.prro.2016.03.007 PG 9 WC Oncology SC Oncology GA DP6RQ UT WOS:000378626600011 PM 27211230 ER PT J AU Kishan, AU Wang, PC Upadhyaya, SK Hauswald, H Demanes, DJ Nickols, NG Kamrava, M Sadeghi, A Kupelian, PA Steinberg, ML Prionas, ND Buyyounouski, MK King, CR AF Kishan, Amar U. Wang, Pin-Chieh Upadhyaya, Shrinivasa K. Hauswald, Henrik Demanes, D. Jeffrey Nickols, Nicholas G. Kamrava, Mitchell Sadeghi, Ahmad Kupelian, Patrick A. Steinberg, Michael L. Prionas, Nicolas D. Buyyounouski, Mark K. King, Christopher R. TI SBRT and HDR brachytherapy produce lower PSA nadirs and different PSA decay patterns than conventionally fractionated IMRT in patients with low- or intermediate-risk prostate cancer SO PRACTICAL RADIATION ONCOLOGY LA English DT Article ID STEREOTACTIC BODY RADIOTHERAPY; EXTERNAL-BEAM RADIOTHERAPY; DOSE-RATE BRACHYTHERAPY; RADIATION-THERAPY; MULTIINSTITUTIONAL ANALYSIS; ANTIGEN BOUNCE; KINETICS; MONOTHERAPY; FAILURE; LEVEL AB Purpose: To compare patterns of prostate-specific antigen (PSA) response following stereotactic body radiation therapy (SBRT), high-dose-rate (HDR) brachytherapy, and conventionally fractionated intensity modulated radiation therapy (IMRT) in patients with low-or intermediate-risk prostate cancer (CaP). Methods and materials: Eligible study patients included 439 patients with low-or intermediate-risk prostate cancer who were treated with radiation therapy (RT) alone between 2003 and 2013, remained free of biochemical recurrence, and had at least 2 PSA values within the first year following RT. Of these, 130 were treated with SBRT, 220 with HDR brachytherapy, and 89 with IMRT. Multivariate regression analysis was used to compare PSA nadirs (nPSA), time to nPSA, and PSA bounce parameters among the 3 modalities. Indicator variable analysis was used to develop empirical models of PSA decay using the treatment modalities as indicator variables. Results: Significantly more patients treated with SBRT or HDR brachytherapy achieved raw nPSAs of <0.5 ng/mL compared with patients treated with IMRT (76.2% and 75.9% vs 44.9%, respectively; P < .0001 for SBRT or HDR brachytherapy vs IMRT). On multivariate analysis, nPSA was significantly lower with SBRT and HDR compared with IMRT (P < .0001). Time to nPSA and bounce parameters was not significantly different among IMRT, SBRT, and HDR. Overall, SBRT and HDR brachytherapy caused significantly larger PSA decay rates (P < .001). When truncating follow-up at 1000 days, the corresponding decay rates were larger for all 3 modalities, with no significant differences between them. Conclusions: Stereotactic body radiation therapy and HDR brachytherapy produce lower nPSAs than IMRT. Within 1000 days of follow-up, the modalities produce similar rates of PSA decay; subsequently, decay continues (albeit at a slower pace) after SBRT and HDR brachytherapy but plateaus with IMRT. Because nPSA is a validated predictor of long-term outcome, these data not only suggest a distinct radiobiological effect with SBRT and HDR brachytherapy, but also predict for clinical outcomes that might equal or surpass those of IMRT. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. C1 [Kishan, Amar U.; Wang, Pin-Chieh; Demanes, D. Jeffrey; Nickols, Nicholas G.; Kamrava, Mitchell; Kupelian, Patrick A.; Steinberg, Michael L.; King, Christopher R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiat Oncol, Los Angeles, CA 90095 USA. [Upadhyaya, Shrinivasa K.] Univ Calif Davis, Dept Biol & Agr Engn, Davis, CA 95616 USA. [Hauswald, Henrik] Univ Heidelberg Hosp, Dept Radiat Oncol & Radiat Therapy, Heidelberg, Germany. [Nickols, Nicholas G.; Prionas, Nicolas D.; Buyyounouski, Mark K.] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA. [Sadeghi, Ahmad] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Radiat Oncol, Los Angeles, CA USA. RP Kishan, AU (reprint author), Dept Radiat Oncol, 200 UCLA Med Plaza,B265, Los Angeles, CA 90095 USA. EM aukishan@gmail.com NR 31 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1879-8500 J9 PRACT RADIAT ONCOL JI Pract. Radiat. Oncol. PD JUL-AUG PY 2016 VL 6 IS 4 BP 268 EP 275 DI 10.1016/j.prro.2015.11.002 PG 8 WC Oncology SC Oncology GA DP6RQ UT WOS:000378626600018 PM 26850649 ER PT J AU Arvold, ND Pinnell, NE Mahadevan, A Connelly, S Silverman, R Weiss, SE Kelly, PJ Alexander, BM AF Arvold, Nils D. Pinnell, Nancy E. Mahadevan, Anand Connelly, Sheila Silverman, Rachel Weiss, Stephanie E. Kelly, Paul J. Alexander, Brian M. TI Steroid and anticonvulsant prophylaxis for stereotactic radiosurgery: Large variation in physician recommendations SO PRACTICAL RADIATION ONCOLOGY LA English DT Article ID CLINICAL-PRACTICE GUIDELINE; GAMMA-KNIFE RADIOSURGERY; BRAIN METASTASES; SEIZURE PROPHYLAXIS; CEREBRAL METASTASES; MANAGEMENT; MELANOMA; RADIOTHERAPY; IPILIMUMAB; EFFICACY AB Purpose/Objective(s): The risk of developing symptomatic edema or seizure following stereotactic radiosurgery (SRS) is poorly defined, and many practitioners prescribe prophylactic corticosteroids and/or anticonvulsants. Because there are no clear guidelines regarding appropriate use, we sought to characterize prescribing practices and factors associated with these recommendations. Methods and materials: We conducted a 1-time, internet-based survey among 500 randomly selected radiation oncologists self-described as specializing in central nervous system diseases who were registered in the American Society for Radiation Oncology directory. Physicians were contacted by e-mail and invited to complete the 22-question survey. Results: The response rate was 32% (n = 161). Sixty-six percent of respondents had been in practice for >10 years, and 45% of respondents practiced at an academic medical center. During/after SRS, 53% of respondents "always" or "usually" recommended corticosteroids, whereas 47% "never," " rarely," or "sometimes" recommended them. When prescribing corticosteroids, the recommended duration of use was <1 week, 1-2 weeks, or >2 weeks among 49%, 33%, and 18% of respondents, respectively. Respondents who worked in an academic medical center were less likely to prescribe corticosteroids, although this did not reach significance (P=.09). Seizure prophylaxis was less common overall, as 79% of respondents "rarely" or "never" prescribed anticonvulsants for SRS. Respondentswho prescribed anticonvulsants more frequently had higher estimations of the risk of seizure within 2 weeks of SRS (P<.001), and their recommended duration of anticonvulsant use was <1 week, 1-2 weeks, and >2 weeks among 35%, 25%, and 41% of respondents, respectively. Conclusions: There is extreme variation in physician recommendations regarding prophylactic corticosteroid and anticonvulsant use for patients undergoing SRS. Further investigation of the risks and benefits of these medications for SRS is warranted, which may promote guideline development and more patient-centered, rational prescribing practices. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. C1 [Arvold, Nils D.; Pinnell, Nancy E.; Connelly, Sheila; Silverman, Rachel; Alexander, Brian M.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. [Arvold, Nils D.; Mahadevan, Anand; Alexander, Brian M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mahadevan, Anand] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Weiss, Stephanie E.] Fox Chase Canc Ctr, Dept Radiat Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Kelly, Paul J.] Cork Univ Hosp, Dept Radiat Oncol, Cork, Ireland. RP Alexander, BM (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM bmalexander@partners.org NR 30 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1879-8500 J9 PRACT RADIAT ONCOL JI Pract. Radiat. Oncol. PD JUL-AUG PY 2016 VL 6 IS 4 BP E89 EP E96 DI 10.1016/j.prro.2015.11.004 PG 8 WC Oncology SC Oncology GA DP6RQ UT WOS:000378626600002 PM 26850650 ER PT J AU Li, XA Chen, XJ Zhang, Q Kirsch, DG Petersen, I DeLaney, TF Freeman, CR Trotti, A Hitchcock, Y Bedi, M Haddock, M Salerno, K Dundas, G Wang, DA AF Li, X. Allen Chen, Xiaojian Zhang, Qiang Kirsch, David G. Petersen, Ivy DeLaney, Thomas F. Freeman, Carolyn R. Trotti, Andy Hitchcock, Ying Bedi, Meena Haddock, Michael Salerno, Kilian Dundas, George Wang, Dian TI Margin reduction from image guided radiation therapy for soft tissue sarcoma: Secondary analysis of Radiation Therapy Oncology Group 0630 results SO PRACTICAL RADIATION ONCOLOGY LA English DT Article ID POSTOPERATIVE RADIOTHERAPY AB Purpose: Six imaging modalities were used in Radiation Therapy Oncology Group (RTOG) 0630, a study of image guided radiation therapy (IGRT) for primary soft tissue sarcomas of the extremity. We analyzed all daily patient-repositioning data collected in this trial to determine the impact of daily IGRT on clinical target volume-to-planning target volume (CTV-to-PTV) margin. Methods and materials: Daily repositioning data, including shifts in right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions and rotations for 98 patients enrolled in RTOG 0630 from 18 institutions were analyzed. Patients were repositioned daily on the basis of bone a natomy by using pretreatment images, including kilovoltage orthogonal images (KVorth), megavoltage orthogonal images (MVorth), KV fan-beam computed tomography (KVCT), KV cone beam CT (KVCB), MV fan-beam CT (MVCT), and MV cone beam CT (MVCB). Means and standard deviations (SDs) for each shift and rotation were calculated for each patient and for each IGRT modality. The Student's t tests and F-tests were performed to analyze the differences in the means and SDs. Necessary CTV-to-PTV margins were estimated. Results: The repositioning shifts and day-to-day variations were large and generally similar for the 6 imaging modalities. Of the 2 most commonly used modalities, MVCT and KVorth, there were no statistically significant differences in the shifts and rotations (P = .15 and .59 for the RL and SI shifts, respectively; and P = .22 for rotation), except for shifts in AP direction (P = .002). The estimated CTV-to-PTV margins in the RL, SI, and AP directions would be 13.0, 10.4, and 11.7 mm from MVCT data, respectively, and 13.1, 8.6, and 10.8 mm from KVorth data, respectively, indicating that margins substantially larger than 5 mm used with daily IGRT would be required in the absence of IGRT. Conclusions: The observed large daily repositioning errors and the large variations among institutions imply that daily IGRT is necessary for this tumor site, particularly in multi-institutional trials. Otherwise, a CTV-to-PTV margin of 1.5 cm is required to account for daily setup variations. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. C1 [Li, X. Allen; Chen, Xiaojian; Bedi, Meena] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Zhang, Qiang] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Kirsch, David G.] Duke Univ, Med Ctr, Durham, NC USA. [Petersen, Ivy; Haddock, Michael] Mayo Clin, Rochester, MN USA. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Freeman, Carolyn R.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Trotti, Andy] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Hitchcock, Ying] Univ Utah, Salt Lake City, UT USA. [Salerno, Kilian] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Dundas, George] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. [Wang, Dian] Rush Univ, Med Ctr, Chicago, IL 60612 USA. RP Li, XA (reprint author), Med Coll Wisconsin, Dept Radiat Oncol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM ali@mcw.edu FU NCI NIH HHS [U10 CA021661, U10 CA037422, U10 CA180818, U10 CA180822, U10 CA180868, U24 CA180803] NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1879-8500 J9 PRACT RADIAT ONCOL JI Pract. Radiat. Oncol. PD JUL-AUG PY 2016 VL 6 IS 4 BP E135 EP E140 DI 10.1016/j.prro.2015.11.012 PG 6 WC Oncology SC Oncology GA DP6RQ UT WOS:000378626600007 PM 26852173 ER PT J AU Woolley, JD Arcuni, PA Stauffer, CS Fulford, D Carson, DS Batki, S Vinogradov, S AF Woolley, Josh D. Arcuni, Peter A. Stauffer, Christopher S. Fulford, Daniel Carson, Dean S. Batki, Steve Vinogradov, Sophia TI The effects of intranasal oxytocin in opioid-dependent individuals and healthy control subjects: a pilot study SO PSYCHOPHARMACOLOGY LA English DT Article DE Oxytocin; Heroin; Opioid; Addiction; Tolerability; Craving; Implicit; Social; RMET; Clinical ID SOCIAL COGNITION; NEURAL SYSTEMS; WITHDRAWAL; TOLERANCE; ADDICTION; HUMANS; ALCOHOLICS; METHADONE; IMPLICIT; RELAPSE AB Rationale There has been an explosion of research on the potential benefits of the social neuropeptide oxytocin for a number of mental disorders including substance use disorders. Recent evidence suggests that intranasal oxytocin has both direct anti-addiction effects and pro-social effects that may facilitate engagement in psychosocial treatment for substance use disorders. Objectives We aimed to assess the tolerability of intranasal oxytocin and its effects on heroin craving, implicit association with heroin and social perceptual ability in opioid-dependent patients receiving opioid replacement therapy (ORT) and healthy control participants. Methods We performed a randomized, double-blind, placebo-controlled, within-and between-subjects, crossover, proof-of-concept trial to examine the effects of oxytocin (40 international units) on a cue-induced craving task (ORT patients only), an Implicit Association Task (IAT), and two social perception tasks: the Reading the Mind in the Eyes Task (RMET) and The Awareness of Social Inference Test (TASIT). Results Oxytocin was well tolerated by patients receiving ORT but had no significant effects on craving or IAT scores. There was a significant reduction in RMET performance after oxytocin administration versus placebo in the patient group only, and a significant reduction in TASIT performance after oxytocin in both the patient and healthy control groups. Conclusions A single dose of intranasal oxytocin is well tolerated by patients receiving ORT, paving the way for future investigations. Despite no significant improvement in craving or IAT scores after a single dose of oxytocin and some evidence that social perception was worsened, further investigation is required to determine the role oxytocin may play in the treatment of opioid use disorder. C1 [Woolley, Josh D.; Stauffer, Christopher S.; Batki, Steve; Vinogradov, Sophia] Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA. [Woolley, Josh D.; Arcuni, Peter A.; Stauffer, Christopher S.; Batki, Steve; Vinogradov, Sophia] San Francisco VA Med Ctr, Dept Mental Hlth, 4150 Clement St 116C-1, San Francisco, CA 94121 USA. [Fulford, Daniel] Boston Univ, Sargent Coll Hlth & Rehabil Sci, 635 Commonwealth Ave,SAR 512, Boston, MA 02215 USA. [Carson, Dean S.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Woolley, JD (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA.; Woolley, JD (reprint author), San Francisco VA Med Ctr, Dept Mental Hlth, 4150 Clement St 116C-1, San Francisco, CA 94121 USA. EM Josh.Woolley@ucsf.edu FU San Francisco Treatment Research Center at the University of California, San Francisco from the National Institute on Drug Abuse [P50 DA009253] FX This project was supported by the San Francisco Treatment Research Center at the University of California, San Francisco, via grant number P50 DA009253 from the National Institute on Drug Abuse. NR 62 TC 1 Z9 1 U1 3 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2016 VL 233 IS 13 BP 2571 EP 2580 DI 10.1007/s00213-016-4308-8 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DP5ZE UT WOS:000378575900015 PM 27137199 ER PT J AU Sampath, SC Sampath, SC Bredella, MA Cypess, AM Torriani, M AF Sampath, Srihari C. Sampath, Srinath C. Bredella, Miriam A. Cypess, Aaron M. Torriani, Martin TI Imaging of Brown Adipose Tissue: State of the Art SO RADIOLOGY LA English DT Article ID IN-VIVO; GLUCOSE-UPTAKE; COLD-EXPOSURE; ADULT HUMANS; ENERGY-EXPENDITURE; BLOOD-FLOW; FDG UPTAKE; CONTRAST ULTRASOUND; BEIGE ADIPOCYTES; FAT-CELLS AB The rates of diabetes, obesity, and metabolic disease have reached epidemic proportions worldwide. In recent years there has been renewed interest in combating these diseases not only by modifying energy intake and lifestyle factors, but also by inducing endogenous energy expenditure. This approach has largely been stimulated by the recent recognition that brown adipose tissue (BAT)-long known to promote heat production and energy expenditure in infants and hibernating mammals-also exists in adult humans. This landmark finding relied on the use of clinical fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography, and imaging techniques continue to play a crucial and increasingly central role in understanding BAT physiology and function. Herein, the authors review the origins of BAT imaging, discuss current preclinical and clinical strategies for imaging BAT, and discuss imaging methods that will provide crucial insight into metabolic disease and how it may be treated by modulating BAT activity. (C) RSNA, 2016 C1 [Sampath, Srihari C.; Sampath, Srinath C.] Novartis Res Fdn, Genom Inst, Dept Pharmacol, Musculoskeletal Biol & Bioimaging, San Diego, CA USA. [Bredella, Miriam A.; Torriani, Martin] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Bredella, Miriam A.; Torriani, Martin] Harvard Univ, Sch Med, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Cypess, Aaron M.] NIDDK, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA.; Torriani, M (reprint author), Harvard Univ, Sch Med, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM mtor-riani@mgh.harvard.edu FU Chugai Pharma; Molecular Metabolism; Pfizer FX Srihari C. Sampath Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is an employee of the Genomics Institute of the Novartis Research Foundation, part of the Novartis Institutes for Biomedical Research. Other relationships: disclosed no relevant relationships. Srinath C. Sampath Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is an employee of the Genomics Institute of the Novartis Research Foundation, part of the Novartis Institutes for Biomedical Research. Other relationships: disclosed no relevant relationships. M.B. disclosed no relevant relationships. A.M.C. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received grants from Chugai Pharma and Molecular Metabolism; received personal fees from Pfizer. Other relationships: disclosed no relevant relationships. M.T. disclosed no relevant relationships. NR 100 TC 1 Z9 1 U1 11 U2 11 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2016 VL 280 IS 1 BP 4 EP 19 DI 10.1148/radiol.2016150390 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900002 PM 27322970 ER PT J AU Davarpanah, AH Spektor, M Mathur, M Israel, GM AF Davarpanah, Amir H. Spektor, Michael Mathur, Mahan Israel, Gary M. TI Homogeneous T1 Hyperintense Renal Lesions with Smooth Borders: Is Contrast-enhanced MR Imaging Needed? SO RADIOLOGY LA English DT Article ID CELL CARCINOMA; MASSES; CYSTS; CT; MANAGEMENT AB Purpose: To retrospectively determine if homogeneous high T1 signal intensity (SI) masses with smooth borders on unenhanced magnetic resonance (MR) images can be characterized as benign. Materials and Methods: Institutional review board approval was obtained for this HIPAA-compliant retrospective study, with waiver of informed consent. MR images in 84 patients with hemorrhagic or proteinaceous cysts and 50 patients with renal cell carcinoma (RCC) were evaluated. Sixty-three cysts and 49 RCCs underwent unenhanced computed tomography (CT). SI ratio and CT attenuation were determined. Two radiologists evaluated lesions as follows: score 1, homogeneous with smooth borders; score 2, mildly heterogeneous with mildly lobulated borders; score 3, moderately heterogeneous and irregular borders; and score 4, markedly heterogeneous with markedly irregular borders. Statistical analysis was performed by using multivariable logistic regression, Welch t test, Z test, Fisher-exact test, Shapiro-Wilk test, and receiver operating characteristic curve analysis. A diagnostic criterion was formulated by using classification and regression tree analysis. Results: SI ratio and attenuation of hemorrhagic or proteinaceous cysts were significantly higher than those of RCCs (SI ratio: cyst 2.4 +/- 0.8, RCC 1.5 +/- 0.3; attenuation: cyst 51.9 +/- 21.5, RCC: 34.8 +/- 10.0). Reader 1 scored morphology of 68 (81%) hemorrhagic or proteinaceous cysts as score 1 on MR images and as score 45 (71%) on CT scans. Reader 2 scored morphology of 59 (70%) hemorrhagic or proteinaceous cysts as score 1 on MR images and as score 43 (68%) on CT scans. Two-step classification tree suggested that homogeneous high T1 SI lesions with smooth borders and SI ratio of greater than 1.6 predict the lesion as benign cysts. Similar algorithm for CT suggested threshold of 51 HU. Increasing threshold to 2.5 for SI ratio and 66 for Hounsfield units resulted in 99.9% confidence for characterizing benign cysts. Conclusion: The retrospective assessment shows that morphologic assessment and SI quantification on unenhanced T1weighted MR images can be used to differentiate benign hemorrhagic or proteinaceous cysts from RCC, although prospective assessment will be needed to confirm these results. (C) RSNA,2016 C1 [Davarpanah, Amir H.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA USA. [Spektor, Michael; Mathur, Mahan; Israel, Gary M.] Yale New Haven Med Ctr, 20 York St, New Haven, CT 06510 USA. RP Davarpanah, AH (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA USA. EM adavarpanah@mgh.harvard.edu NR 16 TC 4 Z9 4 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2016 VL 280 IS 1 BP 128 EP 136 DI 10.1148/radiol.16151240 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900014 PM 26919441 ER PT J AU Hu, RL Besheli, LD Young, J Wu, M Pomerantz, S Lev, MH Gupta, R AF Hu, Ranliang Besheli, Laleh Daftari Young, Joseph Wu, Markus Pomerantz, Stuart Lev, Michael H. Gupta, Rajiv TI Dual-Energy Head CT Enables Accurate Distinction of Intraparenchymal Hemorrhage from Calcification in Emergency Department Patients SO RADIOLOGY LA English DT Article ID IODINATED CONTRAST; INTRACEREBRAL HEMORRHAGE; DIFFERENTIATION AB Purpose: To evaluate the ability of dual-energy (DE) computed tomography (CT) to differentiate calcification from acute hemorrhage in the emergency department setting. Materials and Methods: In this institutional review board-approved study, all unenhanced DE head CT examinations that were performed in the emergency department in November and December 2014 were retrospectively reviewed. Simulated 120kVp single-energy CT images were derived from the DE CT acquisition via postprocessing. Patients with at least one focus of intraparenchymal hyperattenuation on single-energy CT images were included, and DE material decomposition postprocessing was performed. Each focal hyperattenuation was analyzed on the basis of the virtual noncalcium and calcium overlay images and classified as calcification or hemorrhage. Sensitivity, specificity, and accuracy were calculated for single-energy and DE CT by using a common reference standard established by relevant prior and follow-up imaging and clinical information. Results: Sixty-two cases with 68 distinct intraparenchymal hyperattenuating lesions in which the reference standards were available were included in the study, of which 41 (60%) were confirmed as calcification and 27 (40%) were confirmed as hemorrhage. Sensitivity, specificity, and accuracy of DE CT for the detection of hemorrhage were 96% (95% confidence interval [CI]: 81%, 100%), 100% (95% CI: 91%, 100%), and 99% (95% CI: 92%, 100%) and those of single-energy CT were 74% (95% CI: 54%, 89%), 95% (95% CI: 83%, 99%), and 87% (95% CI: 76%, 94%), respectively. Six of 68 (9%) lesions were classified as indeterminate and three (4%) were misinterpreted with single-energy CT alone and were correctly classified with DE CT. Conclusion: DE CT by using material decomposition enables accurate differentiation between calcification and hemorrhage in patients presenting for emergency head imaging and can be especially useful in problem-solving complex cases that are difficult to determine based on conventional CT appearance alone. (C) RSNA, 2016 C1 [Hu, Ranliang; Besheli, Laleh Daftari; Young, Joseph; Wu, Markus; Pomerantz, Stuart; Lev, Michael H.; Gupta, Rajiv] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,GRB 273A, Boston, MA 02114 USA. RP Gupta, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,GRB 273A, Boston, MA 02114 USA. EM rgupta1@partners.orgvv OI Wu, Markus/0000-0002-1885-3250 FU GE Healthcare FX R.H. disclosed no relevant relationships. L.D.B. disclosed no relevant relationships. J.Y. disclosed no relevant relationships. M.W. disclosed no relevant relationships. S.P. disclosed no relevant relationships. M.H.L. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant for institutional research support and consultancy fees from GE Healthcare. Other relationships: disclosed no relevant relationships. R.G. disclosed no relevant relationships. NR 11 TC 1 Z9 1 U1 1 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2016 VL 280 IS 1 BP 177 EP 183 DI 10.1148/radiol.2015150877 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900019 PM 27322974 ER PT J AU Ware, JB Biester, RC Whipple, E Robinson, KM Ross, RJ Nucifora, PG AF Ware, Jeffrey B. Biester, Rosette C. Whipple, Elizabeth Robinson, Keith M. Ross, Richard J. Nucifora, Paolo G. TI Combat-related Mild Traumatic Brain Injury: Association between Baseline Diffusion-Tensor Imaging Findings and Long-term Outcomes SO RADIOLOGY LA English DT Article ID AXONAL INJURY; SYMPTOMS; VETERANS; RETURN; MODEL; WORK; PTSD; IRAQ AB Purpose: To determine whether functional outcomes of veterans who sustained combat-related mild traumatic brain injury (TBI) are associated with scalar metrics derived from diffusion- tensor (DT) imaging at their initial postdeployment evaluation. Materials and Methods: This HIPAA-compliant retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. From 2010 to 2013, initial postdeployment evaluation, including clinical assessment and brain magnetic resonance (MR) examination with DT imaging, was performed in combat veterans who sustained mild TBI while deployed. Outcomes from chart review encompassed initial postdeployment clinical assessment as well as later functional status, including evaluation of occupational status and health care utilization. Scalar diffusion metrics from the initial postdeployment evaluation were compared with outcomes by using multivariate analysis. Veterans who did and did not return to work were also compared for differences in clinical variables by using t and x(2) tests. Results: Postdeployment evaluation was performed a mean of 3.8 years after injury (range, 0.5-9 years; standard deviation, 2.5 years). After a mean follow-up of 1.4 years (range, 0.5-2.5 years; standard deviation, 0.8 year), 34 of 57 veterans (60%) had returned to work. Return to work was associated with diffusion metrics in multiple regions of white matter, particularly in the left internal capsule and the left frontal lobe (P = .02-.05). Overall, veterans had a mean of 46 health care visits per year during the follow-up period (range, 3-196 visits per year; standard deviation, 41 visits per year). Cumulative health care visits over time were inversely correlated with diffusion anisotropy of the splenium of the corpus callosum and adjacent parietal white matter (P < .05). Clinical measures obtained during initial postdeployment evaluation were not predictive of later functional status (P = .12-.8). Conclusion: Differences in white matter microstructure may partially account for the variance in functional outcomes among veterans who sustained combat-related mild TBI. (C) RSNA, 2016 C1 [Ware, Jeffrey B.; Nucifora, Paolo G.] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA USA. [Biester, Rosette C.; Whipple, Elizabeth; Robinson, Keith M.] Philadelphia VA Med Ctr, Dept Rehabil Med, Philadelphia, PA USA. [Ross, Richard J.] Philadelphia VA Med Ctr, Behav Hlth Serv, Philadelphia, PA USA. [Ware, Jeffrey B.; Nucifora, Paolo G.] Univ Penn, Perelman Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Ross, Richard J.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Nucifora, PG (reprint author), Loyola Univ, Med Ctr, Dept Radiol, Maywood, IL 60153 USA.; Nucifora, PG (reprint author), Loyola Univ, Med Ctr, Dept Neurol, 2160 S 1st Ave, Maywood, IL 60153 USA. EM paolo.nucifora@lumc.edu NR 30 TC 1 Z9 1 U1 5 U2 7 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2016 VL 280 IS 1 BP 212 EP 219 DI 10.1148/radiol.2016151013 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900023 PM 27022770 ER PT J AU Huang, SY Tobyne, SM Nummenmaa, A Witzel, T Wald, LL McNab, JA Klawiter, EC AF Huang, Susie Y. Tobyne, Sean M. Nummenmaa, Aapo Witzel, Thomas Wald, Lawrence L. McNab, Jennifer A. Klawiter, Eric C. TI Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-GradientDiffusion MR Imaging SO RADIOLOGY LA English DT Article ID HUMAN CONNECTOME PROJECT; VIVO DIFFUSION MRI; DIAMETER DISTRIBUTION; CORPUS-CALLOSUM; SPINAL-CORD; DEMYELINATION; BRAIN AB Purpose: To evaluate the ability of high-gradient-diffusion magnetic resonance (MR) imaging by using gradient strengths of up to 300 mT/m to depict axonal disease in lesions and normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) and to compare high-gradient-diffusion MR findings in these patients with those in healthy control subjects. Materials and Methods: In this HIPAA-compliant institutional review board-approved prospective study in which all subjects provided written informed consent, six patients with relapsing-remitting MS and six healthy control subjects underwent diffusion- weighted imaging with a range of diffusion weightings performed with a 3-T human MR imager by using gradient strengths of up to 300 mT/m. A model of intraaxonal, extra-axonal, and free water diffusion was fitted to obtain estimates of axon diameter and density. Differences in axon diameter and density between lesions and NAWM in patients with MS were assessed by using the nonparametric Wilcoxon matched-pairs signed rank test, and differences between NAWM in subjects with MS and white matter in healthy control subjects were assessed by using the Mann-Whitney U test. Results: MS lesions showed increased mean axon diameter (10.3 vs 7.9 mu m in the genu, 10.4 vs 9.3 mu m in the body, and 10.6 vs 8.2 mu m in the splenium; P,.05) and decreased axon density ([0.48 vs 1.1] X 10(10)/m(2) in the genu, [0.40 vs 0.70] X 10(10)/m(2) in the body, and [0.35 vs 1.1] X 10(10)/m(2) in the splenium; P < .05) compared with adjacent NAWM. No significant difference in mean axon diameter or axon density was detected between NAWM in subjects with MS and white matter in healthy control subjects. Conclusion: High-gradient-diffusion MR imaging using gradient strengths of up to 300 mT/ m can be used to characterize axonal disease in patients with MS, with results that agree with known trends from neuropathologic data showing increased axon diameter and decreased axon density in MS lesions when compared with NAWM. (C) RSNA, 2016 C1 [Huang, Susie Y.; Nummenmaa, Aapo; Witzel, Thomas; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. [Tobyne, Sean M.; Klawiter, Eric C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McNab, Jennifer A.] Stanford Univ, Richard M Lucas Ctr Imaging, Dept Radiol, Stanford, CA 94305 USA. RP Huang, SY (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM syhuang@nmr.mgh.harvard.edu RI Wald, Lawrence/D-4151-2009; OI Tobyne, Sean/0000-0001-5985-7920 FU NIBIB NIH HHS [R01 EB006847, K99 EB015445, P41 EB015896, R00 EB015445]; NIMH NIH HHS [U01 MH093765]; NINDS NIH HHS [K23 NS078044, K23 NS096056] NR 25 TC 0 Z9 0 U1 2 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2016 VL 280 IS 1 BP 244 EP 251 DI 10.1148/radiol.2016151582 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900027 PM 26859256 ER PT J AU Harvey, HB Brink, JA Frush, DP AF Harvey, H. Benjamin Brink, James A. Frush, Donald P. TI DNA Repair after Exposure to Ionizing Radiation Is Not Error-Free Response SO RADIOLOGY LA English DT Letter C1 [Harvey, H. Benjamin; Brink, James A.] Massachusetts Gen Hosp, Dept Radiol, 175 Cambridge St,Suite 200, Boston, MA USA. [Harvey, H. Benjamin; Brink, James A.] Harvard Univ, Sch Med, Boston, MA USA. [Frush, Donald P.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. RP Harvey, HB (reprint author), Massachusetts Gen Hosp, Dept Radiol, 175 Cambridge St,Suite 200, Boston, MA USA. EM hbharvey@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2016 VL 280 IS 1 BP 323 EP 323 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8BC UT WOS:000378721900036 ER PT J AU Villiger, M Lorenser, D McLaughlin, RA Quirk, BC Kirk, RW Bouma, BE Sampson, DD AF Villiger, Martin Lorenser, Dirk McLaughlin, Robert A. Quirk, Bryden C. Kirk, Rodney W. Bouma, Brett E. Sampson, David D. TI Deep tissue volume imaging of birefringence through fibre-optic needle probes for the delineation of breast tumour SO SCIENTIFIC REPORTS LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; POLARIZATION MODE DISPERSION; MUELLER-MATRIX; SENSITIVE OCT; CONSERVING SURGERY; ANISOTROPIC MEDIA; CANCER; ORIENTATION; CONTRAST; COLLAGEN AB Identifying tumour margins during breast-conserving surgeries is a persistent challenge. We have previously developed miniature needle probes that could enable intraoperative volume imaging with optical coherence tomography. In many situations, however, scattering contrast alone is insufficient to clearly identify and delineate malignant regions. Additional polarization-sensitive measurements provide the means to assess birefringence, which is elevated in oriented collagen fibres and may offer an intrinsic biomarker to differentiate tumour from benign tissue. Here, we performed polarization-sensitive optical coherence tomography through miniature imaging needles and developed an algorithm to efficiently reconstruct images of the depth-resolved tissue birefringence free of artefacts. First ex vivo imaging of breast tumour samples revealed excellent contrast between lowly birefringent malignant regions, and stromal tissue, which is rich in oriented collagen and exhibits higher birefringence, as confirmed with co-located histology. The ability to clearly differentiate between tumour and uninvolved stroma based on intrinsic contrast could prove decisive for the intraoperative assessment of tumour margins. C1 [Villiger, Martin; Bouma, Brett E.] Harvard Med Sch, Boston, MA USA. [Villiger, Martin; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. [Lorenser, Dirk; McLaughlin, Robert A.; Quirk, Bryden C.; Kirk, Rodney W.; Sampson, David D.] Univ Western Australia, Opt Biomed Engn Lab, Perth, WA 6009, Australia. [Bouma, Brett E.] Harvard Massachusetts Inst Technol, Program Hlth Sci & Technol, Cambridge, MA 02142 USA. [Sampson, David D.] Univ Western Australia, Ctr Microscopy Characterisat & Anal, Perth, WA 6009, Australia. [McLaughlin, Robert A.; Quirk, Bryden C.; Kirk, Rodney W.] Univ Adelaide, Fac Hlth Sci, Sch Med, Australian Res Council,Ctr Excellence Nanoscale B, Adelaide, SA 5005, Australia. RP Villiger, M (reprint author), Harvard Med Sch, Boston, MA USA.; Villiger, M (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. EM mvilliger@mgh.harvard.edu RI Sampson, David/B-2931-2011; McLaughlin, Robert/E-1430-2011 OI Sampson, David/0000-0001-6724-3873; McLaughlin, Robert/0000-0001-6947-5061 FU United States National Institutes of Health [P41 EB015903]; National Health and Medical Research Council, Australia; University of Western Australia FX We thank Dr. Greg Sterrett and staff from PathWest Laboratory Medicine WA and The Breast Centre, Sir Charles Gairdner Hospital, Perth, Western Australia, for help with the human breast samples. We acknowledge the facilities, and the scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Centre for Microscopy, Characterisation & Analysis, University of Western Australia, a facility funded by the University, State and Commonwealth Governments. Research reported in this publication was supported in part by the United States National Institutes of Health, grants P41 EB015903, and the National Health and Medical Research Council, Australia. M.V. was supported by a Gledden visiting fellowship from The University of Western Australia. NR 58 TC 6 Z9 6 U1 9 U2 12 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 JUL 1 PY 2016 VL 6 AR 28771 DI 10.1038/srep28771 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0JA UT WOS:000378884000001 PM 27364229 ER PT J AU Martin, JL AF Martin, Jennifer L. TI What to do about the Growing Number of Veterans with Diagnosed Sleep Disorders SO SLEEP LA English DT Editorial Material ID DISSEMINATION C1 [Martin, Jennifer L.] Univ Calif Los Angeles, Geriat Res Educ & Clin Ctr, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Martin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. RP Martin, JL (reprint author), VAGLAHS GRECC 11E,16111 Plummer St, North Hills, CA 91343 USA. EM Jennifer.Martin@va.gov NR 11 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD JUL 1 PY 2016 VL 39 IS 7 BP 1331 EP 1332 DI 10.5665/sleep.5956 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DP9SJ UT WOS:000378837000001 PM 27306268 ER PT J AU Graham, ZA Qin, W Harlow, LC Ross, NH Bauman, WA Gallagher, PM Cardozo, CP AF Graham, Z. A. Qin, W. Harlow, L. C. Ross, N. H. Bauman, W. A. Gallagher, P. M. Cardozo, C. P. TI Focal adhesion kinase signaling is decreased 56 days following spinal cord injury in rat gastrocnemius SO SPINAL CORD LA English DT Article ID INDUCED MUSCLE ATROPHY; SKELETAL-MUSCLE; PROTEIN-SYNTHESIS; GENE-EXPRESSION; FIBER-TYPE; PHOSPHORYLATION; EXERCISE; RESISTANCE; MASS; MEN AB Study design: Descriptive study. Objectives: The goal of this study was to determine the effects of spinal cord injury (SCI) on aspects of the focal adhesion kinase (FAK) signaling pathway 56 days post injury in rat gastrocnemius. Setting: This study was conducted in Bronx, NY, USA. Methods: Three-month-old male Wistar rats were exposed to either a sham surgery (n=10) or complete T4 spinal cord transection (n=10). Rats were killed 56 days following surgery and the muscle was collected. Following homogenization, proteins of the FAK pathway were analyzed by western immunoblotting or reverse transcription-qPCR. In addition, cellular markers for proteins that target the degradation of FAK were investigated. Results: SCI resulted in significantly lower levels of total and phosphorylated FAK, cSrc and p70S6k, and a trend for increased FRNK protein expression. SCI did not change levels of the alpha 7 or beta 1 integrin subunits, total or phosphorylated ERK1/2, phosphorylated Akt and TSC2 or total p70S6k. SCI resulted in a greater expression of total Akt. mRNA expression of FAK and the alpha 7 or beta 1 integrins remained unchanged between sham and SCI groups. Caspase-3/7 activity and Trim72 mRNA and protein expression remained unchanged following SCI. Conclusion: SCI results in diminished FAK signaling and is independent of ERK1/2 and Akt. SCI has no effect on mRNA levels for genes encoding components of the focal adhesion 56 days after injury. C1 [Graham, Z. A.; Qin, W.; Harlow, L. C.; Ross, N. H.; Bauman, W. A.; Cardozo, C. P.] Natl Ctr Excellence Med Consequences Spinal Cord, James J Peters Vet Affairs Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. [Graham, Z. A.; Qin, W.; Bauman, W. A.; Cardozo, C. P.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA. [Bauman, W. A.; Cardozo, C. P.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY USA. [Gallagher, P. M.] Univ Kansas, Appl Physiol Lab, Lawrence, KS USA. [Cardozo, C. P.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY USA. RP Cardozo, CP (reprint author), Natl Ctr Excellence Med Consequences Spinal Cord, James J Peters Vet Affairs Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM christopher.cardozo@mssm.edu RI Gallagher, Philip/R-9937-2016 OI Gallagher, Philip/0000-0003-4563-4536 FU Department of Veterans Affairs Rehabilitation Research and Development Service [B1313R, B0687R, B9212C]; University of Kansas FX This work was supported by the Department of Veterans Affairs Rehabilitation Research and Development Service (B1313R and B0687R) to WQ, (B9212C) to WAB and CPC, and a University of Kansas General Research Grant to PMG. NR 40 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 EI 1476-5624 J9 SPINAL CORD JI Spinal Cord PD JUL PY 2016 VL 54 IS 7 BP 502 EP 509 DI 10.1038/sc.2015.183 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA DQ0FA UT WOS:000378872700003 PM 26481700 ER PT J AU Xu, GF Zhang, WJ Lv, Y Zhang, B Sun, Q Ling, TS Zhang, XQ Zhou, ZH Wang, L Huang, Q Zou, XP AF Xu, Guifang Zhang, Weijie Lv, Ying Zhang, Bin Sun, Qi Ling, Tingsheng Zhang, Xiaoqi Zhou, Zhihua Wang, Lei Huang, Qin Zou, Xiaoping TI Risk factors for under-diagnosis of gastric intraepithelial neoplasia and early gastric carcinoma in endoscopic forceps biopsy in comparison with endoscopic submucosal dissection in Chinese patients SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Endoscopic forceps biopsies; Endoscopic submucosal dissection; Gastric epithelial neoplasia; Early gastric carcinoma; Chinese ID EPITHELIAL NEOPLASIA; RESECTION SPECIMEN; DISCREPANCY; CANCER; ADENOMA; LESIONS; POLYPS; SYSTEM; KOREA AB Differences in pathologic diagnosis between endoscopic forceps biopsy (EFB) and endoscopic submucosal dissection (ESD) for gastric intraepithelial neoplasia (GIN) and early gastric carcinoma (EGC) in Chinese patients remain unknown. The aim of the study was to investigate risk factors for under-diagnosed pathology in initial EFB, compared to final ESD. We reviewed endoscopic and histopathologic findings for tumor location, size, macroscopic pattern, nodularity, erythema, erosion, GIN (low and high grade), and EGC diagnosed with the WHO criteria. Differences in those features between EFB and ESD were compared and risk factors for under-diagnosis by EFB were analyzed. Although concordant in most (74.9 %) cases between EFBs and ESDs, pathological diagnoses in 57 (25.1 %) cases were upgraded in ESDs. Compared to the concordant group, the lesion size a parts per thousand yen2 cm, and depressed and excavated patterns were significantly more frequent in the upgraded group. Further multivariate regression analysis demonstrated the depressed pattern and lesion size a parts per thousand yen2 cm as independent risk factors for upgraded pathology with the odds ratio of 5.778 (95 % confidence interval 2.893-11.542) and 2.535 (95 % confidence interval 1.257-5.111), respectively. Lesion size a parts per thousand yen2.0 cm and the depressed pattern at initial EFB were independent risk factors for pathologic upgrade to advanced diseases in ESD. Therefore, these endoscopic characteristics should be considered together with the initial EFB diagnosis to guide the optimal clinical management of patients with GIN and EGC. C1 [Xu, Guifang; Lv, Ying; Zhang, Bin; Ling, Tingsheng; Zhang, Xiaoqi; Wang, Lei; Zou, Xiaoping] Nanjing Univ, Sch Med, Dept Gastroenterol, Affiliated Drum Tower Hosp, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China. [Zhang, Weijie] Nanjing Univ, Sch Med, Dept Gen Surg, Affiliated Drum Tower Hosp, Nanjing 210008, Jiangsu, Peoples R China. [Sun, Qi; Huang, Qin] Nanjing Univ, Sch Med, Dept Pathol, Affiliated Drum Tower Hosp, Nanjing 210008, Jiangsu, Peoples R China. [Zhou, Zhihua] PLA, Dept Pathol, Hosp 101, Wuxi, Peoples R China. [Huang, Qin] VA Boston Healthcare Syst, Dept Pathol & Lab Med, 1400 VFW Pkwy, West Roxbury, MA USA. [Huang, Qin] Harvard Univ, Sch Med, 1400 VFW Pkwy, West Roxbury, MA USA. RP Xu, GF (reprint author), Nanjing Univ, Sch Med, Dept Gastroenterol, Affiliated Drum Tower Hosp, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China. EM 13852293376@163.com; qinhuang0122@gmail.com; 13770771661@163.com NR 23 TC 0 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 EI 1432-2218 J9 SURG ENDOSC JI Surg. Endosc. PD JUL PY 2016 VL 30 IS 7 BP 2716 EP 2722 DI 10.1007/s00464-015-4534-x PG 7 WC Surgery SC Surgery GA DP9BH UT WOS:000378791200010 PM 26423416 ER PT J AU Zar-Kessler, C Karaa, A Sims, KB Clarke, V Kuo, B AF Zar-Kessler, Claire Karaa, Amel Sims, Katherine Bustin Clarke, Virginia Kuo, Braden TI Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis SO THERAPEUTIC ADVANCES IN GASTROENTEROLOGY LA English DT Review DE abdominal pain; diarrhea; lysosomal storage disease; neuropathy ID ENZYME-REPLACEMENT THERAPY; CLINICAL-MANIFESTATIONS; ALPHA-GALACTOSIDASE; PEDIATRIC-PATIENTS; AGALSIDASE-ALPHA; OUTCOME SURVEY; SYMPTOMS; INVOLVEMENT; DYSFUNCTION; FEMALES AB Fabry disease is a rare X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement such as diarrhea, abdominal pain, early satiety and nausea. The gastrointestinal symptoms of Fabry disease are thought to be due to neuropathic and myopathic changes leading to symptoms of dysmotility that are encountered in many other disorders. The gastrointestinal symptoms can often be one of the presenting signs of the disease in childhood, but can be misdiagnosed by gastroenterologists for many years due to their nonspecific presentation. As the chief treatment for Fabry is enzyme-replacement therapy that has been shown to stabilize and possibly reverse disease course, recognition of these symptoms and early diagnosis in an attempt to prevent progression with treatment, is critical. C1 [Zar-Kessler, Claire] Massachusetts Gen Hosp Children, Div Pediat Gastroenterol Hepatol & Nutr, MGH Ctr Neurointestinal Hlth, 175 Cambridge St CPZ-575, Boston, MA 02114 USA. [Karaa, Amel] Massachusetts Gen Hosp, Genet Unit, Boston, MA 02114 USA. [Sims, Katherine Bustin; Clarke, Virginia] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kuo, Braden] Massachusetts Gen Hosp, MGH Ctr Neurointestinal Hlth, GI Unit, Boston, MA 02114 USA. RP Zar-Kessler, C (reprint author), Massachusetts Gen Hosp Children, Div Pediat Gastroenterol Hepatol & Nutr, MGH Ctr Neurointestinal Hlth, 175 Cambridge St CPZ-575, Boston, MA 02114 USA. EM czarkessler@partners.org FU Genzyme FX Claire Zar-Kessler, Katherine Bustin Sims and Braden Kuo participated in a Fabry training fellowship supported by an unrestricted grant from Genzyme. NR 45 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1756-283X EI 1756-2848 J9 THER ADV GASTROENTER JI Ther. Adv. Gastroenterol. PD JUL PY 2016 VL 9 IS 4 BP 626 EP 634 DI 10.1177/1756283X16642936 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DP9CG UT WOS:000378793700018 PM 27366228 ER PT J AU Fesnak, A Lin, CY Siegel, DL Maus, MV AF Fesnak, Andrew Lin, ChieYu Siegel, Don L. Maus, Marcela V. TI CAR-T Cell Therapies From the Transfusion Medicine Perspective SO TRANSFUSION MEDICINE REVIEWS LA English DT Review DE T cells; Adoptive immunotherapy; Gene transfer; Leukapheresis; Cell processing ID CHIMERIC ANTIGEN RECEPTORS; CYTOKINE RELEASE SYNDROME; 2 APHERESIS SYSTEMS; ADOPTIVE IMMUNOTHERAPY; MONOCYTE ISOLATION; DENDRITIC CELLS; HUMAN CANCER; HUMAN-BLOOD; LEUKEMIA; LEUKAPHERESIS AB The use of chimeric antigen receptor (CAR)-T cell therapy for the treatment of hematologic malignancies has generated significant excitement over the last several years. From a transfusion medicine perspective, the implementation of CAR-T therapy as a potential mainstay treatment for not only hematologic but also solid-organ malignancies represents a significant opportunity for growth and expansion. In this review, we will describe the rationale for the development of genetically redirected T cells as a cancer therapeutic, the different elements that are required to engineer these cells, as well as an overview of the process by which patient cells are harvested and processed to create and subsequently validate CAR-T cells. Finally, we will briefly describe some of the toxicities and clinical efficacy of CAR-T cells in the setting of patients with advanced malignancy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Fesnak, Andrew; Siegel, Don L.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Div Transfus Med & Therapeut Pathol, Philadelphia, PA USA. [Lin, ChieYu; Maus, Marcela V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. RP Maus, MV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,Thirteenth St, Charlestown, MA 02129 USA. EM mvmaus@mgh.harvard.edu RI Fesnak, Andrew/M-4753-2016; OI Fesnak, Andrew/0000-0002-2705-803X; Maus, Marcela/0000-0002-7578-0393 FU National Cancer Institute [K08 CA166039]; National Institutes of Health [5T32HL007775] FX MVM was supported by National Cancer Institute K08 CA166039. ADF is supported by National Institutes of Health grant 5T32HL007775. NR 66 TC 2 Z9 2 U1 9 U2 30 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 2016 VL 30 IS 3 BP 139 EP 145 DI 10.1016/j.tmrv.2016.03.001 PG 7 WC Hematology SC Hematology GA DP7GB UT WOS:000378666100005 PM 27067907 ER PT J AU Nguyen, ET Ackman, JB Rajiah, P Little, B Wu, C Bueno, JM Gilman, MD Christensen, JD Madan, R Laroia, AT Lee, C Kanne, JP Collins, J AF Nguyen, Elsie T. Ackman, Jeanne B. Rajiah, Prabhakar Little, Brent Wu, Carol Bueno, Juliana M. Gilman, Mathew D. Christensen, Jared D. Madan, Rachna Laroia, Archana T. Lee, Christopher Kanne, Jeffrey P. Collins, Jannette TI What's New in 10 Years? A Revised Cardiothoracic Curriculum for Diagnostic Radiology Residency with Goals and Objectives Related to General Competencies SO ACADEMIC RADIOLOGY LA English DT Article DE curriculum; cardiothoracic; radiology residency; Accreditation Council for Graduate Medical Education (ACGME); American Board of Radiology (ABR); study guide; examination AB This is a cardiothoracic curriculum document for radiology residents meant to serve not only as a study guide for radiology residents but also as a teaching and curriculum reference for radiology educators and radiology residency program directors. This document represents a revision of a cardiothoracic radiology resident curriculum that was published 10 years ago in Academic Radiology. The sections that have been significantly revised, expanded, or added are (1) lung cancer screening, (2) lung cancer genomic profiling, (3) lung adenocarcinoma revised nomenclature, (4) lung biopsy technique, (5) nonvascular thoracic magnetic resonance, (6) updates to the idiopathic interstitial pneumonias, (7) cardiac computed tomography updates, (8) cardiac magnetic resonance updates, and (9) new and emerging techniques in cardiothoracic imaging. This curriculum was written and endorsed by the Education Committee of the Society of Thoracic Radiology. This curriculum operates in conjunction with the Accreditation Council for Graduate Medical Education (ACGME) milestones project that serves as a framework for semiannual evaluation of resident physicians as they progress through their training in an ACGME-accredited residency or fellowship programs. This cardiothoracic curriculum document is meant to serve not only as a more detailed guide for radiology trainees, educators, and program directors but also complementary to and guided by the ACGME milestones. C1 [Nguyen, Elsie T.] Univ Toronto, Toronto Gen Hosp, Room 1-295,585 Univ Ave, Toronto, ON M5G 2N2, Canada. [Ackman, Jeanne B.; Gilman, Mathew D.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rajiah, Prabhakar] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Little, Brent] Emory Univ, Emory Univ Hosp, Atlanta, GA 30322 USA. [Wu, Carol] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bueno, Juliana M.] Univ Virginia, Med Ctr, Charlottesville, VA USA. [Christensen, Jared D.] Duke Univ, Duke Univ Hosp, Durham, NC USA. [Madan, Rachna] Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA. [Laroia, Archana T.] Univ Iowa, Univ Iowa Hosp & Clin, Iowa City, IA USA. [Lee, Christopher] Univ So Calif, Keck Sch Med, Keck Hosp, Los Angeles, CA 90033 USA. [Kanne, Jeffrey P.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Collins, Jannette] Univ Cincinnati, UC Acad Hlth Ctr, Cincinnati, OH USA. RP Nguyen, ET (reprint author), Univ Toronto, Toronto Gen Hosp, Room 1-295,585 Univ Ave, Toronto, ON M5G 2N2, Canada. EM elsie.nguyen@uhn.ca OI Rajiah, Prabhakar/0000-0001-7538-385X NR 6 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 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2016 VL 23 IS 7 BP 911 EP 918 DI 10.1016/j.acra.2016.01.022 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP4DC UT WOS:000378444600023 PM 27241013 ER PT J AU Lee, SJ Jacobson, MA Johnston, CB AF Lee, Sei J. Jacobson, Margaret A. Johnston, C. Bree TI Improving Diabetes Care for Hospice Patients SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Editorial Material DE diabetes mellitus; hospice; hypoglycemia; glycemic control; glucose lowering medication; hyperglycemia ID PALLIATIVE CARE; BLOOD-GLUCOSE; MANAGEMENT; HYPERGLYCEMIA AB Although type 2 diabetes guidelines recommend less aggressive glycemic control for patients with limited life expectancy, many hospice patients continue their glucose-lowering medications, resulting in an increased risk of hypoglycemia. Three common reasons for overly tight glycemic control in hospice patients include (1) discussions about reducing or stopping chronic medications are uncomfortable; (2) many patients and families believe that mild hyperglycemia can cause symptoms; and (3) until 2014, Healthcare Information and Data Information Set (HEDIS) quality indicators for glycemic control included hospice patients. To address these issues, we recommend (1) providers discuss with patients and families upon hospice enrollment that diabetes medications can be reduced or discontinued as their life-limiting disease progresses; (2) keeping blood glucose levels between 200 and 300 mg/dL; and (3) educate providers that HEDIS measures now exclude hospice patients. Implementing these recommendations should decrease the risk of hypoglycemia in hospice patients and improve their quality of life. C1 [Lee, Sei J.] Univ Calif San Francisco, Div Geriatr, 4150 Clement St,Bldg 1,Rm 220F, San Francisco, CA 94121 USA. [Lee, Sei J.] San Francisco VA Med Ctr, San Francisco, CA USA. [Jacobson, Margaret A.] Whatcom Hosp, Bellingham, WA USA. [Johnston, C. Bree] PeaceHlth Med Syst, Bellingham, WA USA. RP Lee, SJ (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,Bldg 1,Rm 220F, San Francisco, CA 94121 USA. EM sei.lee@ucsf.edu NR 9 TC 0 Z9 0 U1 3 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD JUL PY 2016 VL 33 IS 6 BP 517 EP 519 DI 10.1177/1049909115578386 PG 3 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DP3NJ UT WOS:000378401100001 PM 25852204 ER PT J AU Cruz-Oliver, DM Malmstrom, TK Fernandez, N Parikh, M Garcia, J Sanchez-Reilly, S AF Cruz-Oliver, Dulce M. Malmstrom, Theodore K. Fernandez, Natalia Parikh, Manas Garcia, Jessica Sanchez-Reilly, Sandra TI Education Intervention "Caregivers Like Me" for Latino Family Caregivers Improved Attitudes Toward Professional Assistance at End-of-life Care SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE family caregivers; Latino; culture; end of life; hospice; palliative; education intervention; pretest-posttest ID UNITED-STATES; CANCER-PATIENTS; ETHNIC-DIFFERENCES; OLDER LATINOS; HOSPICE; HEALTH; DEATH; EXPERIENCE; BURDEN; PLACE AB Objective: This study explores the ability of a culturally sensitive and case-based education intervention, Caregivers Like Me, to improve knowledge and attitudes regarding end-of-life (EOL) resources among Latino caregivers. Methods: A multicentered, cross-sectional study of Latino communities from different geographical regions and cultural backgrounds. An educational intervention was administered to family caregivers of Latino elders using a case-based video telenovela and pretest-posttest questionnaires. Results: Participants (N = 145) were mostly females (79%) with mean age of 56 15 years. They reported active learning from intervention (91%) and high satisfaction (92%) with educational experience. Both caregiver stress self-awareness and willingness to accept professional help improved significantly from pretest to posttest. Conclusion: A culturally sensitive educational intervention increased Latino caregivers' self-awareness about caregiver stress and the need to consider professional assistance for EOL care. C1 [Cruz-Oliver, Dulce M.] St Louis Univ, Div Geriatr Med, South Grand Blvd, St Louis, MO 63104 USA. [Malmstrom, Theodore K.] St Louis Univ, Sch Med, Dept Neurol & Psychiat, 1402 South Grand Blvd M238, St Louis, MO 63104 USA. [Fernandez, Natalia] Univ Puerto Rico, Med Sci Campus, San Juan, PR 00936 USA. [Parikh, Manas] St Louis Univ, Sch Med, Div Geriatr Med, 1402 South Grand Blvd M238, St Louis, MO 63104 USA. [Garcia, Jessica] Univ Texas Hlth Sci Ctr San Antonio, Div Geriatr Med, San Antonio, TX 78229 USA. [Garcia, Jessica; Sanchez-Reilly, Sandra] South Texas Vet Hlth Care Syst, GEC, San Antonio, TX USA. [Garcia, Jessica; Sanchez-Reilly, Sandra] South Texas Vet Hlth Care Syst, GRECC, San Antonio, TX USA. [Sanchez-Reilly, Sandra] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Cruz-Oliver, DM (reprint author), St Louis Univ, Dept Internal Med, Div Geriatr, 1402 South Grand Blvd M238, St Louis, MO 63104 USA. EM dcruzoli@slu.edu FU Health Resources and Services Administration (HRSA) Geriatric Academic Career Award [K01HP20479-03-00] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Health Resources and Services Administration (HRSA) Geriatric Academic Career Award K01HP20479-03-00. NR 44 TC 0 Z9 0 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD JUL PY 2016 VL 33 IS 6 BP 527 EP 536 DI 10.1177/1049909115584315 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DP3NJ UT WOS:000378401100003 PM 26019262 ER PT J AU Duncan, MD Vazirani, SS AF Duncan, Mark D. Vazirani, Sondra S. TI An Unusual Rapid Response Call: Malignant Catatonia SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID ELECTROCONVULSIVE-THERAPY; LORAZEPAM C1 [Duncan, Mark D.; Vazirani, Sondra S.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, 757 Westwood Plaza,B7-111, Los Angeles, CA 90095 USA. [Vazirani, Sondra S.] Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. RP Duncan, MD (reprint author), Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, 757 Westwood Plaza,B7-111, Los Angeles, CA 90095 USA. EM mduncan@mednet.ucla.edu NR 10 TC 2 Z9 2 U1 1 U2 2 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 2016 VL 129 IS 7 BP 678 EP 680 DI 10.1016/j.amjmed.2016.03.005 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DO8WJ UT WOS:000378065800036 PM 27046246 ER PT J AU Boyce, R Mitton, J Chu, J Finn, K AF Boyce, Ross Mitton, Julian Chu, Jacqueline Finn, Kathleen TI South Sudan to Martha's Vineyard: Malaria Always First! Reply SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Boyce, Ross; Mitton, Julian; Finn, Kathleen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chu, Jacqueline] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Boyce, R (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. OI Boyce, Ross/0000-0002-9489-6324 NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUL PY 2016 VL 129 IS 7 BP E101 EP E101 DI 10.1016/j.amjmed.2016.01.032 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DO8WJ UT WOS:000378065800024 PM 27320706 ER PT J AU Gaffo, AL Mikuls, TR Stamp, LK Neogi, T AF Gaffo, Angelo L. Mikuls, Ted R. Stamp, Lisa K. Neogi, Tuhina TI Allopurinol Dose Reductions Based on Creatinine Alert Redesign System SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter ID HYPERURICEMIA; CLEARANCE C1 [Gaffo, Angelo L.] Univ Alabama Birmingham, Dept Med, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Mikuls, Ted R.] Univ Nebraska Med Ctr, Div Rheumatol, Vet Affairs Nebraska Western Iowa Hlth Care Syst, Omaha, NE USA. [Stamp, Lisa K.] Univ Otago, Dept Med, Christchurch, New Zealand. [Neogi, Tuhina] Boston Univ, Dept Med, Med Sch Med, Boston, MA 02215 USA. RP Gaffo, AL (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. NR 5 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUL PY 2016 VL 129 IS 7 BP E95 EP E95 DI 10.1016/j.amjmed.2015.12.035 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DO8WJ UT WOS:000378065800021 PM 27320718 ER PT J AU Ramly, EP Bohnen, JD Farhat, MR Razmdjou, S Mavros, MN Yeh, DD Lee, J Butler, K De Moya, M Velmahos, GC Kaafarani, HMA AF Ramly, Elie P. Bohnen, Jordan D. Farhat, Maha R. Razmdjou, Shadi Mavros, Michael N. Yeh, Daniel D. Lee, Jarone Butler, Kathryn De Moya, Marc Velmahos, George C. Kaafarani, Haytham M. A. TI The nature, patterns, clinical outcomes, and financial impact of intraoperative adverse events in emergency surgery SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Intraoperative adverse events; Emergency surgery; Patient safety ID QUALITY-IMPROVEMENT-PROGRAM; GENERAL-SURGERY; PATIENT SAFETY; ABDOMINAL-SURGERY; MULTIVARIABLE PREDICTORS; NONTEACHING HOSPITALS; VASCULAR-SURGERY; HERNIA REPAIR; RISK-FACTORS; MORBIDITY AB BACKGROUND: Little is known about intraoperative adverse events (iAEs) in emergency surgery (ES). We sought to describe iAEs in ES and to investigate their clinical and financial impact. METHODS: The 2007 to 2012 administrative and American College of Surgeons-National Surgical Quality Improvement Program databases at our tertiary academic center were: (1) linked, (2) queried for all ES procedures, and then (3) screened for iAEs using the ICD-9-CM-based Patient Safety Indicator "accidental puncture/laceration". Flagged cases were systematically reviewed to: (1) confirm or exclude the occurrence of iAEs (defined as inadvertent injuries during the operation) and (2) extract additional variables such as procedure type, approach, complexity (measured by relative value units), need for adhesiolysis, and extent of repair. Univariate and multivariate analyses were performed to assess the independent impact of iAEs on 30-day morbidity, mortality, and hospital charges. RESULTS: Of a total of 9,288 patients, 1,284 (13.8%) patients underwent ES, of which 23 had iAEs (1.8%); 18 of 23 (78.3%) of the iAEs involved the small bowel or spleen, 10 of 23 (43.5%) required suture repair, and 8 of 23 (34.8%) required tissue or organ resection. Compared with those without iAEs, patients with iAEs were older (median age 62 vs 50; P = .04); their procedures were more complex (total relative value unit 46.7, interquartile range [27.5 to 52.6] vs 14.5 [.5 to 30.2]; P < .001), longer in duration (>3 hours: 52% vs 8%; P < .001), and more often required adhesiolysis (39.1% vs 13.5% P = .001). Patients with iAEs had increased total charges ($31,080 vs $11,330, P < .001), direct charges ($20,030 vs $7,387, P < .001), and indirect charges ($11,460 vs $4,088, P < .001). On multivariable analyses, iAEs were independently associated with increased 30-day morbidity (odds ratio, 3.56 [CI, 1.10 to 11.54]; P = .03) and prolonged postoperative length of stay (LOS; LOS >7 days; odds ratio, 5.60 [1.54 to 20.35]; P = .01]. A trend toward increased mortality did not reach statistical significance. CONCLUSIONS: In ES, iAEs are independently associated with significantly higher postoperative morbidity and prolonged LOS. (C) 2015 Elsevier Inc. All rights reserved. C1 [Ramly, Elie P.; Bohnen, Jordan D.; Farhat, Maha R.; Razmdjou, Shadi; Mavros, Michael N.; Yeh, Daniel D.; Lee, Jarone; Butler, Kathryn; De Moya, Marc; Velmahos, George C.; Kaafarani, Haytham M. A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Trauma Emergency Surg & Surg Crit C, 165 Cambridge St Suite 810, Boston, MA 02114 USA. RP Kaafarani, HMA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Trauma Emergency Surg & Surg Crit C, 165 Cambridge St Suite 810, Boston, MA 02114 USA. EM hkaafarani@mgh.harvard.edu NR 39 TC 0 Z9 0 U1 0 U2 0 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 2016 VL 212 IS 1 BP 16 EP 23 DI 10.1016/j.amjsurg.2015.07.023 PG 8 WC Surgery SC Surgery GA DO8VM UT WOS:000378063100003 PM 26601649 ER PT J AU Chen, Q Mull, HJ Rosen, AK Borzecki, AM Pilver, C Itani, KMF AF Chen, Qi Mull, Hillary J. Rosen, Amy K. Borzecki, Ann M. Pilver, Corey Itani, Kamal M. F. TI Measuring readmissions after surgery: do different methods tell the same story? SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Veterans Health Administration; Surgical readmissions; 30-Day all-cause hospital-wide readmissions; Potentially preventable readmissions; Administrative data ID HOSPITAL READMISSION; SURGICAL COMPLICATIONS; QUALITY; PROGRAM; RATES; CARE AB BACKGROUND: Readmission is widely used as a quality metric to assess hospital performance. However, different methods to calculate readmissions may produce various results, leading to differences in classification with respect to hospital performance. This study compared 2 commonly used approaches to measure surgical readmissions: the 30-day all-cause hospital-wide readmissions (HWRs) and the potentially preventable readmissions (PPRs). METHODS: We examined the correlation between hospitals' risk-adjusted HWR and PPR rates and whether there was agreement in categorizing hospital performance between these measures among 111 hospitals with inpatient surgical programs in the Veterans Health Administration. RESULTS: We found that hospitals' HWR and PPR rates were highly correlated (r = .85, P < .0001). The overall agreement between these 2 methods in categorizing hospital performance was 82% for all surgeries, 82% for colectomy, 84% for coronary bypass, and 87% for hip/knee replacement, respectively. CONCLUSIONS: Despite differences in methodologies, the HWR and the PPR measures provided relatively consistent perceptions of hospitals' performance on surgical readmissions. Published by Elsevier Inc. C1 [Chen, Qi; Mull, Hillary J.; Rosen, Amy K.; Pilver, Corey] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 South Huntington Ave,152M, Boston, MA 02130 USA. [Mull, Hillary J.; Rosen, Amy K.; Itani, Kamal M. F.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Borzecki, Ann M.] Bedford VAMC, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Borzecki, Ann M.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Borzecki, Ann M.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Itani, Kamal M. F.] VA Boston Healthcare Syst, Dept Surg, Boston, MA USA. [Itani, Kamal M. F.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Chen, Q (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 South Huntington Ave,152M, Boston, MA 02130 USA. EM qi.chen2@va.gov FU VA Health Services Research and Development Service [IIR 09-369] FX This study was supported by funding from the VA Health Services Research and Development Service, grant number IIR 09-369 (Rosen, PI). NR 31 TC 1 Z9 1 U1 1 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2016 VL 212 IS 1 BP 24 EP 33 DI 10.1016/j.amjsurg.2015.08.020 PG 10 WC Surgery SC Surgery GA DO8VM UT WOS:000378063100004 PM 26506557 ER PT J AU Naguib, M Brewer, L LaPierre, C Kopman, AF Johnson, KB AF Naguib, Mohamed Brewer, Lara LaPierre, Cristen Kopman, Aaron F. Johnson, Ken B. TI The Myth of Rescue Reversal in "Can't Intubate, Can't Ventilate" Scenarios SO ANESTHESIA AND ANALGESIA LA English DT Article ID FUNCTIONAL RESIDUAL CAPACITY; RAPID-SEQUENCE INDUCTION; MORBIDLY OBESE-PATIENTS; HEMOGLOBIN DESATURATION; NEUROMUSCULAR BLOCKADE; HEALTHY-VOLUNTEERS; INDUCED APNEA; SUCCINYLCHOLINE; SUGAMMADEX; ROCURONIUM AB BACKGROUND: An unanticipated difficult airway during induction of anesthesia can be a vexing problem. In the setting of can't intubate, can't ventilate (CICV), rapid recovery of spontaneous ventilation is a reasonable goal. The urgency of restoring ventilation is a function of how quickly a patient's hemoglobin oxygen saturation decreases versus how much time is required for the effects of induction drugs to dissipate, namely the duration of unresponsiveness, ventilatory depression, and neuromuscular blockade. It has been suggested that prompt reversal of rocuronium-induced neuromuscular blockade with sugammadex will allow respiratory activity to recover before significant arterial desaturation. Using pharmacologic simulation, we compared the duration of unresponsiveness, ventilatory depression, and neuromuscular blockade in normal, obese, and morbidly obese body sizes in this life-threatening CICV scenario. We hypothesized that although neuromuscular function could be rapidly restored with sugammadex, significant arterial desaturation will occur before the recovery from unresponsiveness and/or central ventilatory depression in obese and morbidly obese body sizes. METHODS: We used published models to simulate the duration of unresponsiveness and ventilatory depression using a common induction technique with predicted rates of oxygen desaturation in various size patients and explored to what degree rapid reversal of rocuronium-induced neuromuscular blockade with sugammadex might improve the return of spontaneous ventilation in CICV situations. RESULTS: Our simulations showed that the duration of neuromuscular blockade was longer with 1.0 mg/kg succinylcholine than with 1.2 mg/kg rocuronium followed 3 minutes later by 16 mg/kg sugammadex (10.0 vs 4.5 minutes). Once rocuronium neuromuscular blockade was completely reversed with sugammadex, the duration of hemoglobin oxygen saturation >90%, loss of responsiveness, and intolerable ventilatory depression (a respiratory rate of <= 4 breaths/min) were dependent on the body habitus and duration of oxygen administration. There is a high probability of intolerable ventilatory depression that extends well beyond the time when oxygen saturation decreases <90%, especially in obese and morbidly obese patients. If ventilatory rescue is inadequate, oxygen desaturation will persist in the latter groups, despite full reversal of neuromuscular blockade. Depending on body habitus, the duration of intolerable ventilatory depression after sugammadex reversal may be as long as 15 minutes in 5% of individuals. CONCLUSIONS: The clinical management of CICV should focus primarily on restoration of airway patency, oxygenation, and ventilation consistent with the American Society of Anesthesiologist's practice guidelines for management of the difficult airway. Pharmacologic intervention cannot be relied upon to rescue patients in a CICV crisis. C1 [Naguib, Mohamed; Johnson, Ken B.] Cleveland Clin, Inst Anesthesiol, Dept Gen Anesthesia, 9500 Euclid Ave,NE6-306, Cleveland, OH 44195 USA. [Brewer, Lara] Univ Utah, Dept Anesthesiol, Salt Lake City, UT USA. [LaPierre, Cristen] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Naguib, M (reprint author), Cleveland Clin, Inst Anesthesiol, Dept Gen Anesthesia, 9500 Euclid Ave,NE6-306, Cleveland, OH 44195 USA. EM naguibm@ccf.org NR 41 TC 1 Z9 1 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD JUL PY 2016 VL 123 IS 1 BP 82 EP 92 DI 10.1213/ANE.0000000000001347 PG 11 WC Anesthesiology SC Anesthesiology GA DO9DA UT WOS:000378083300012 PM 27140684 ER PT J AU Culley, DJ Flaherty, D Reddy, S Fahey, MC Rudolph, J Huang, CC Liu, XX Xie, ZC Bader, AM Hyman, BT Blacker, D Crosby, G AF Culley, Deborah J. Flaherty, Devon Reddy, Srini Fahey, Margaret C. Rudolph, James Huang, Chuan Chin Liu, Xiaoxia Xie, Zhongcong Bader, Angela M. Hyman, Bradley T. Blacker, Deborah Crosby, Gregory TI Preoperative Cognitive Stratification of Older Elective Surgical Patients: A Cross-Sectional Study SO ANESTHESIA AND ANALGESIA LA English DT Article ID NURSING-HOME RESIDENTS; PRIMARY-CARE; POSTOPERATIVE DELIRIUM; CARDIAC-SURGERY; MINI-COG; NONCARDIAC SURGERY; IMPAIRMENT; DEMENTIA; DECLINE; METAANALYSIS AB BACKGROUND: Preexisting cognitive impairment is emerging as a predictor of poor postoperative outcomes in seniors. We hypothesized that preoperative cognitive screening can be performed in a busy preadmission evaluation center and that cognitive impairment is prevalent in elective geriatric surgical patients. METHODS: We approached 311 patients aged 65 years and older presenting for preoperative evaluation before elective surgery in a prospective, observational, single-center study. Forty-eight patients were ineligible, and 63 declined. The remaining 200 were randomly assigned to the Mini-Cog (N = 100) or Clock-in-the-Box [CIB; N = 100)] test. Study staff administered the test in a quiet room, and 2 investigators scored the tests independently. Probable cognitive impairment was defined as a Mini-Cog <= 2 or a CIB <= 5. RESULTS: The age of consenting patients was 73.7 +/- 6.4 (mean +/- SD) years. There were no significant differences between patients randomly assigned to the Mini-Cog and CIB test in age, weight, gender, education, ASA physical status, or Charlston Index. Overall, 23% of patients met criteria for probable cognitive impairment, and prevalence was virtually identical regardless of the test used; 22% screened with the Mini-Cog and 23% screened with the CIB scored as having probable cognitive impairment (P = 1.0 by chi(2) analysis). Both tests had good interrater reliability (Krippendroff alpha = 0.86 [0.72-0.93] for Mini-Cog and 1(1) for CIB). CONCLUSIONS: Preoperative cognitive screening is feasible in most geriatric elective surgical patients and reveals a substantial prevalence of probable cognitive impairment in this population. C1 [Culley, Deborah J.; Flaherty, Devon; Fahey, Margaret C.; Huang, Chuan Chin; Liu, Xiaoxia; Bader, Angela M.; Crosby, Gregory] Harvard Univ, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Sch Med, Boston, MA 02115 USA. [Reddy, Srini] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Rudolph, James] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA USA. [Xie, Zhongcong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Hyman, Bradley T.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Culley, DJ (reprint author), Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. EM dculley@partners.org FU Anesthesia Patient Safety Foundation; MSTAR [T 35AG038027-01]; Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts FX Supported by Anesthesia Patient Safety Foundation grant (to DJC); an MSTAR grant T 35AG038027-01 (to SR); and the Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts. NR 51 TC 2 Z9 2 U1 6 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD JUL PY 2016 VL 123 IS 1 BP 186 EP 192 DI 10.1213/ANE.0000000000001277 PG 7 WC Anesthesiology SC Anesthesiology GA DO9DA UT WOS:000378083300025 PM 27028776 ER PT J AU Singh, JA AF Singh, Jasvinder A. TI Cervical cancer risk with the use of tumour necrosis factor inhibitors in rheumatoid arthritis: to worry or not to worry? SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Editorial Material ID BIOLOGICS REGISTER; FACTOR THERAPY; BRITISH SOCIETY; MALIGNANCY; DIAGNOSIS; LYMPHOMA; TIME C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] UAB, Sch Publ Hlth, Sch Med, Dept Med,Div Epidemiol, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. RP Singh, JA (reprint author), Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com NR 18 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2016 VL 75 IS 7 BP 1265 EP 1267 DI 10.1136/annrheumdis-2015-208526 PG 3 WC Rheumatology SC Rheumatology GA DO8SZ UT WOS:000378055400013 PM 26951640 ER PT J AU Schoenfeld, SR Lu, L Rai, SK Seeger, JD Zhang, YQ Choi, HK AF Schoenfeld, Sara R. Lu, Leo Rai, Sharan K. Seeger, John D. Zhang, Yuqing Choi, Hyon K. TI Statin use and mortality in rheumatoid arthritis: a general population-based cohort study SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; PROPENSITY SCORE; CARDIOVASCULAR-DISEASE; RISK; CHOLESTEROL; THERAPY; ATORVASTATIN; TRIAL; ROSUVASTATIN AB Background Dual lipid-lowering and anti-inflammatory properties of statins may lead to survival benefits in patients with rheumatoid arthritis (RA). However, data on this topic are limited, and the role of statins in RA remains unclear. Objectives To examine the association of statin use with overall mortality among patients with RA in a general population context. Methods We conducted an incident user cohort study with time-stratified propensity score matching using a UK general population database. The study population included individuals aged >= 20 years who had a diagnosis of RA and had used at least one disease-modifying antirheumatic drug (DMARD) between January 2000 and December 2012. To closely account for potential confounders, we compared propensity score matched cohorts of statin initiators and comparators (non-initiators) within 1-year cohort accrual blocks. Results 432 deaths occurred during follow-up (mean 4.51 years) of the 2943 statin initiators for an incidence rate of 32.6/1000 person-years (PY), while the 513 deaths among 2943 matched comparators resulted in an incidence rate of 40.6/1000 PY. Baseline characteristics were well-balanced across the two groups. Statin initiation was associated with a 21% lower risk of all-cause mortality (HR=0.79, 95% CI 0.68 to 0.91). When we defined RA by its diagnosis code alone (not requiring DMARD use), the corresponding HR was 0.81 (95% CI 0.74 to 0.90). Conclusions Statin initiation is associated with a lower risk of mortality among patients with RA. The magnitude of association is similar to that seen in previous randomised trials among the general population. C1 [Schoenfeld, Sara R.; Lu, Leo; Choi, Hyon K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, 55 Fruit St,Bulfinch 165, Boston, MA 02114 USA. [Lu, Leo; Zhang, Yuqing; Choi, Hyon K.] Boston Univ, Sch Med, Clin Epidemiol Unit, Boston, MA 02118 USA. [Rai, Sharan K.] Univ British Columbia, Arthrit Res Ctr Canada, Vancouver, BC V5Z 1M9, Canada. [Seeger, John D.] Harvard Univ, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med,Med Sch, Boston, MA 02115 USA. RP Choi, HK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, 55 Fruit St,Bulfinch 165, Boston, MA 02114 USA. EM choi.hyon@mgh.harvard.edu FU NIH [P60AR047785, T32AR007258-36A1] FX This work was supported in part by grants from the NIH (P60AR047785 and T32AR007258-36A1). NR 39 TC 3 Z9 3 U1 1 U2 3 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 2016 VL 75 IS 7 BP 1315 EP 1320 DI 10.1136/annrheumdis-2015-207714 PG 6 WC Rheumatology SC Rheumatology GA DO8SZ UT WOS:000378055400021 PM 26245753 ER PT J AU Roohipoor, R Karkhaneh, R Farahani, A Ebrahimiadib, N Modjtahedi, B Fotouhi, A Yaseri, M Khodabande, A Zarei, M Fuladi, MI Taheri, A Esfahani, MR Loewenstein, J AF Roohipoor, Ramak Karkhaneh, Reza Farahani, Afsar Ebrahimiadib, Nazanin Modjtahedi, Bobeck Fotouhi, Akbar Yaseri, Mehdi Khodabande, Alireza Zarei, Mohammad Fuladi, Marjan Imani Taheri, Arash Esfahani, Mohammad Riazi Loewenstein, John TI Retinopathy of prematurity screening criteria in Iran: new screening guidelines SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article ID RISK-FACTORS; COUNTRIES; INFANTS; BABIES AB Objective To test the applicability of existing retinopathy of prematurity (ROP) guidelines on Iranian patients and to develop novel ROP screening criteria in Iran. Methods Both eyes of 1932 infants born <= 37 weeks of gestation and/or weighting <= 3000 g were included in this prospective cohort study that was conducted across nine neonatal intensive care units and a tertiary eye hospital ROP clinic. The patients were examined for ROP and the need for treatment (type 1 ROP or worse). All the patients were screened 4 weeks after birth or at 31 weeks of postmenstrual age, whichever was later. The patients were followed until retinal vascularisation was completed or the patients reached 50 weeks of gestational age (GA) without prethreshold ROP. A receiver operating characteristic curve was used to determine the best screening criteria for ROP. Screening criteria from other countries were applied to our patient data to determine their ability to appropriately detect ROP. Main outcome measure Patients with ROP requiring treatment. Results The mean GA +/- SD and birth weight (BW)+/- SD of the screened patients were 32 +/- 2.7 weeks and 1713 +/- 516 g, respectively. Using criteria of GA <= 32 weeks or BW <= 2000 yielded sensitivity and specificity of 100% and 26.7%, respectively, for treatment requiring ROP regardless of clinical comorbidities. Using screening recommendations of American Academy of Pediatrics would miss 25.4% of ROP and 8.4% ROP requiring treatment in our cohort. Conclusions Other countries screening recommendations would result in a significant amount of missed cases of treatment requiring ROP when applied to Iran. As a result, we have proposed new guidelines for premature babies in Iran. C1 [Roohipoor, Ramak; Karkhaneh, Reza; Farahani, Afsar; Ebrahimiadib, Nazanin; Khodabande, Alireza; Zarei, Mohammad; Fuladi, Marjan Imani; Taheri, Arash; Esfahani, Mohammad Riazi] Univ Tehran Med Sci, Farabi Eye Hosp, Eye Res Ctr, Qazvin Sq,South Kargar St, Tehran 1336616351, Iran. [Modjtahedi, Bobeck; Loewenstein, John] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA USA. [Fotouhi, Akbar; Yaseri, Mehdi] Univ Tehran Med Sci, Sch Publ Hlth, Dept Epidemiol & Biostat, Tehran, Iran. [Esfahani, Mohammad Riazi] Noor Eye Hosp, Retina Serv, Tehran, Iran. RP Esfahani, MR (reprint author), Univ Tehran Med Sci, Farabi Eye Hosp, Eye Res Ctr, Qazvin Sq,South Kargar St, Tehran 1336616351, Iran. EM riazifahimi@yahoo.com RI Fotouhi, Akbar/F-5618-2011; OI Khodabande, Alireza/0000-0002-3957-7515; Yaseri, Mehdi/0000-0002-4066-873X; Taheri, Arash/0000-0003-4068-7575 NR 31 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 1359-2998 EI 1468-2052 J9 ARCH DIS CHILD-FETAL JI Arch. Dis. Child.-Fetal Neonatal Ed. PD JUL PY 2016 VL 101 IS 4 BP F288 EP F293 DI 10.1136/archdischild-2015-309137 PG 6 WC Pediatrics SC Pediatrics GA DP1MS UT WOS:000378254700005 PM 27073259 ER PT J AU Norrholm, SD Jovanovic, T Gerardi, M Breazeale, KG Price, M Davis, M Duncan, E Ressler, KJ Bradley, B Rizzo, A Tuerk, PW Rothbaum, BO AF Norrholm, Seth Davin Jovanovic, Tanja Gerardi, Maryrose Breazeale, Kathryn G. Price, Matthew Davis, Michael Duncan, Erica Ressler, Kerry J. Bradley, Bekh Rizzo, Albert Tuerk, Peter W. Rothbaum, Barbara O. TI Baseline psychophysiological and cortisol reactivity as a predictor of PTSD treatment outcome in virtual reality exposure therapy SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Acoustic startle; Posttraumatic stress disorder; Virtual reality; Psychophysiology; Exposure therapy; Cortisol ID POSTTRAUMATIC-STRESS-DISORDER; CONDITIONED FEAR EXTINCTION; COGNITIVE-BEHAVIORAL TREATMENT; OBSESSIVE-COMPULSIVE DISORDER; RANDOMIZED CLINICAL-TRIAL; SOCIAL ANXIETY DISORDER; D-CYCLOSERINE; POTENTIATED STARTLE; PROLONGED EXPOSURE; TREATMENT RESPONSE AB Baseline cue-dependent physiological reactivity may serve as an objective measure of posttraumatic stress disorder (PTSD) symptoms. Additionally, prior animal model and psychological studies would suggest that subjects with greatest symptoms at baseline may have the greatest violation of expectancy to danger when undergoing exposure based psychotherapy; thus treatment approaches which enhanced the learning under these conditions would be optimal for those with maximal baseline cue-dependent reactivity. However methods to study this hypothesis objectively are lacking. Virtual reality (VR) methodologies have been successfully employed as an enhanced form of imaginal prolonged exposure therapy for the treatment of PTSD. Our goal was to examine the predictive nature of initial psychophysiological (e.g., startle, skin conductance, heart rate) and stress hormone responses (e.g., cortisol) during presentation of VR-based combat-related stimuli on PTSD treatment outcome. Combat veterans with PTSD underwent 6 weeks of VR exposure therapy combined with either D-cycloserine (DCS), alprazolam (ALP), or placebo (PBO). In the DCS group, startle response to VR scenes prior to initiation of treatment accounted for 76% of the variance in CAPS change scores, p < 0.001, in that higher responses predicted greater changes in symptom severity over time. Additionally, baseline cortisol reactivity was inversely associated with treatment response in the ALP group, p = 0.04. We propose that baseline cue-activated physiological measures will be sensitive to predicting patients' level of response to exposure therapy, in particular in the presence of enhancement (e.g., DCS). Published by Elsevier Ltd. C1 [Norrholm, Seth Davin; Duncan, Erica; Bradley, Bekh] Mental Hlth Serv, Atlanta Vet Affairs Med Ctr, Washington, DC USA. [Norrholm, Seth Davin; Jovanovic, Tanja; Gerardi, Maryrose; Breazeale, Kathryn G.; Davis, Michael; Duncan, Erica; Ressler, Kerry J.; Bradley, Bekh; Rothbaum, Barbara O.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Price, Matthew] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Rizzo, Albert] Univ So Calif, Dept Psychiat, Inst Creat Technol, Los Angeles, CA 90089 USA. [Rizzo, Albert] Univ So Calif, Sch Gerontol, Los Angeles, CA 90089 USA. [Tuerk, Peter W.] Ralph H Johnson VAMC, Charleston, SC USA. [Tuerk, Peter W.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. RP Norrholm, SD (reprint author), Atlanta VAMC, MHSL 116A,1670 Clairmont Rd, Decatur, GA 30033 USA. EM seth.norrholm@va.gov FU Department of Defense Clinical Trial Grant [W81XWH-10-1-1045]; NIMH [U19 MH-069056, R01 MH-70880, R01 MH-094757]; Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Grant ("Optimal Dose of Early Intervention to Prevent PTSD"); McCormick Foundation ("BraveHeart: MLB's Welcome Back Veterans Southeast Initiative"); Genentech; Posit Science Corporation; National Institute on Drug Abuse FX Dr. Rothbaum is a consultant to and owns equity in Virtually Better, Inc., which creates virtual environments; however, Virtually Better did not create the Virtual Iraq environment tested in this study; the terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. Rothbaum also has funding from Department of Defense Clinical Trial Grant W81XWH-10-1-1045 ("Enhancing Exposure Therapy for PTSD: Virtual Reality and Imaginal Exposure With a Cognitive Enhancer"), from NIMH grant U19 MH-069056 ("The Emory-MSSM-GSK-NIMH Collaborative Mood and Anxiety Disorders Initiative"), from NIMH grant R01 MH-70880 ("A Cognitive Enhancer May Facilitate Behavioral Exposure Therapy"), from NIMH grant R01 MH-094757 ("Prospective Determination of Psychobiological Risk Factors for Posttraumatic Stress"), from a Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Grant ("Optimal Dose of Early Intervention to Prevent PTSD"), and from the McCormick Foundation ("BraveHeart: MLB's Welcome Back Veterans Southeast Initiative"); she has received previous support from Transcept Pharmaceuticals ("A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Low-Dose Ondansetron for Adjunctive Therapy in Adult Patients With Obsessive Compulsive Disorder Who Have Not Adequately Responded to Treatment With a Serotonin Reuptake Inhibitor"); she receives royalties from Oxford University Press, Guilford, American Psychiatric Publishing, and Emory University; and she received one advisory board payment from Genentech. Drs. Ressler and Davis are founding members of Extinction Pharmaceuticals/Therapade Technologies, which seek to develop D-cycloserine and other compounds for use to augment the effectiveness of psychotherapy; they have received no equity or income from this relationship within the last 3 years; the terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. Duncan has received research support from the Posit Science Corporation and grant support from NIMH and the National Institute on Drug Abuse. The remaining authors report no financial relationships with commercial interests. NR 80 TC 1 Z9 1 U1 22 U2 34 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 2016 VL 82 BP 28 EP 37 DI 10.1016/j.brat.2016.05.002 PG 10 WC Psychology, Clinical SC Psychology GA DP0PD UT WOS:000378190800004 PM 27183343 ER PT J AU Wolf, EJ Schnurr, PP AF Wolf, Erika J. Schnurr, Paula P. TI Developing Comprehensive Models of the Effects of Stress and Trauma on Biology, Brain, Behavior, and Body SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID OXIDATIVE STRESS; PTSD; ASSOCIATION; DISORDER C1 [Wolf, Erika J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Wolf, Erika J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Schnurr, Paula P.] Natl Ctr PTSD, White River Jct, VT USA. [Schnurr, Paula P.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Wolf, EJ (reprint author), VA Boston Healthcare Syst 116B 2, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. EM erika.wolf@va.gov FU Intramural VA [CDA-2-067-10S] NR 10 TC 0 Z9 0 U1 5 U2 5 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 2016 VL 80 IS 1 BP 6 EP 8 DI 10.1016/j.biopsych.2016.04.016 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DO8TB UT WOS:000378055600006 PM 27312232 ER PT J AU Philip, NS Dunner, DL Dowd, SM Aaronson, ST Brock, DG Carpenter, LL Demitrack, MA Hovav, S Janicak, PG George, MS AF Philip, Noah S. Dunner, David L. Dowd, Sheila M. Aaronson, Scott T. Brock, David G. Carpenter, Linda L. Demitrack, Mark A. Hovav, Sarit Janicak, Philip G. George, Mark S. TI Can Medication Free, Treatment-Resistant, Depressed Patients Who Initially Respond to TMS Be Maintained Off Medications? A Prospective, 12-Month Multisite Randomized Pilot Study (vol 9, pg 251, 2016) SO BRAIN STIMULATION LA English DT Correction C1 [Philip, Noah S.] Providence VA Med Ctr, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. [Philip, Noah S.; Carpenter, Linda L.] Butler Hosp, Providence, RI 02906 USA. [Dunner, David L.] Ctr Anxiety & Depress, Mercer Isl, WA USA. [Dowd, Sheila M.; Janicak, Philip G.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Aaronson, Scott T.] Sheppard Pratt Hlth Syst, Baltimore, MD USA. [Brock, David G.; Demitrack, Mark A.] Neuronetics Inc, Malvern, PA USA. [Hovav, Sarit] Univ Nebraska Med Ctr, Creighton Univ, Omaha, NE USA. [George, Mark S.] Med Univ S Carolina, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Philip, NS (reprint author), Providence VA Med Ctr, Ctr Neurorestorat & Neurotechnol, Providence, RI USA.; Philip, NS (reprint author), Butler Hosp, Providence, RI 02906 USA. EM Noah_Philip@Brown.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X EI 1876-4754 J9 BRAIN STIMUL JI Brain Stimul. PD JUL-AUG PY 2016 VL 9 IS 4 BP 639 EP 639 DI 10.1016/j.brs.2016.03.015 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DO8VL UT WOS:000378063000027 ER PT J AU Baltzis, D Bakker, JP Patel, SR Veves, A AF Baltzis, Dimitrios Bakker, Jessie P. Patel, Sanjay R. Veves, Aristidis TI Obstructive Sleep Apnea and Vascular Diseases SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID POSITIVE AIRWAY PRESSURE; CORONARY-HEART-DISEASE; ENDOTHELIAL PROGENITOR CELLS; PERIPHERAL ARTERIAL-DISEASE; C-REACTIVE PROTEIN; INTERMITTENT HYPOXIA; OXIDATIVE STRESS; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; SYMPATHETIC ACTIVITY AB Obstructive sleep apnea (OSA) affects a large proportion of adults, and is as an independent risk factor for cerebrovascular and cardiovascular disease. The repetitive airway obstruction that characterizes OSA results in intermittent hypoxia, intrathoracic pressure swings, and sleep fragmentation, which in turn lead to sympathetic activation, oxidative stress, inflammation, and endothelial dysfunction. This review outlines the associations between OSA and vascular diseases and describes basic mechanisms that may be responsible for this association, in both the micro- and macrocirculation. It also reports on interventional studies that aim to ameliorate OSA and thereby reduce vascular disease burden. (C) 2016 American Physiological Society. C1 [Baltzis, Dimitrios; Veves, Aristidis] Harvard Univ, Sch Med, Microcirculat Lab, Boston, MA 02115 USA. [Baltzis, Dimitrios; Veves, Aristidis] Harvard Univ, Sch Med, Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02115 USA. [Bakker, Jessie P.; Patel, Sanjay R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. RP Veves, A (reprint author), Harvard Univ, Sch Med, Microcirculat Lab, Boston, MA 02115 USA.; Veves, A (reprint author), Harvard Univ, Sch Med, Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02115 USA. EM aveves@bidmc.harvard.edu OI Patel, Sanjay/0000-0002-9142-5172 FU National Institutes of Health [R01 NS066205, R01 DK076937, R01 HL110350]; American Heart Association [14SDG20160000]; American Thoracic Society FX This work was partly supported by National Institutes of Health R01 NS066205 (A. Veves), R01 DK076937 (A. Veves), and R01 HL110350 (A. Veves and S. R. Patel), the American Heart Association 14SDG20160000 (J. P. Bakker), and the American Thoracic Society (J. P. Bakker). NR 132 TC 1 Z9 1 U1 4 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD JUL PY 2016 VL 6 IS 3 BP 1519 EP 1528 DI 10.1002/cphy.c150029 PG 10 WC Physiology SC Physiology GA DP1EB UT WOS:000378232200013 PM 27347900 ER PT J AU Villar, J Ambros, A Soler, JA Martinez, D Ferrando, C Solano, R Mosteiro, F Blanco, J Martin-Rodriguez, C Fernandez, MD Lopez, J Diaz-Dominguez, FJ Andaluz-Ojeda, D Merayo, E Perez-Mendez, L Fernandez, RL Kacmarek, RM AF Villar, Jesus Ambros, Alfonso Alfonso Soler, Juan Martinez, Domingo Ferrando, Carlos Solano, Rosario Mosteiro, Fernando Blanco, Jesus Martin-Rodriguez, Carmen del Mar Fernandez, Maria Lopez, Julia Diaz-Dominguez, Francisco J. Andaluz-Ojeda, David Merayo, Eleuterio Perez-Mendez, Lina Lidia Fernandez, Rosa Kacmarek, Robert M. CA Stratification Outcome Acute TI Age, Pao(2)/Fio(2), and Plateau Pressure Score: A Proposal for a Simple Outcome Score in Patients With the Acute Respiratory Distress Syndrome SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; age; arterial partial pressure of oxygen/fraction of inspired oxygen; plateau pressure; scoring system ID ACUTE LUNG INJURY; BERLIN DEFINITION; MORTALITY; RISK; ARDS; CLASSIFICATION; MULTICENTER; VALIDATION; MEDICINE; SYSTEMS AB Objectives: Although there is general agreement on the characteristic features of the acute respiratory distress syndrome, we lack a scoring system that predicts acute respiratory distress syndrome outcome with high probability. Our objective was to develop an outcome score that clinicians could easily calculate at the bedside to predict the risk of death of acute respiratory distress syndrome patients 24 hours after diagnosis. Design: A prospective, multicenter, observational, descriptive, and validation study. Setting: A network of multidisciplinary ICUs. Patients: Six-hundred patients meeting Berlin criteria for moderate and severe acute respiratory distress syndrome enrolled in two independent cohorts treated with lung-protective ventilation. Interventions: None. Measurements and Main Results: Using individual demographic, pulmonary, and systemic data at 24 hours after acute respiratory distress syndrome diagnosis, we derived our prediction score in 300 acute respiratory distress syndrome patients based on stratification of variable values into tertiles, and validated in an independent cohort of 300 acute respiratory distress syndrome patients. Primary outcome was in-hospital mortality. We found that a 9-point score based on patient's age, Pao(2)/Fio(2) ratio, and plateau pressure at 24 hours after acute respiratory distress syndrome diagnosis was associated with death. Patients with a score greater than 7 had a mortality of 83.3% (relative risk, 5.7; 95% CI, 3.0-11.0), whereas patients with scores less than 5 had a mortality of 14.5% (p < 0.0000001). We confirmed the predictive validity of the score in a validation cohort. Conclusions: A simple 9-point score based on the values of age, Pao(2)/Fio(2) ratio, and plateau pressure calculated at 24 hours on protective ventilation after acute respiratory distress syndrome diagnosis could be used in real time for rating prognosis of acute respiratory distress syndrome patients with high probability. C1 [Villar, Jesus; Blanco, Jesus; Perez-Mendez, Lina; Lidia Fernandez, Rosa] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus; Lidia Fernandez, Rosa] Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain. [Ambros, Alfonso; Martin-Rodriguez, Carmen] Hosp Gen Ciudad Real, Intens Care Unit, Ciudad Real, Spain. [Alfonso Soler, Juan] Hosp Univ Morales Meseguer, Intens Care Unit, Murcia, Spain. [Martinez, Domingo] Hosp Univ Virgen Arrixaca, Intens Care Unit, Murcia, Spain. [Ferrando, Carlos] Hosp Clin Valencia, Dept Anesthesia, Postsurg Unit, Valencia, Spain. [Solano, Rosario] Hosp Virgen Luz, Intens Care Unit, Cuenca, Spain. [Mosteiro, Fernando] Hosp Univ A Coruna, Intens Care Unit, Coruna, Spain. [Blanco, Jesus] Hosp Univ Rio Hortega, Intens Care Unit, Valladolid, Spain. [del Mar Fernandez, Maria] Hosp Univ Mutua Terrassa, Intens Care Unit, Barcelona, Spain. [Lopez, Julia] Hosp Univ La Paz, Intens Care Unit, Madrid, Spain. [Diaz-Dominguez, Francisco J.] Hosp Gen Leon, Intens Care Unit, Leon, Spain. [Andaluz-Ojeda, David] Hosp Clin Valladolid, Intens Care Unit, Valladolid, Spain. [Merayo, Eleuterio] Hosp Bierzo, Intens Care Unit, Leon, Spain. [Perez-Mendez, Lina] Hosp Univ NS Candelaria, Res Unit, Santa Cruz De Tenerife, Spain. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesia, Boston, MA 02115 USA. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.; Villar, J (reprint author), Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain. EM jesus.villar54@gmail.com FU Instituto de Salud Carlos III [CB06/06/1088, PI10/0393, PI13/0119]; Fundacion Mutua Madrilena [AP101822012]; Asociacion Cientifica Pulmon y Ventilacion Mecanica; Maquet; Covidien; Venner Medical FX Supported, in part, by Instituto de Salud Carlos III (CB06/06/1088, PI10/0393, and PI13/0119), Fundacion Mutua Madrilena (AP101822012), and Asociacion Cientifica Pulmon y Ventilacion Mecanica. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.; Dr. Villar has received a research grant from Maquet. Dr. Kacmarek served as a consultant for Covidien and Orange Med on mechanical ventilators and received research grants from Covidien and Venner Medical for evaluation of mechanical ventilators and airways. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 31 TC 9 Z9 9 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2016 VL 44 IS 7 BP 1361 EP 1369 DI 10.1097/CCM.0000000000001653 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA DO9BX UT WOS:000378080400037 PM 27035239 ER PT J AU Davies, E Chodosh, J AF Davies, Emma Chodosh, James TI Infections after keratoprosthesis SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Review DE endophthalmitis; keratoprosthesis; microbial keratitis ID BOSTON TYPE-1 KERATOPROSTHESIS; I KERATOPROSTHESIS; TERM OUTCOMES; RISK-FACTORS; ENDOPHTHALMITIS; IMPLANTATION; PREVENTION; MULTICENTER; RETENTION; KERATITIS AB Purpose of reviewThe purpose is to provide an overview of the recent advancements in the diagnosis and treatment of microbial keratitis and endophthalmitis after keratoprosthesis implantation.Recent findingsThe addition of vancomycin daily to a fluoroquinolone in the postoperative management of keratoprosthesis patients successfully reduced the number of cases of bacterial keratitis and endophthalmitis with an increased number of fungal infections now documented both in the United States and abroad.SummaryCompliance with the regimen of a fluoroquinolone and vancomycin daily for life after keratoprosthesis implantation should be stressed with the patient. Further research is needed to investigate whether intermittent use of 5% povidone-iodine and frequent replacement of the bandage contact lens could reduce fungal infection after keratoprosthesis surgery. Future advancements in the Boston keratoprosthesis design and/or postoperative management are needed to further reduce infection after keratoprosthesis placement. C1 [Davies, Emma; Chodosh, James] Harvard Univ, Cornea & External Dis Serv, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02115 USA. EM James_Chodosh@meei.harvard.edu FU Research to Prevent Blindness, NY, NY FX This work was supported by an unrestricted grant to the Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, NY, NY. NR 22 TC 0 Z9 0 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD JUL PY 2016 VL 27 IS 4 BP 373 EP 377 DI 10.1097/ICU.0000000000000270 PG 5 WC Ophthalmology SC Ophthalmology GA DP3TH UT WOS:000378417800017 PM 27138637 ER PT J AU Sarkissian, T Arya, R Gyonjyan, S Taylor, B White, K AF Sarkissian, Tatevik Arya, Richa Gyonjyan, Seda Taylor, Barbara White, Kristin TI Cell death regulates muscle fiber number SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Drosophila; Muscle; Apoptosis; FGF ID CENTRAL-NERVOUS-SYSTEM; DROSOPHILA-MELANOGASTER; NEUROBLAST APOPTOSIS; MUSCULAR-DYSGENESIS; ADULT MYOGENESIS; FOUNDER CELLS; EXPRESSION; DIFFERENTIATION; MOTONEURONS; SURVIVAL AB Cell death can have both cell autonomous and non-autonomous roles in normal development. Previous studies have shown that the central cell death regulators grim and reaper are required for the developmentally important elimination of stem cells and neurons in the developing central nervous system (CNS). Here we show that cell death in the nervous system is also required for normal muscle development. In the absence of grim and reaper, there is an increase in the number of fibers in the ventral abdominal muscles in the Drosophila adult. This phenotype can be partially recapitulated by inhibition of cell death specifically in the CNS, indicating a non-autonomous role for neuronal death in limiting muscle fiber number. We also show that FGFs produced in the cell death defective nervous system are required for the increase in muscle fiber number. Cell death in the muscle lineage during pupal stages also plays a role in specifying fiber number. Our work suggests that FGFs from the CNS act as a survival signal for muscle founder cells. Thus, proper muscle fiber specification requires cell death in both the nervous system and in the developing muscle itself. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sarkissian, Tatevik; Arya, Richa; Gyonjyan, Seda; White, Kristin] Harvard Univ, Sch Med, Res Inst, CBRC,Massachusetts Gen Hosp, Boston, MA 02129 USA. [Taylor, Barbara] Oregon State Univ, Dept Integrat Biol, Corvallis, OR 97331 USA. RP White, K (reprint author), Massachusetts Gen Hosp, Res Inst, CBRC, Bldg 149,13th St, Charlestown, MA 02129 USA. EM kristin.white@mgh.harvard.edu FU N.I.H. grants [GM56920, GM110477, S10RR027673] FX We would like to thank Mary Baylies, the VDRC and the Bloomington Stock Center for important fly stocks, the Developmental Studies Hybridoma Bank, Rachel Wilson and Jim Skeath for antibodies, and the CBRC confocal core. Joyce Fernandes shared important unpublished data and advice. The work was supported by N.I.H. grants GM56920 to BJT and GM110477 and S10RR027673 to KW. NR 47 TC 0 Z9 0 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JUL 1 PY 2016 VL 415 IS 1 BP 87 EP 97 DI 10.1016/j.ydbio.2016.04.018 PG 11 WC Developmental Biology SC Developmental Biology GA DP0NY UT WOS:000378187700009 PM 27131625 ER PT J AU Dauriz, M Meigs, JB AF Dauriz, Marco Meigs, James B. TI The power of numbers SO DIABETOLOGIA LA English DT Editorial Material DE Genetic epidemiology; Genome-wide association study; Spectrum bias; Type 2 diabetes; Winner's curse ID ASSOCIATION; SUSCEPTIBILITY C1 [Dauriz, Marco] Univ Verona, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Ple Stefani 1 Pad 22, I-37126 Verona, Italy. [Dauriz, Marco] Osped Civile, Hosp Trust Verona, Ple Stefani 1 Pad 22, I-37126 Verona, Italy. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Dauriz, M (reprint author), Univ Verona, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Ple Stefani 1 Pad 22, I-37126 Verona, Italy.; Dauriz, M (reprint author), Osped Civile, Hosp Trust Verona, Ple Stefani 1 Pad 22, I-37126 Verona, Italy. EM marco.dauriz@univr.it RI Dauriz, Marco/S-5843-2016 OI Dauriz, Marco/0000-0002-5542-5941 FU NIDDK NIH HHS [K24 DK080140] NR 12 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2016 VL 59 IS 7 BP 1400 EP 1402 DI 10.1007/s00125-016-3962-z PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO8QH UT WOS:000378047800013 PM 27115413 ER PT J AU Mansouri, M Aran, S Shaqdan, KW Abujudeh, HH AF Mansouri, Mohammad Aran, Shima Shaqdan, Khalid W. Abujudeh, Hani H. TI How often are Patients Harmed When They Visit the Computed Tomography Suite? A Multi-year Experience, in Incident Reporting, in a Large Academic Medical Center SO EUROPEAN RADIOLOGY LA English DT Article DE Safety incident reporting; Safety incident reporting system; CT incident reporting; Incident reporting rate; CT quality and safety ID INTRAVENOUS CONTRAST EXTRAVASATION; ADVERSE EVENTS; HOSPITALIZED-PATIENTS; SAFETY INCIDENTS; INTENSIVE-CARE; ERRORS; RADIOLOGY; SYSTEM; FALLS; CT AB Our goal is to present our multi-year experience in incident reporting in CT in a large medical centre. This is an IRB-approved, HIPAA-compliant study. Informed consent was waived for this study. The electronic safety incident reporting system of our hospital was searched for the variables from April 2006 to September 2012. Incident classifications were diagnostic test orders, ID/documentation, safety/security/conduct, service coordination, surgery/procedure, line/tube, fall, medication/IV safety, employee general incident, environment/equipment, adverse drug reaction, skin/tissue and diagnosis/treatment. A total of 1918 incident reports occurred in the study period and 843,902 CT examinations were performed. The rate of safety incident was 0.22 % (1918/843,902). The highest incident rates were due to adverse drug reactions (652/843,902 = 0.077 %) followed by medication/IV safety (573/843,902 = 0.068 %) and diagnostic test orders (206/843,902 = 0.024 %). Overall 45 % of incidents (869/1918) caused no harm and did not affect the patient, 33 % (637/1918) caused no harm but affected the patient, 22 % (420/1918) caused temporary or minor harm/damage and less than 1 % (10/1918) caused permanent or major harm/damage or death. Our study shows a total safety incident report rate of 0.22 % in CT. The most common incidents are adverse drug reaction, medication/IV safety and diagnostic test orders. aEuro cent Total safety incident report rate in CT is 0.22 %. aEuro cent Adverse drug reaction is the most common safety incident in CT. aEuro cent Medication/IV safety is the second most common safety incident in CT. C1 [Mansouri, Mohammad; Aran, Shima; Shaqdan, Khalid W.; Abujudeh, Hani H.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 55 Fruit St,Founders Bldg,Room 210, Boston, MA 02114 USA. [Abujudeh, Hani H.] Rowan Univ, Cooper Univ Hosp, Dept Radiol, One Cooper Plaza, Camden, NJ 08103 USA. RP Abujudeh, HH (reprint author), Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 55 Fruit St,Founders Bldg,Room 210, Boston, MA 02114 USA.; Abujudeh, HH (reprint author), Rowan Univ, Cooper Univ Hosp, Dept Radiol, One Cooper Plaza, Camden, NJ 08103 USA. EM mmansouri1@partners.org; aran.shima@mgh.harvard.edu; kshaqdan@partners.org; haniabujudeh@gmail.com RI Mansouri, Mohammad/M-4774-2016 OI Mansouri, Mohammad/0000-0002-7472-1287 NR 68 TC 0 Z9 0 U1 1 U2 2 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 2016 VL 26 IS 7 BP 2064 EP 2072 DI 10.1007/s00330-015-4061-0 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO7XK UT WOS:000377996200011 PM 26560719 ER PT J AU Attai, DJ Sedrak, MS Katz, MS Thompson, MA Anderson, PF Kesselheim, JC Fisch, MJ Graham, DL Utengen, A Johnston, C Miller, RS Dizon, DS AF Attai, Deanna J. Sedrak, Mina S. Katz, Matthew S. Thompson, Michael A. Anderson, Patricia F. Kesselheim, Jennifer C. Fisch, Michael J. Graham, David L. Utengen, Audun Johnston, Claire Miller, Robert S. Dizon, Don S. CA COSMO TI Social media in cancer care: highlights, challenges & opportunities SO FUTURE ONCOLOGY LA English DT Editorial Material DE cancer; cancer research; clinical trials; communication; crowdsourcing; health information; health promotion; social media; social support; Twitter C1 [Attai, Deanna J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Sedrak, Mina S.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Katz, Matthew S.] Lowell Gen Hosp, Dept Radiat Med, Lowell, MA USA. [Thompson, Michael A.] Aurora Hlth Care, Aurora Res Inst, Milwaukee, WI USA. [Anderson, Patricia F.] Univ Michigan, Taubman Hlth Sci Lib, Ann Arbor, MI 48109 USA. [Kesselheim, Jennifer C.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Fisch, Michael J.] AIM Specialty Hlth, Chicago, IL USA. [Graham, David L.] Levine Canc Inst, Charlotte, NC USA. [Utengen, Audun] Symplur LLC, Los Angeles, CA USA. [Johnston, Claire; Miller, Robert S.] Amer Soc Clin Oncol, Alexandria, VA USA. [Dizon, Don S.] Massachusetts Gen Hosp, Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA. RP Attai, DJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. EM dattai@mednet.ucla.edu OI Utengen, Audun/0000-0003-4851-269X NR 18 TC 2 Z9 2 U1 4 U2 9 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD JUL PY 2016 VL 12 IS 13 BP 1549 EP 1552 DI 10.2217/fon-2016-0065 PG 4 WC Oncology SC Oncology GA DP3RS UT WOS:000378413200003 PM 27025657 ER PT J AU Shelton, E Laharie, D Scott, FI Mamtani, R Lewis, JD Colombel, JF Ananthakrishnan, AN AF Shelton, Edward Laharie, David Scott, Frank I. Mamtani, Ronac Lewis, James D. Colombel, Jean-Frederic Ananthakrishnan, Ashwin N. TI Cancer Recurrence Following Immune-Suppressive Therapies in Patients With Immune-Mediated Diseases: A Systematic Review and Meta-analysis SO GASTROENTEROLOGY LA English DT Review DE Immunosuppression; Melanoma; Lymphoma; IBD ID INFLAMMATORY-BOWEL-DISEASE; MODIFYING ANTIRHEUMATIC DRUGS; NONMELANOMA SKIN-CANCER; NECROSIS FACTOR THERAPY; TNF INHIBITOR THERAPY; RHEUMATOID-ARTHRITIS; ANTI-TNF; IMMUNOSUPPRESSIVE THERAPY; EULAR RECOMMENDATIONS; PSORIATIC-ARTHRITIS AB BACKGROUND & AIMS: Physicians frequently encounter patients with immune-mediated diseases and a history of malignancy. There are limited data on the safety of immunosuppressive therapy for these patients. Published studies have been small with few events, precluding robust estimates of risk. METHODS: We searched Medline, EMBASE, and conference proceedings for terms related to immune-mediated disease, immune-suppressive therapy, and cancer recurrence from inception to April 2015. We included 16 studies (9 of patients with rheumatoid arthritis, 8 of patients with inflammatory bowel disease, and 1 of patients with psoriasis) and stratified studies by type of immune-suppressive therapy (monoclonal antibodies to tumor necrosis factor [anti-TNF], conventional immune-modulatory agents, or no immune suppression). A random-effects meta-analysis was performed to calculate the pooled incidence rates as well as risk differences between the various treatments. RESULTS: Our analysis included 11,702 persons contributing 31,258 person-years (p-y) of follow-up evaluation after a prior diagnosis of cancer. Rates of cancer recurrence were similar among individuals receiving anti-TNF therapy (33.8 per 1000 p-y), immunemodulator therapy (36.2 per 1000 p-y), or no immunosuppression (37.5 per 1000 p-y), but were numerically higher among patients receiving combination immune suppression (54.5 per 1000 p-y) (P > .1 for all). Subgroup analysis of new and recurrent cancers separately, type of immune-modulator therapy, or immune-mediated disease showed similar results, with no increase in risk. We found similar pooled incidence values for new or primary cancers when immunosuppression was initiated within 6 years (33.6 per 1000 p-y for immunemodulatory agents and 43.7 per 1000 p-y for anti-TNF agents) vs more than 6 years after the index cancer (32.9 per 1000 p-y for immune-modulatory agents, P = .86; and 21.0 per 1000 p-y for anti-TNF agents, P = .43). CONCLUSIONS: In a meta-analysis of 16 studies, we observed similar rates of cancer recurrence among individuals with prior cancer who received no immunosuppression, anti-TNF therapy, immune-modulator therapy, or combination treatments. Prospective studies are needed to ascertain optimal intervals for re-initiation of immune-suppressive therapies for individuals with specific cancers. C1 [Shelton, Edward; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Gastroenterol Unit, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.] Harvard Univ, Sch Med, Boston, MA USA. [Laharie, David] Univ Bordeaux, Lab Bacteriol, Serv Hepatogastroenterol, Bordeaux, France. [Scott, Frank I.; Lewis, James D.] Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA. [Mamtani, Ronac] Univ Penn, Div Oncol, Philadelphia, PA 19104 USA. [Colombel, Jean-Frederic] Icahn Sch Med Mt Sinai, Div Gastroenterol, New York, NY 10029 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU US National Institutes of Health [K23-DK097142, K23-CA187185, K08-DK095951-02, K24-DK078228] FX Supported by funding from the US National Institutes of Health (K23-DK097142 to A.A., K23-CA187185 to R.M., K08-DK095951-02 to F.I.S., and K24-DK078228 to J. D. L.). NR 67 TC 5 Z9 5 U1 2 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2016 VL 151 IS 1 BP 97 EP + DI 10.1053/j.gastro.2016.03.037 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DP5QD UT WOS:000378551400026 PM 27039969 ER PT J AU Lynch, PM Morris, JS Wen, SJ Advani, SM Ross, W Chang, GJ Rodriguez-Bigas, M Raju, GS Ricciardiello, L Iwama, T Rossi, BM Pellise, M Stoffel, E Wise, PE Bertario, L Saunders, B Burt, R Belluzzi, A Ahnen, D Matsubara, N Bulow, S Jespersen, N Clark, SK Erdman, SH Markowitz, AJ Bernstein, I De Haas, N Syngal, S Moeslein, G AF Lynch, Patrick M. Morris, Jeffrey S. Wen, Sijin Advani, Shailesh M. Ross, William Chang, George J. Rodriguez-Bigas, Miguel Raju, Gottumukkala S. Ricciardiello, Luigi Iwama, Takeo Rossi, Benedito M. Pellise, Maria Stoffel, Elena Wise, Paul E. Bertario, Lucio Saunders, Brian Burt, Randall Belluzzi, Andrea Ahnen, Dennis Matsubara, Nagahide Bulow, Steffen Jespersen, Niels Clark, Susan K. Erdman, Steven H. Markowitz, Arnold J. Bernstein, Inge De Haas, Niels Syngal, Sapna Moeslein, Gabriela TI A proposed staging system and stage-specific interventions for familial adenomatous polyposis SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID CANCER; CELECOXIB AB Background and Aims: It is not possible to accurately count adenomas in many patients with familial adenomatous polyposis (FAP). Nevertheless, polyp counts are critical in evaluating each patient's response to interventions. However, the U.S. Food and Drug Administration no longer recognizes the decrease in polyp burden as a sufficient chemoprevention trial treatment endpoint requiring a measure of "clinical benefit." To develop endpoints for future industry-sponsored chemopreventive trials, the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) developed an FAP staging and intervention classification scheme for lower-GI tract polyposis. Methods: Twenty-four colonoscopy or sigmoidoscopy videos were reviewed by 26 clinicians familiar with diagnosis and treatment of FAP. The reviewers independently assigned a stage to a case by using the proposed system and chose a stage-specific intervention for each case. Our endpoint was the degree of concordance among reviewers staging and intervention assessments. Results: The staging and intervention ratings of the 26 reviewers were highly concordant (rho = 0.710; 95% credible interval, 0.651-0.759). Sixty-two percent of reviewers agreed on the FAP stage, and 90% of scores were within +/- 1 stage of the mode. Sixty percent of reviewers agreed on the intervention, and 86% chose an intervention within +/- 1 level of the mode. Conclusions: The proposed FAP colon polyposis staging system and stage-specific intervention are based on a high degree of agreement on the part of experts in the review of individual cases of polyposis. Therefore, reliable and clinically relevant means for measuring trial outcomes can be developed. Outlier cases showing wide scatter in stage assignment call for individualized attention and may be inappropriate for enrollment in clinical trials for this reason. C1 [Lynch, Patrick M.; Advani, Shailesh M.; Ross, William; Raju, Gottumukkala S.] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, 1515 Holcombe Blvd, Houston, TX 77054 USA. [Morris, Jeffrey S.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Wen, Sijin] W Virginia Univ, Hlth Sci Ctr, Dept Biostat, Morgantown, WV 26506 USA. [Chang, George J.; Rodriguez-Bigas, Miguel] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Ricciardiello, Luigi] Univ Bologna, Dept Med & Surg Sci, Bologna, Italy. [Iwama, Takeo] Saitama Med Univ, Dept Digest Tract & Gen Surg, Saitama, Japan. [Rossi, Benedito M.] Hosp Sirio Libanes, Hereditary Canc Registry, Div Surg Oncol, Sao Paulo, Brazil. [Pellise, Maria] Univ Barcelona, Inst Malalties Digest & Metab, Hosp Clin, Dept Gastroenterol,CIBERehd,IDIBAPS, Barcelona, Spain. [Stoffel, Elena] Univ Michigan Hlth Syst, Div Internal Med, Ann Arbor, MI USA. [Wise, Paul E.] Washington Univ, Sch Med, Sect Colon & Rectal Surg, St Louis, MO USA. [Bertario, Lucio] Fdn IRCCS, Ist Nazl Tumori, Unit Hereditary Digest Tract Tumors, Milan, Italy. [Saunders, Brian] St Marks Hosp, Wolfson Unit Endoscopy, Harrow, Middx, England. [Burt, Randall] Univ Utah, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Belluzzi, Andrea] S Orsola Malpighi Univ Hosp, Dept Med & Surg Sci, Bologna, Italy. [Ahnen, Dennis] Dept Vet Affairs Eastern Colorado Hlth Care Syst, Div Gastroenterol, Denver, CO USA. [Ahnen, Dennis] Univ Colorado, Sch Med, Denver, CO USA. [Matsubara, Nagahide] Hyogo Coll Med, Dept Surg, Nishinomiya, Hyogo 6638501, Japan. [Bulow, Steffen; Jespersen, Niels] Hvidovre Univ Hosp, Gastrointestinal Unit, Danish Polyposis Register, Copenhagen, Denmark. [Clark, Susan K.] St Marks Hosp, Polyposis Registry, Harrow, Middx, England. [Erdman, Steven H.] Ohio State Univ, Nationwide Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Columbus, OH 43210 USA. [Markowitz, Arnold J.] Mem Sloan Kettering Canc Ctr, Serv Gastroenterol & Nutr, 1275 York Ave, New York, NY 10021 USA. [Bernstein, Inge; De Haas, Niels] Aalborg Univ Hosp, Dept Surg Gastroenterol, Aalborg, Denmark. [Syngal, Sapna] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Gastroenterol, Div Populat Sci, 75 Francis St, Boston, MA 02115 USA. [Syngal, Sapna] Harvard Univ, Sch Med, Boston, MA USA. [Moeslein, Gabriela] Univ Witten Herdecke, HELIOS Klinikum Wuppertal, Ctr Hereditary Tumors, Wuppertal, Germany. RP Lynch, PM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, 1515 Holcombe Blvd, Houston, TX 77054 USA. EM plynch@mdanderson.org OI RICCIARDIELLO, LUIGI/0000-0003-2568-6208 FU SLA Pharma (UK) FX The authors thank all of our reviewers for their time and contribution to this study, SLA Pharma (UK) for their funding support, and the entire team who made this study possible. NR 13 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 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JUL PY 2016 VL 84 IS 1 BP 115 EP + DI 10.1016/j.gie.2015.12.029 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DO9HB UT WOS:000378095000018 PM 26769407 ER PT J AU Valentine, SE Gerber, MW Nobles, CJ Shtasel, DL Marques, L AF Valentine, Sarah E. Gerber, Monica W. Nobles, Carrie J. Shtasel, Derri L. Marques, Luana TI Longitudinal Study of Mental Health and Pain-Related Functioning Following a Motor Vehicle Collision SO HEALTH PSYCHOLOGY LA English DT Article DE depression; motor vehicle collisions; pain; physical complaints; posttraumatic stress ID POSTTRAUMATIC-STRESS-DISORDER; MUTUAL MAINTENANCE; WHIPLASH INJURY; GULF-WAR; VETERANS; PTSD; ACCIDENT; SYMPTOMS; DISTRESS; TRAUMA AB Objective: Relations between mental and physical health symptoms are well-established in the literature on recovery following motor vehicle collisions (MVCs). To understand the temporal sequencing and evolution of these relations, we examined the bidirectional association between mental and physical health symptoms at 4 and 16 weeks following a MVC. Methods: The sample consisted of 103 participants recruited through public MVC police reports. The study included self-report assessments for posttraumatic stress symptoms, depressive symptoms, bodily pain, and role limitations attributable to physical health. A series of multivariable linear regression analyses were conducted to estimate the associations between these mental and physical health outcomes. Results: The analysis revealed that mental health symptoms at 4 weeks post-MVC were associated with higher bodily pain at 16 weeks post-MVC (PTSD symptoms: beta = -0.74, 95% CI: -1.06, -0.42; depressive symptoms: beta = -1.34, 95% CI: -1.90, -0.78), but not higher health-related role limitations. Physical health symptoms at 4 weeks post-MVC were not associated with PTSD or depressive symptoms at 16 weeks post-MVC. Conclusions: The results indicate the predictive strength of mental health symptoms at 4 weeks post-MVC in identifying individuals at risk for bodily pain at 16 weeks and shed light on the temporal sequencing of how relations between physical and mental health symptoms emerge over time. This suggests that early assessment of mental health symptoms may have significant implications for the treatment of these patients. C1 [Valentine, Sarah E.; Gerber, Monica W.; Nobles, Carrie J.; Shtasel, Derri L.; Marques, Luana] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Valentine, Sarah E.; Nobles, Carrie J.; Shtasel, Derri L.; Marques, Luana] Harvard Univ, Dept Psychiat, Sch Med, Cambridge, MA 02138 USA. RP Valentine, SE (reprint author), Massachusetts Gen Hosp, Community Psychiat Program Res Implementat & Diss, 70 Everett Ave,Suite 516, Chelsea, MA 02150 USA. EM sevalentine@mgh.harvard.edu OI Nobles, Carrie/0000-0002-2182-8486 FU National Institute of Mental Health (NIMH) [MH075383-02]; Mark Diamond Research Award (State University of New York); K23 Mentored Patient-Oriented Research Career Development Award from the NIMH [K23MH096029] FX This project was supported by grants from the National Institute of Mental Health (NIMH; MH075383-02) and by the Mark Diamond Research Award (State University of New York) awarded to Dr. Marques and mentored by J. Gayle Beck, PhD. Dr. Marques' time is supported by a K23 Mentored Patient-Oriented Research Career Development Award from the NIMH (K23MH096029). NR 47 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 2016 VL 35 IS 7 BP 742 EP 750 DI 10.1037/hea0000329 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA DP1GJ UT WOS:000378238200011 ER PT J AU Januszkiewicz, L Vegh, E Borgquist, R Bose, A Sharma, A Orencole, M Mela, T Singh, JP Parks, KA AF Januszkiewicz, Lukasz Vegh, Eszter Borgquist, Rasmus Bose, Abhishek Sharma, Ajay Orencole, Mary Mela, Theofanie Singh, Jagmeet P. Parks, Kimberly A. TI Reply to the Editor-Prognostic implication of baseline PR interval in patients undergoing cardiac resynchronization therapy SO HEART RHYTHM LA English DT Letter C1 [Januszkiewicz, Lukasz] Med Univ Warsaw, Dept Cardiol 1, Warsaw, Poland. [Vegh, Eszter; Borgquist, Rasmus; Bose, Abhishek; Sharma, Ajay; Orencole, Mary; Mela, Theofanie; Singh, Jagmeet P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Parks, Kimberly A.] VA Healthcare Syst Boston, West Rozbury, MA 02132 USA. RP Parks, KA (reprint author), VA Healthcare Syst Boston, West Rozbury, MA 02132 USA. EM kimberly1022@gmail.com NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2016 VL 13 IS 7 BP 1573 EP 1574 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9FK UT WOS:000378090000032 PM 27018379 ER PT J AU Gokengin, D Madani, N AF Gokengin, Deniz Madani, Navid TI Response to letter to the editor re 'HIV Trends: Defining "The Middle East' SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 [Gokengin, Deniz] Ege Univ, Fac Med, Dept Clin Microbiol & Infect Dis, Izmir, Turkey. [Madani, Navid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & Virol,Dept Global Hlth & Soci, 44 Binney St, Boston, MA 02115 USA. RP Gokengin, D (reprint author), Ege Univ, Fac Med, Dept Clin Microbiol & Infect Dis, Izmir, Turkey. NR 1 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 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD JUL PY 2016 VL 48 BP 124 EP 124 DI 10.1016/j.ijid.2016.04.015 PG 1 WC Infectious Diseases SC Infectious Diseases GA DO8PW UT WOS:000378046700031 PM 27109106 ER PT J AU Kwon, YM AF Kwon, Young-Min TI Evaluation of the Painful Dual Taper Modular Neck Stem Total Hip Arthroplasty: Do They All Require Revision? SO JOURNAL OF ARTHROPLASTY LA English DT Article DE modular femoral neck stem; taper corrosion; metal ion levels; MARS MRI; adverse local tissue reaction ID METAL-ON-METAL; LOCAL TISSUE REACTION; FEMORAL STEMS; ADVERSE-REACTIONS; CORROSION; RETRIEVAL; REPLACEMENT; JUNCTION; FAILURE; MANAGEMENT AB Although dual taper modular-neck total hip arthroplasty (THA) design with additional neck-stem modularity has the potential to optimize hip biomechanical parameters by facilitating adjustments of leg length, femoral neck version and offset, there is increasing concern regarding this stem design as a result of the growing numbers of adverse local tissue reactions due to fretting and corrosion at the neck-stem taper junction. Implant factors such as taper cone angle, taper surface roughness, taper contact area, modular neck taper metallurgy, and femoral head size play important roles in influencing extent of taper corrosion. There should be a low threshold to conduct a systematic clinical evaluation of patients with dual-taper modular-neck stem THA using systematic risk stratification algorithms as early recognition and diagnosis will ensure prompt and appropriate treatment. Although specialized tests such as metal ion analysis and cross-sectional imaging modalities such as metal artifact reduction sequence magnetic resonance imaging (MARS MRI) are useful in optimizing clinical decision-making, overreliance on any single investigative tool in the clinical decision-making process for revision surgery should be avoided. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kwon, Young-Min] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. NR 52 TC 0 Z9 0 U1 1 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 2016 VL 31 IS 7 BP 1385 EP 1389 DI 10.1016/j.arth.2016.01.074 PG 5 WC Orthopedics SC Orthopedics GA DO8WL UT WOS:000378066000003 PM 27118353 ER PT J AU Dimitriou, D Liow, MHL Tsai, TY Leone, WA Li, GA Kwon, YM AF Dimitriou, Dimitris Liow, Ming Han Lincoln Tsai, Tsung-Yuan Leone, William A. Li, Guoan Kwon, Young-Min TI Early Outcomes of Revision Surgery for Taper Corrosion of Dual Taper Total Hip Arthroplasty in 187 Patients SO JOURNAL OF ARTHROPLASTY LA English DT Article DE revision total hip arthroplasty; taper corrosion; clinical outcomes; modular femoral neck stem; dual taper; systematic evaluation ID LOCAL TISSUE REACTION; MODULAR-NECK; FEMORAL IMPLANTS; FOLLOW-UP; METAL; PSEUDOTUMOR; RESURFACINGS; REPLACEMENT; STEMS AB Background: Modular dual taper femoral neck designs have been associated with taper corrosion requiring revision surgery. However, outcomes after revision dual taper total hip arthroplasty in patients with symptomatic adverse local tissue reaction due to taper corrosion remain largely unknown. Methods: A total of 198 revision surgeries in 187 patients with dual taper femoral stem total hip arthroplasty with minimum 12-month follow-up were evaluated. Results: At mean follow-up of 18 months, at least 1 complication had occurred in 39 patients (20%) of 198 revisions. Single episode of dislocation, treated with close reduction, occurred in 16, whereas 2 patients required rerevision due to multiple dislocations. Infection requiring rerevision occurred in 3 patients. Adverse local tissue reaction recurrence requiring reoperation occurred in 6 patients. Implant survivorship for revision for any cause was 86% at 30 months. The reoperation rate of revised dual taper was 8% (16 out of 198 hips). The median serum levels of cobalt, chromium, and cobalt/chromium ratio decreased (P < .01) from 5.3 mu g/L (range: 2.3-48.5 mu g/L), 2.6 mu g/L (range: 0.2-64 mu g/L), and 4.7 (range: 2.1-35) prerevision to 1.4 mu g/L (range: 0.2-8.8 mu g/L), 0.7 mu g/L (range: 0.1-3.9 mu g/L), and 2.2 (range: 0.4-8.8) postrevision, respectively. Conclusion: This pilot study demonstrates that intraoperative tissue necrosis was associated with a high rate of early complications (20%) and revisions (8%), suggesting the importance of a systematic evaluation of these patients including metal ion levels and metal artifact reduction sequence magnetic resonance imaging in optimizing revision outcome, as early diagnosis will facilitate the initiation of appropriate treatment before significant adverse tissue necrosis. (C) 2016 Elsevier Inc. All rights reserved. C1 [Dimitriou, Dimitris; Liow, Ming Han Lincoln; Tsai, Tsung-Yuan; Li, Guoan; Kwon, Young-Min] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. [Leone, William A.] Holy Cross Hosp, Orthoped Ctr, Dept Orthopaed Surg, Ft Lauderdale, FL USA. RP Kwon, YM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. OI Dimitriou, Dimitris/0000-0002-9558-7080; LIOW, MING HAN LINCOLN/0000-0002-4496-8035 NR 25 TC 1 Z9 1 U1 0 U2 0 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 2016 VL 31 IS 7 BP 1549 EP 1554 DI 10.1016/j.arth.2016.01.015 PG 6 WC Orthopedics SC Orthopedics GA DO8WL UT WOS:000378066000032 PM 26895822 ER PT J AU Lozano-Calderon, SA Kaiser, CL Osler, PM Raskin, KA AF Lozano-Calderon, Santiago A. Kaiser, Courtney L. Osler, Polina M. Raskin, Kevin A. TI Cemented Total Hip Arthroplasty With Retrograde Ischioacetabular Steinmann Pin Reconstruction for Periacetabular Metastatic Carcinoma SO JOURNAL OF ARTHROPLASTY LA English DT Article DE acetabulum; periacetabular metastasis; Steinmann pin reconstruction; total hip arthroplasty; modified Harrington technique ID MANAGEMENT; DISEASE; BONE AB Background: Surgical management of advanced periacetabular lesions is challenging because of extensive bone loss, particularly for Modified American Academy of Orthopaedic Surgeons Classification defects type IV (pelvic discontinuity with posterior column involvement). Multiple methods for rebuilding the acetabulum have been described; all involve passing Steinmann pins in a retrograde or an antegrade fashion from the anterior iliac wing or iliac crest around the acetabulum in an attempt to recreate the normal bony anatomy. However, these techniques fail to engage the ischium in its entirety. The ischial contribution to the posterior column is a critical element in a stable acetabular construct. Methods: After curettage of the acetabular lesion, Steinmann pins are passed through the ischial tuberosity and posterior column into the sciatic buttress in a retrograde manner. The number of pins depends on the size of the defect and involvement of the posterior column. Patients and Methods: Medical records of 11 patients with a Modified American Academy of Orthopaedic Surgeons Classification defect type IV treated with retrograde ischioacetabular Steinmann pin reconstruction at our institution between 2007 and 2012 were reviewed. European Quality of Life-5 dimensions and Lower Extremity Functional Scale questionnaires were used to assess patient functional outcomes. Results: The 6 patients (4 females and 2 males; age range, 56-81 years) surviving 12 months post-operatively reported improved mobility and good quality-of-life scores. Conclusion: We described a new method for posterior acetabular column reconstruction that uses the ischial tuberosity and body as additional points of stabilization during the reconstruction of the posterior column. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lozano-Calderon, Santiago A.; Kaiser, Courtney L.; Osler, Polina M.; Raskin, Kevin A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Musculoskeletal Oncol Serv,Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. RP Lozano-Calderon, SA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Musculoskeletal Oncol Serv,Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. OI Kaiser, Courtney/0000-0002-1405-0442 NR 12 TC 0 Z9 0 U1 0 U2 0 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 2016 VL 31 IS 7 BP 1555 EP 1560 DI 10.1016/j.arth.2016.01.014 PG 6 WC Orthopedics SC Orthopedics GA DO8WL UT WOS:000378066000033 PM 26872586 ER PT J AU Nebergall, AK Freiberg, AA Greene, ME Malchau, H Muratoglu, O Rowell, S Zumbrunn, T Varadarajan, KM AF Nebergall, Audrey K. Freiberg, Andrew A. Greene, Meridith E. Malchau, Henrik Muratoglu, Orhun Rowell, Shannon Zumbrunn, Thomas Varadarajan, Kartik M. TI Analysis of Dual Mobility Liner Rim Damage Using Retrieved Components and Cadaver Models SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total hip arthroplasty; dual mobility; intraprosthetic dislocation; retrievals; cadavers ID TOTAL HIP-ARTHROPLASTY; INTRAPROSTHETIC DISLOCATION; RECURRENT DISLOCATION; PREVENT DISLOCATION; FEMORAL-HEAD; FOLLOW-UP; SOCKET; CUPS; THA; COMPLICATION AB Background: The objective of this study was to assess the retentive rim of retrieved dual mobility liners for visible evidence of deformation from femoral neck contact and to use cadaver models to determine if anterior soft tissue impingement could contribute to such deformation. Methods: Fifteen surgically retrieved polyethylene liners were assessed for evidence of rim deformation. The average time in vivo was 31.4 months, and all patients were revised for reasons other than intraprosthetic dislocation. Liner interaction with the iliopsoas was studied visually and with fluoroscopy in cadaver specimens using a dual mobility system different than the retrieval study. For fluoroscopic visualization, a metal wire was sutured to the iliopsoas and wires were also embedded into grooves on the outer surface of the liner and the inner head. Results: All retrievals showed evidence of femoral neck contact. The cadaver experiments showed that liner motion was impeded by impingement with the iliopsoas tendon in low flexion angles. When observing the hip during maximum hyperextension, 0 degrees, 15 degrees, and 30 degrees of flexion, there was noticeable tenting of the iliopsoas caused by impingement with the liner. Conclusion: Liner rim deformation resulting from contact with the femoral neck likely begins during early in vivo function. The presence of deformation is indicative of a mechanism inhibiting mobility of the liner. The cadaver studies showed that liner motion could be impeded because of its impingement with the iliopsoas. Such soft tissue impingement may be one mechanism by which liner motion is routinely inhibited, which can result in load transfer from the neck to the rim. (C) 2015 Elsevier Inc. All rights reserved. C1 [Nebergall, Audrey K.; Freiberg, Andrew A.; Greene, Meridith E.; Malchau, Henrik; Muratoglu, Orhun; Rowell, Shannon; Zumbrunn, Thomas; Varadarajan, Kartik M.] Massachusetts Gen Hosp, Dept Orthopaed, Harris Orthopaed Lab, 55 Fruit St, Boston, MA 02114 USA. RP Varadarajan, KM (reprint author), Massachusetts Gen Hosp, Dept Orthopaed, Harris Orthopaed Lab, 55 Fruit St, Boston, MA 02114 USA. NR 26 TC 2 Z9 2 U1 1 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 2016 VL 31 IS 7 BP 1595 EP 1602 DI 10.1016/j.arth.2015.12.032 PG 8 WC Orthopedics SC Orthopedics GA DO8WL UT WOS:000378066000040 PM 26796773 ER PT J AU Ge, L AF Ge, Liang TI A Characteristic-Based Constitutive Law for Dispersed Fibers SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article ID HUMAN CORONARY-ARTERIES; MECHANICAL-PROPERTIES; COLLAGENOUS TISSUES; WALL MECHANICS; MODEL; ORIENTATION; KINEMATICS; FRAMEWORK; ANEURYSMS; BEHAVIOR AB Biological tissues are typically constituted of dispersed fibers. Modeling the constitutive laws of such tissues remains a challenge. Direct integration over all fibers is considered to be accurate but requires very expensive numerical integration. A general structure tensor (GST) model was previously developed to bypass this costly numerical integration step, but there are concerns about the model's accuracy. Here we estimate the approximation error of the GST model. We further reveal that the GST model ignores strain energy induced by shearing motions. Subsequently, we propose a new characteristic-based constitutive law to better approximate the direct integration model. The new model is very cost-effective and closely approximates the "true" strain energy as calculated by the direct integration when stress-strain nonlinearity or fiber dispersion angle is small. C1 [Ge, Liang] Univ Calif San Francisco, Dept Surg, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. RP Ge, L (reprint author), Univ Calif San Francisco, Dept Surg, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. EM liang.ge@va.gov FU National Institutes of Health [R01 HL119857, HL063348, HL128278, HL118627] FX This work was supported by the National Institutes of Health (Grant Nos. R01 HL119857, HL063348, HL128278, and HL118627). NR 30 TC 0 Z9 0 U1 1 U2 2 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD JUL PY 2016 VL 138 IS 7 AR 071006-1 DI 10.1115/1.4033517 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DP1FV UT WOS:000378236800011 ER PT J AU Regan, MM Francis, PA Pagani, O Fleming, GF Walley, BA Viale, G Colleoni, M Lang, I Gomez, HL Tondini, C Pinotti, G Price, KN Coates, AS Goldhirsch, A Gelber, RD AF Regan, Meredith M. Francis, Prudence A. Pagani, Olivia Fleming, Gini F. Walley, Barbara A. Viale, Giuseppe Colleoni, Marco Lang, Istvan Gomez, Henry L. Tondini, Carlo Pinotti, Graziella Price, Karen N. Coates, Alan S. Goldhirsch, Aron Gelber, Richard D. TI Absolute Benefit of Adjuvant Endocrine Therapies for Premenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer: TEXT and SOFT Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTERNATIONAL EXPERT CONSENSUS; PATIENT-REPORTED OUTCOMES; OVARIAN SUPPRESSION; CLINICAL-TRIALS; TAMOXIFEN; EXEMESTANE; KI-67 AB Purpose Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer, testing exemestane plus ovarian function suppression (OFS), tamoxifen plus OFS, and tamoxifen alone. We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 (HER2) -negative disease. Patients and Methods The TEXT and SOFT hormone receptor-positive, HER2-negative analysis population included 4,891 women. The end point was breast cancer-free interval (BCFI), defined as time from random assignment to first occurrence of invasive locoregional, distant, or contralateral breast cancer. A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. Subpopulation treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk. Results SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone, reaching 10% to 15% at intermediate to high composite risk; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk. The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies. For TEXT patients, the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5% to 15%; patients not receiving chemotherapy and with lowest composite risk did well with both treatments. Conclusion Premenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk. (C) 2016 by American Society of Clinical Oncology C1 [Regan, Meredith M.; Gelber, Richard D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Price, Karen N.; Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Gelber, Richard D.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Francis, Prudence A.] Univ Melbourne, St Vincents Hosp, MacCallum Canc Ctr, Melbourne, Vic 3010, Australia. [Francis, Prudence A.] Univ Newcastle, Newcastle, NSW 2300, Australia. [Coates, Alan S.] Univ Sydney, Sydney, NSW 2006, Australia. [Pagani, Olivia] Inst Oncol Southern Switzerland, Lugano Viganello, Switzerland. [Fleming, Gini F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Walley, Barbara A.] Natl Canc Inst Canada Clin Trials Grp, Calgary, AB, Canada. [Viale, Giuseppe] Univ Milan, I-20122 Milan, Italy. [Viale, Giuseppe; Colleoni, Marco; Goldhirsch, Aron] European Inst Oncol, Milan, Italy. [Tondini, Carlo] Osped Papa Giovanni XXIII, Bergamo, Italy. [Pinotti, Graziella] Osped Circolo & Fdn Macchi, Varese, Italy. [Lang, Istvan] Natl Inst Oncol, Budapest, Hungary. [Gomez, Henry L.] Inst Nacl Enfermedades Neoplast, Lima, Peru. RP Regan, MM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Mailstop CLS 11007, Boston, MA 02215 USA. EM mregan@jimmy.harvard.edu FU NCI NIH HHS [U10 CA016116, N01 CA032102, U10 CA012027, U10 CA021115, U10 CA032102, U10 CA037377, U10 CA069651, U10 CA069974, U10 CA077202, U10 CA180821, U24 CA075362] NR 22 TC 9 Z9 10 U1 5 U2 8 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 JUL 1 PY 2016 VL 34 IS 19 BP 2221 EP + DI 10.1200/JCO.2015.64.3171 PG 13 WC Oncology SC Oncology GA DP6YW UT WOS:000378647000005 PM 27044936 ER PT J AU Henry, NL Somerfield, MR Abramson, VG Allison, KH Anders, CK Chingos, DT Hurria, A Openshaw, TH Krop, IE AF Henry, N. Lynn Somerfield, Mark R. Abramson, Vandana G. Allison, Kimberly H. Anders, Carey K. Chingos, Diana T. Hurria, Arti Openshaw, Thomas H. Krop, Ian E. TI Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: American Society of Clinical Oncology Endorsement of Cancer Care Ontario Guideline Recommendations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTERNATIONAL EXPERT CONSENSUS; CHEMOTHERAPY; VALIDATION; EXPRESSION; MANAGEMENT; RECEPTORS; TAMOXIFEN; ESTROGEN; WOMEN AB Purpose An American Society of Clinical Oncology (ASCO) panel considered the Cancer Care Ontario (CCO) recommendations on the role of patient and disease factors in selecting adjuvant therapy for women with early-stage breast cancer for endorsement. Methods ASCO staff reviewed the CCO guideline for methodologic rigor, and an ASCO panel of content experts reviewed the content of the recommendations. CCO Recommendations For making decisions regarding adjuvant therapy, nodal status, tumor size, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) status, tumor grade, and lymphovascular invasion are relevant; Oncotype DX score and Adjuvant! Online may be used as risk stratification tools; and age, menopausal status, and medical comorbidities should be considered. Chemotherapy should be considered for patients with positive lymph nodes, ER-negative disease, HER2-positive disease, Adjuvant! Online mortality greater than 10%, grade 3 lymph node-negative tumors (T > 5 mm), triple-negative (ER-negative, PgR-negative, HER2-negative) tumors, lymphovascular invasion positivity, or estimated distant relapse risk of greater than 15% at 10 years based on Oncotype DX recurrence score (RS). Chemotherapy may not be beneficial or required for small node-negative tumors (T < 5 mm) without high-risk features or for patients with HER2-negative, strongly ER-positive, and PgR-positive cancer with micrometastatic nodal disease, T less than 5 mm, or Oncotype DXRS with an estimated distant relapse risk of less than 15% at 10 years. ASCO Panel Conclusion The ASCO panel endorses the recommendations with minor suggested revisions and highlights three areas that warrant further consideration: tumor histology and adjuvant therapy recommendations, risk stratification tools and proposed Oncotype DX RS thresholds to guide decisions about chemotherapy, and patient factors in decision making. (C) 2016 by American Society of Clinical Oncology C1 [Somerfield, Mark R.] Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. [Henry, N. Lynn] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Abramson, Vandana G.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Chingos, Diana T.] Univ So Calif, Young Survival Coalit, Los Angeles, CA USA. [Hurria, Arti] City Hope Natl Med Ctr, Duarte, CA USA. [Anders, Carey K.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Openshaw, Thomas H.] Eastern Maine Med Ctr Canc Care, Brewer, ME USA. [Krop, Ian E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Henry, NL (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. NR 20 TC 6 Z9 6 U1 2 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2016 VL 34 IS 19 BP 2303 EP + DI 10.1200/JCO.2015.65.8609 PG 11 WC Oncology SC Oncology GA DP6YW UT WOS:000378647000015 PM 27001586 ER PT J AU Stockmann, JP Cooley, CZ Guerin, B Rosen, MS Wald, LL AF Stockmann, Jason P. Cooley, Clarissa Z. Guerin, Bastien Rosen, Matthew S. Wald, Lawrence L. TI Transmit Array Spatial Encoding (TRASE) using broadband WURST pulses for RF spatial encoding in inhomogeneous B-0 fields SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Transmit Array Spatial Encoding; Swept RF pulses; Low field imaging; Portable MRI; Quadratic phase modulation ID SINGLE-SCAN; SPIN-ECHO; NUCLEAR-RELAXATION; PHASE GRADIENTS; MAGNETIC-FIELD; IN-VIVO; MRI; NMR; EXCITATION; CPMG AB Transmit Array Spatial Encoding (TRASE) is a promising new MR encoding method that uses transmit RF (B-1(+)) phase gradients over the field-of-view to perform Fourier spatial encoding. Acquisitions use a spin echo train in which the transmit coil phase ramp is modulated to jump from one k-space point to the next. This work extends the capability of TRASE by using swept radiofrequency (RF) pulses and a quadratic phase removal method to enable TRASE where it is arguably most needed: portable imaging systems with inhomogeneous B-0 fields. The approach is particularly well-suited for portable MR scanners where (a) inhomogeneous B-0 fields are a byproduct of lightweight magnet design, (b) heavy, high power consumption gradient coil systems are a limitation to siting the system in non-conventional locations and (c) synergy with the use of spin echo trains is required to overcome intra-voxel dephasing (short T-2*) in the inhomogeneous field. TRASE does not use a modulation of the B-0 field to encode, but it does suffer from secondary effects of the inhomogeneous field. Severe artifacts arise in TRASE images due to off-resonance effects when the RF pulse does not cover the full bandwidth of spin resonances in the imaging FOV. Thus, for highly inhomogeneous B-0 fields, the peak RF power needed for high-bandwidth refocusing hard pulses becomes very expensive, in addition to requiring RF coils that can withstand thousands of volts. In this work, we use swept WURST RF pulse echo trains to achieve TRASE imaging in a highly inhomogeneous magnetic field (Delta B-0/B-0 similar to 0.33% over the sample). By accurately exciting and refocusing the full bandwidth of spins, the WURST pulses eliminate artifacts caused by the limited bandwidth of the hard pulses used in previous realizations of TRASE imaging. We introduce a correction scheme to remove the unwanted quadratic phase modulation caused by the swept pulses. Also, a phase alternation scheme is employed to mitigate artifacts caused by mixture of the even and odd-echo coherence pathways due to defects in the refocusing pulse. In this paper, we describe this needed methodology and demonstrate the ability of TRASE to Fourier encode in an inhomogeneous field (Delta B-0/B-0 similar to 1% over the full FOV). (C) 2016 Elsevier Inc. All rights reserved. C1 [Stockmann, Jason P.; Cooley, Clarissa Z.; Guerin, Bastien; Rosen, Matthew S.; Wald, Lawrence L.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. [Rosen, Matthew S.] Harvard Univ, Dept Phys, Cambridge, MA 02141 USA. [Guerin, Bastien; Rosen, Matthew S.; Wald, Lawrence L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Stockmann, JP (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM jaystock@nmr.mgh.harvard.edu RI Wald, Lawrence/D-4151-2009 FU NIH [R01EB018976, K99 EB019482]; DoD/USAMRRA [W81XWH-11-2-0076 (DM09094)] FX The authors thank Jonathan Sharp, Scott King, Michael Garwood, Robin de Graaf, Soumyajit Mandal, and Mathieu Sarracanie for illuminating discussions, and Lina Colucci for help with relaxation measurements. We also thank the anonymous reviewers of this work for their many helpful insights and suggestions. Support comes from NIH R01EB018976, K99 EB019482 and DoD/USAMRRA W81XWH-11-2-0076 (DM09094). NR 54 TC 1 Z9 1 U1 6 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2016 VL 268 BP 36 EP 48 DI 10.1016/j.jmr.2016.04.005 PG 13 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA DP0NG UT WOS:000378185900005 PM 27155906 ER PT J AU Garrett, GL Lowenstein, SE Singer, JP He, SY Arron, ST AF Garrett, Giorgia L. Lowenstein, Stefan E. Singer, Jonathan P. He, Steven Y. Arron, Sarah T. TI Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013 SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE cause of death; cutaneous carcinoma; iatrogenic immunosuppression; mortality outcomes; nonmelanoma skin cancer; organ transplant recipients; rate; solid organ transplantation ID RISK-FACTORS; KIDNEY-TRANSPLANTATION; ORGAN-TRANSPLANTATION; HEART-TRANSPLANT; CELL-CARCINOMA; RECIPIENTS; SURVIVAL; THERAPY; DEATH AB Background: Solid organ transplant recipients are at increased risk of skin cancer, but population-based mortality data are limited. Objective: Mortality and predictors of skin cancer death posttransplantation were investigated. Methods: All US organ transplant recipients between 1987 and 2013, identified through the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research file, were included. Mortality and hazard ratios (HR) were calculated for the overall population and patient subgroups. Results: The overall mortality was 5308 per 100,000 person-years and the skin cancer-specific mortality was 35.27 per 100,000 person-years. Risk factors associated with skin cancer death included thoracic versus abdominal transplantation (HR 2.90, 95% confidence interval [CI] 2.52-3.34), age over 50 years (HR 2.86, CI 2.43-3.38), white race (HR 6.29, CI 4.63-8.53), and male sex (HR 1.85, CI 1.57-2.19). Mortality was highest for malignant melanoma (mortality of 11.48), followed by squamous cell carcinoma (mortality of 4.94) and Merkel cell carcinoma (mortality of 4.59). Limitations: Limitations of this study included potential underreporting and misclassification of death from skin cancer in the data set. Conclusion: Mortality from posttransplantation skin cancer is reported. Older patients, male patients, white patients, and thoracic transplant recipients had increased mortality from skin cancer. C1 [Garrett, Giorgia L.; Arron, Sarah T.] Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St, San Francisco, CA 94143 USA. [Singer, Jonathan P.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Lowenstein, Stefan E.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [He, Steven Y.] Harvard Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. RP Arron, ST (reprint author), Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St, San Francisco, CA 94143 USA. EM Arrons@derm.ucsf.edu RI bebarta, vikhyat/K-3476-2015 FU American Academy of Dermatology Transplant Skin Cancer Network; Galderma FX Drs Arron and Garrett are funded by the American Academy of Dermatology Transplant Skin Cancer Network. Dr Garrett was funded by an unrestricted fellowship award from Galderma. NR 27 TC 1 Z9 1 U1 1 U2 3 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 2016 VL 75 IS 1 BP 106 EP 112 DI 10.1016/j.jaad.2016.02.1155 PG 7 WC Dermatology SC Dermatology GA DO9GN UT WOS:000378093300029 PM 27067869 ER PT J AU Aldridge, MD Epstein, AJ Brody, AA Lee, EJ Cherlin, E Bradley, EH AF Aldridge, Melissa D. Epstein, Andrew J. Brody, Abraham A. Lee, Eric J. Cherlin, Emily Bradley, Elizabeth H. TI The Impact of Reported Hospice Preferred Practices on Hospital Utilization at the End of Life SO MEDICAL CARE LA English DT Article DE end of life care; hospice preferred practices; end of life hospitalization; transitions; end of life intensity; hospice ID OF-LIFE; UNITED-STATES; PROFIT STATUS; FOR-PROFIT; CARE; CANCER; MEDICARE; HEALTH; PLACE; INTENSITY AB Background: The Affordable Care Act requires hospices to report quality measures across a range of processes and practices. Yet uncertainties exist regarding the impact of hospice preferred practices on patient outcomes. Objective: Assess the impact of 6 hospice preferred practices and hospice organizational characteristics on hospital utilization and death using the first national data on hospice preferred practices. Design: Longitudinal cohort study (2008-2011) of Medicare beneficiaries (N = 149,814) newly enrolled in a national random sample of hospices (N = 577) from the National Hospice Survey (84% response rate) and followed until death. Outcome Measures: The proportion of patients at each hospice admitted to the hospital, emergency department (ED), and intensive care unit (ICU), and who died in the hospital after hospice enrollment. Results: Hospices that reported assessing patient preferences for site of death at admission had lower odds of being in the highest quartile for hospital death (AOR = 0.36; 95% CI, 0.14-0.93) and ED visits (AOR = 0.27; 95% CI, 0.10-0.76). Hospices that reported more frequently monitoring symptoms had lower odds of being in the highest quartile for ICU stays (AOR = 0.48; 95% CI, 0.24-0.94). In adjusted analyses, a higher proportion of patients at for-profit compared with nonprofit hospices experienced a hospital admission (15.3% vs. 10.9%, P < 0.001), ED visit (21.8% vs. 15.6%, P < 0.001), and ICU stay (5.1% vs. 3.0%, P < 0.001). Conclusions: Hospitalization of patients following hospice enrollment varies substantially across hospices. Two of the 6 preferred practices examined were associated with hospitalization rates and for-profit hospices had persistently high hospitalization rates regardless of preferred practice implementation. C1 [Aldridge, Melissa D.; Lee, Eric J.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, One Gustave L Levy Pl,POB 1070, New York, NY 10029 USA. [Aldridge, Melissa D.; Brody, Abraham A.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Epstein, Andrew J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Brody, Abraham A.] NYU, Coll Nursing, New York, NY USA. [Cherlin, Emily; Bradley, Elizabeth H.] Yale Univ, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, New Haven, CT 06520 USA. RP Aldridge, MD (reprint author), Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, One Gustave L Levy Pl,POB 1070, New York, NY 10029 USA. EM melissa.aldridge@mssm.edu OI Brody, Abraham/0000-0002-3405-7043 FU National Institute of Nursing Research [5R01NR013499]; National Cancer Institute [1R01CA116398-01A2]; John D. Thompson Foundation FX Supported by the National Institute of Nursing Research 5R01NR013499 (M.D.A.), the National Cancer Institute 1R01CA116398-01A2 (E.B.), and the John D. Thompson Foundation (E.B.). NR 36 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2016 VL 54 IS 7 BP 657 EP 663 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DO8UW UT WOS:000378061000004 PM 27299952 ER PT J AU Wang, SY Aldridge, MD Gross, CP Canavan, M Cherlin, E Johnson-Hurzeler, R Bradley, E AF Wang, Shi-Yi Aldridge, Melissa D. Gross, Cary P. Canavan, Maureen Cherlin, Emily Johnson-Hurzeler, Rosemary Bradley, Elizabeth TI End-of-Life Care Intensity and Hospice Use A Regional-level Analysis SO MEDICAL CARE LA English DT Article DE Medicare hospice benefit; health services research; geographic variation; end-of-life care ID MEDICARE BENEFICIARIES; LAST YEAR; HEALTH; DEATH; PATTERNS; FAMILIES; PAYMENTS; QUALITY; CANCER; TRENDS AB Objectives: Despite increased hospice use over the last decade, end-of-life care intensity continues to increase. To understand this puzzle, we sought to examine regional variation in intensive end-of life care and determine its associations with hospice use patterns. Methods: Using Medicare claims for decedents aged 66 years and above in 2011, we assessed end-of-life care intensity in the last 6 months of life across hospital referral regions (HRRs) as measured by proportion of decedents per HRR experiencing hospitalization, emergency department use, intensive care unit (ICU) admission, and number of days spent in hospital (hospital-days) and ICU (ICU days). Using hierarchical generalized linear models and adjusting for patient characteristics, we examined whether these measures were associated with overall hospice use, very short (<7 d), medium (8-179 d), or very long (> 180 d) hospice enrollment, focusing on very short stay. Results: End-of-life care intensity and hospice use patterns varied substantially across HRRs. Regional-level end-of-life care intensity was positively correlated with very short hospice enrollment. Comparing HRRs in the highest versus the lowest quintiles of intensity in end-of-life care, regions with more intensive care had higher rates of very short hospice enrollment, with adjusted odds ratios (AOR) 1.14 [99% confidence interval (CI), 1.04-1.25] for hospitalization; AOR, 1.23 (CI, 1.12-1.36) for emergency department use; AOR, 1.25 (CI, 1.14-1.38) for ICU admission; AOR, 1.10 (CI, 1.00-1.21) for hospital -days; and AOR, 1.20 (CI, 1.08-1.32) for ICU-days. Conclusions: At the regional level, increased end-of-life care intensity was consistently associated with very short hospice use. C1 [Wang, Shi-Yi] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, 60 Coll St, New Haven, CT 06520 USA. [Wang, Shi-Yi; Gross, Cary P.] Yale Canc Ctr, Canc Outcomes Publ Policy & Effectiveness Res COP, New Haven, CT USA. [Wang, Shi-Yi; Gross, Cary P.] Yale Univ, Sch Med, 60 Coll St, New Haven, CT 06520 USA. [Aldridge, Melissa D.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Aldridge, Melissa D.] James J Peters VA Med Ctr, Bronx, NY USA. [Gross, Cary P.] Yale Univ, Sch Med, Dept Internal Med, Sect Gen Internal Med, 60 Coll St, New Haven, CT 06520 USA. [Canavan, Maureen; Cherlin, Emily; Bradley, Elizabeth] Yale Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 60 Coll St, New Haven, CT 06520 USA. [Johnson-Hurzeler, Rosemary] John D Thompson Hosp Inst Educ Training & Res Inc, Branford, CT USA. RP Wang, SY (reprint author), Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, 60 Coll St, New Haven, CT 06520 USA. EM shiyi.wang@yale.edu FU National Cancer Institute [1R01CA116398-01A2]; John D. Thompson Foundation; National Institute of Nursing Research [1R01NR013499-01A1]; Agency for Healthcare Research and Quality [1K01HS023900-01] FX Supported by grant 1R01CA116398-01A2 from the National Cancer Institute (M.D.A. and E.B.); the John D. Thompson Foundation (E.B.); grant 1R01NR013499-01A1 from the National Institute of Nursing Research (M.D.A.); and grant 1K01HS023900-01 from the Agency for Healthcare Research and Quality (S.-Y.W.). These sources of support were not used for any portion of the current manuscript. NR 20 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2016 VL 54 IS 7 BP 672 EP 678 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DO8UW UT WOS:000378061000006 PM 27111747 ER PT J AU Lo-Ciganic, WH Gellad, WF Huskamp, HA Choudhry, NK Chang, CCH Zhang, R Jones, BL Guclu, H Richards-Shubik, S Donohue, JM AF Lo-Ciganic, Wei-Hsuan Gellad, Walid F. Huskamp, Haiden A. Choudhry, Niteesh K. Chang, Chung-Chou H. Zhang, Ruoxin Jones, Bobby L. Guclu, Hasan Richards-Shubik, Seth Donohue, Julie M. TI Who Were the Early Adopters of Dabigatran? An Application of Group-based Trajectory Models SO MEDICAL CARE LA English DT Article DE anticoagulants; direct thrombin inhibitor; physician prescribing behavior; dabigatran; group-based trajectory models ID NONVALVULAR ATRIAL-FIBRILLATION; GENERAL-PRACTITIONERS; ORAL ANTICOAGULANTS; UNITED-STATES; RISK-FACTORS; DRUGS; PHYSICIAN; ADOPTION; WARFARIN; PATIENT AB Background: Variation in physician adoption of new medications is poorly understood. Traditional approaches (eg, measuring time to first prescription) may mask substantial heterogeneity in technology adoption. Objective: Apply group-based trajectory models to examine the physician adoption of dabigratran, a novel anticoagulant. Methods: A retrospective cohort study using prescribing data from IMS Xponenem on all Pennsylvania physicians regularly prescribing anticoagulants (n=3911) and data on their characteristics from the American Medical Association Masterfile. We examined time to first dabigatran prescription and group-based trajectory models to identify adoption trajectories in the first 15 months. Factors associated with rapid adoption were examined using multivariate logistic regressions. Outcomes: Trajectories of monthly share of oral anticoagulant prescriptions for dabigatran. Results: We identified 5 distinct adoption trajectories: 3.7% rapidly and extensively adopted dabigatran (adopting in <3 mo with 45% of prescriptions) and 13.4% were rapid and moderate adopters (< 3 mo with 20% share). Two groups accounting for 21.6% and 16.1% of physicians, respectively, were slower to adopt (6-10 mo post-introduction) and dabigatran accounted for <10% share. Nearly half (45.2%) of anticoagulant prescribers did not adopt dabigatran. Cardiologists were much more likely than primary care physicians to rapidly adopt [odds ratio (OR) = 12.2; 95% confidence interval (CI), 9.27-16.1] as were younger prescribers (age 36-45 y: OR= 1.49, 95% CI, 1.13-1.95; age 46-55: OR = 1.34, 95% CI, 1.07-1.69 vs. >55 y). Conclusions: Trajectories of physician adoption of dabigatran were highly variable with significant differences across specialties. Heterogeneity in physician adoption has potential implications for the cost and effectiveness of treatment. C1 [Lo-Ciganic, Wei-Hsuan] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Drachman Hall Room B307E,1295N Martin Ave, Tucson, AZ 85719 USA. [Lo-Ciganic, Wei-Hsuan; Gellad, Walid F.; Donohue, Julie M.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Hlth Policy Inst, Pittsburgh, PA 15260 USA. [Gellad, Walid F.; Chang, Chung-Chou H.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. [Gellad, Walid F.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Huskamp, Haiden A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Choudhry, Niteesh K.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Choudhry, Niteesh K.] Harvard Univ, Sch Med, Boston, MA USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Zhang, Ruoxin; Guclu, Hasan] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15261 USA. [Jones, Bobby L.] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Guclu, Hasan] Istanbul Medeniyet Univ, Stat Dept, Istanbul, Turkey. [Richards-Shubik, Seth] Lehigh Univ, Coll Business & Econ, Dept Econ, Bethlehem, PA 18015 USA. RP Lo-Ciganic, WH (reprint author), Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Drachman Hall Room B307E,1295N Martin Ave, Tucson, AZ 85719 USA. EM lociganic@pharmacy.arizona.edu FU National Heart, Lung, and Blood Institute [R01HL119246]; University of Pittsburgh Health Policy Institute, Center for Pharmaceutical Policy and Prescribing FX Supported by National Heart, Lung, and Blood Institute (R01HL119246). W.-H.L.-C. was funded by a post-doctoral fellowship through the University of Pittsburgh Health Policy Institute, Center for Pharmaceutical Policy and Prescribing. NR 49 TC 1 Z9 1 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2016 VL 54 IS 7 BP 725 EP 732 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DO8UW UT WOS:000378061000013 PM 27116109 ER PT J AU Tsai, TY Dimitriou, D Hosseini, A Liow, MHL Torriani, M Li, GA Kwon, YM AF Tsai, Tsung-Yuan Dimitriou, Dimitris Hosseini, Ali Liow, Ming Han Lincoln Torriani, Martin Li, Guoan Kwon, Young-Min TI Assessment of accuracy and precision of 3D reconstruction of unicompartmental knee arthroplasty in upright position using biplanar radiography SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE Unicompartmental knee arthroplasty; Component position; Biplanar radiograph; Lower limb alignment ID COMPUTED-TOMOGRAPHY; POLYETHYLENE WEAR; EARLY FAILURE; IN-VIVO; SYSTEM; ALIGNMENT; REPLACEMENT; KINEMATICS; TORSION AB This study aimed to evaluate the precision and accuracy of 3D reconstruction of UKA component position, contact location and lower limb alignment in standing position using biplanar radiograph. Two human specimens with 4 medial UKAs were implanted with beads for radiostereometric analysis (RSA). The specimens were frozen in standing position and CT-scanned to obtain relative positions between the beads, bones and UKA components. The specimens were then imaged using biplanar radiograph (EOS). The positions of the femur, tibia, UKA components and UKA contact locations were obtained using RSA and EOS-based techniques. Intraclass correlation coefficient (ICC) was calculated for inter-observer reliability of the EOS technique. The average (standard deviation) of the differences between two techniques in translations and rotations were less than 0.18 (0.29) mm and 0.39 degrees (0.66 degrees) for UKA components. The root-mean-square-errors (RMSE) of contact location along the anterior/posterior and medial/lateral directions were 0.84 mm and 0.30 mm. The RMSEs of the knee rotations were less than 1.70 degrees. The ICCs for the EOS-based segmental orientations between two raters were larger than 0.98. The results suggest the EOS-based 3D reconstruction technique can precisely determine component position, contact location and lower limb alignment for UKA patients in weight-bearing standing position. (c) 2016 IPEM. C1 [Tsai, Tsung-Yuan; Dimitriou, Dimitris; Hosseini, Ali; Liow, Ming Han Lincoln; Torriani, Martin; Li, Guoan; Kwon, Young-Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. EM YMKWON@mgh.harvard.edu OI Dimitriou, Dimitris/0000-0002-9558-7080; LIOW, MING HAN LINCOLN/0000-0002-4496-8035 NR 28 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 EI 1873-4030 J9 MED ENG PHYS JI Med. Eng. Phys. PD JUL PY 2016 VL 38 IS 7 BP 633 EP 638 DI 10.1016/j.medengphy.2016.04.002 PG 6 WC Engineering, Biomedical SC Engineering GA DP3AH UT WOS:000378364300005 PM 27117422 ER PT J AU Tan, Y Ren, HX Shi, Z Yao, XL He, CW Kang, JX Wan, JB Li, P Yuan, TF Su, HX AF Tan, Yuan Ren, Huixia Shi, Zhe Yao, Xiaoli He, Chengwei Kang, Jing-X Wan, Jian-Bo Li, Peng Yuan, Ti-Fei Su, Huanxing TI Endogenous Docosahexaenoic Acid (DHA) Prevents A beta 1-42 Oligomer-Induced Neuronal Injury SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Alzheimer's disease; A beta oligomers; DHA; Omega-3; Fat-1 mice ID N-3 FATTY-ACIDS; ALZHEIMERS-DISEASE; COGNITIVE DECLINE; BRAIN; TRIAL; RISK; FISH; SUPPLEMENTATION; OMEGA-3-FATTY-ACIDS; PHOSPHOLIPIDS AB The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) or n-3 fatty acid has been associated with reduced risk of Alzheimer's disease (AD) in epidemiological reports. However, the underlying mechanism remains to be elucidated. Here, we report that exogenous DHA administration could protect neurons against A beta oligomer-induced injury both in vitro and in vivo, partly through reducing the endoplasmic reticulum (ER) stress, and preventing cell apoptosis. In transgenic fat-1 mice with enriched omega-3 fatty acids, A beta oligomers induced fewer neuronal losses, when compared to wild-type (WT) mice. We conclude that endogenous DHA are neuroprotective in pathogenesis processes of AD. C1 [Tan, Yuan; Ren, Huixia; Shi, Zhe; He, Chengwei; Wan, Jian-Bo; Li, Peng; Su, Huanxing] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Peoples R China. [Yao, Xiaoli] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Neurol, Natl Key Clin Dept & Key Discipline Neurol, Guangzhou 510080, Guangdong, Peoples R China. [Kang, Jing-X] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02114 USA. [Kang, Jing-X] Harvard Univ, Sch Med, Boston, MA USA. [Yuan, Ti-Fei] Nanjing Normal Univ, Sch Psychol, Nanjing 210097, Jiangsu, Peoples R China. RP Su, HX (reprint author), Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Peoples R China.; Yuan, TF (reprint author), Nanjing Normal Univ, Sch Psychol, Nanjing 210097, Jiangsu, Peoples R China. EM ytf0707@126.com; huanxingsu@umac.mo RI Wan, Jian-Bo/D-8368-2014 OI Wan, Jian-Bo/0000-0002-6750-2617 FU Macao Science and Technology Development Fund [018/2013/A1]; university of Macau [MYRG122 (Y1-L3)-ICMS12-SHX, MYRG110 (Y1-L2)-ICMS13-SHX]; Hundred Talents program; "Qing Lan Project" of Nanjing Normal University; Jiangsu Provincial Natural Science Foundation [BK20140917]; [MRG003/SHX/2014/ICMS] FX This study is supported by the Macao Science and Technology Development Fund (018/2013/A1), matching grant project MRG003/SHX/2014/ICMS, and multi-year research grant, university of Macau, MYRG122 (Y1-L3)-ICMS12-SHX and MYRG110 (Y1-L2)-ICMS13-SHX (H.S.). The study is also supported by "Hundred Talents program," "Qing Lan Project" of Nanjing Normal University, and Jiangsu Provincial Natural Science Foundation (No. BK20140917) (T-F.Y.). NR 29 TC 2 Z9 2 U1 3 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD JUL PY 2016 VL 53 IS 5 BP 3146 EP 3153 DI 10.1007/s12035-015-9224-0 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DO7AU UT WOS:000377935400036 PM 26021747 ER PT J AU Yu, ZY Zhang, Y Liu, N Yuan, J Lin, L Zhuge, QC Xiao, J Wang, XY AF Yu, Zhanyang Zhang, Yu Liu, Ning Yuan, Jing Lin, Li Zhuge, Qichuan Xiao, Jian Wang, Xiaoying TI Roles of Neuroglobin Binding to Mitochondrial Complex III Subunit Cytochrome c1 in Oxygen-Glucose Deprivation-Induced Neurotoxicity in Primary Neurons SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Neuroglobin; Complex III; Cytochrome c1; Primary neurons; Oxygen-glucose deprivation; Superoxide anion ID MOUSE CORTICAL-NEURONS; ENDOGENOUS NEUROPROTECTANT; SPECIES GENERATION; CULTURED NEURONS; ROS PRODUCTION; NITRIC-OXIDE; CELL-DEATH; IN-VIVO; MECHANISMS; BRAIN AB Neuroglobin (Ngb) is a tissue globin specifically expressed in brain neurons. Recent studies by our laboratory and others have demonstrated that Ngb is protective against stroke and related neurological disorders, but the mechanisms remain poorly understood. We previously identified cytochrome c1 (Cyc1) as an Ngb-interacting molecule by yeast two-hybrid screening. Cyc1 is a subunit of mitochondria complex III, which is a component of mitochondrial respiratory chain and a major source of reactive oxygen species (ROS) production under both physiological and pathological conditions. In this study, we for the first time defined Ngb-Cyc1 binding, and investigated its roles in oxygen-glucose deprivation (OGD)/reoxygenation-induced neurotoxicity and ROS production in primary neurons. Immunocytochemistry and co-immunoprecipitation validated Ngb-Cyc1 binding, which was significantly increased by OGD and Ngb overexpression. We found 4 h OGD with/without 4 h reoxygenation significantly increased complex III activity, but this activity elevation was significantly attenuated in three groups of neurons: Ngb overexpression, specific complex III inhibitor stigmatellin, or stigmatellin plus Ngb overexpression, whereas there was no significant differences between these three groups, suggesting Ngb-Cyc1 binding may function in suppressing OGD-mediated complex III activity elevation. Importantly, these three groups of neurons also showed significant decreases in OGD-induced superoxide anion generation and neurotoxicity. These results suggest that Ngb can bind to mitochondrial complex III subunit Cyc1, leading to suppression of OGD-mediated complex III activity and subsequent ROS production elevation, and eventually reduction of OGD-induced neurotoxicity. This molecular signaling cascade may be at least part of the mechanisms of Ngb neuroprotection against OGD-induced neurotoxicity. C1 [Yu, Zhanyang; Zhang, Yu; Lin, Li; Zhuge, Qichuan; Xiao, Jian] Wenzhou Med Univ, Dept Neurosurg, Coll Pharm, Affiliated Hosp 1, Wenzhou 325000, Zhejiang, Peoples R China. [Liu, Ning; Yuan, Jing] Hunan Normal Univ, Key Lab Prot Biochem & Dev Biol, State Educ Minist, Coll Life Sci, Changsha 410081, Hunan, Peoples R China. [Yu, Zhanyang; Yuan, Jing; Wang, Xiaoying] Harvard Univ, Sch Med, Neuroprotect Res Lab, Dept Neurol, 149 13th St,Room 2411A, Charlestown, MA 02129 USA. [Yu, Zhanyang; Yuan, Jing; Wang, Xiaoying] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 149 13th St,Room 2411A, Charlestown, MA 02129 USA. [Yu, Zhanyang; Yuan, Jing; Wang, Xiaoying] Harvard Univ, Sch Med, Program Neurosci, 149 13th St,Room 2411A, Charlestown, MA 02129 USA. RP Yu, ZY (reprint author), Wenzhou Med Univ, Dept Neurosurg, Coll Pharm, Affiliated Hosp 1, Wenzhou 325000, Zhejiang, Peoples R China.; Yu, ZY; Wang, XY (reprint author), Harvard Univ, Sch Med, Neuroprotect Res Lab, Dept Neurol, 149 13th St,Room 2411A, Charlestown, MA 02129 USA.; Yu, ZY; Wang, XY (reprint author), Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 149 13th St,Room 2411A, Charlestown, MA 02129 USA.; Yu, ZY; Wang, XY (reprint author), Harvard Univ, Sch Med, Program Neurosci, 149 13th St,Room 2411A, Charlestown, MA 02129 USA. EM yuzywzmu@126.com; wangxi@helix.mgh.harvard.edu FU National Natural Science Foundation of China [81371351]; NIH [R01-NS049476] FX This work was in part supported by National Natural Science Foundation of China grant 81371351 to Z.Y. and NIH grants R01-NS049476 to X.W. NR 45 TC 2 Z9 2 U1 4 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD JUL PY 2016 VL 53 IS 5 BP 3249 EP 3257 DI 10.1007/s12035-015-9273-4 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DO7AU UT WOS:000377935400045 PM 26050086 ER PT J AU Subramaniam, R Mukherjee, S Chen, H Keshava, S Neuenschwander, P Shams, H AF Subramaniam, R. Mukherjee, S. Chen, H. Keshava, S. Neuenschwander, P. Shams, H. TI Restoring cigarette smoke-induced impairment of efferocytosis in alveolar macrophages SO MUCOSAL IMMUNOLOGY LA English DT Article ID INGESTED APOPTOTIC CELLS; GM-CSF; EPIDEMIC INFLUENZA; LUNG INFLAMMATION; PHAGOCYTOSIS; RECEPTOR; RESOLUTION; ENGULFMENT; CLEARANCE; ENDOSOMES AB Cigarette smoke has been associated with susceptibility to different pulmonary and airway diseases. Impaired alveolar macrophages (AMs) that are major phagocytes in the lung have been associated with patients with airway diseases and active smokers. In the current report, we show that exposure to second-hand cigarette smoke (SHS) significantly reduced efferocytosis in vivo. More importantly, delivery of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to the alveolar space restored and refurbished the efferocytosis capability of AMs. Exposure to SHS significantly reduced expression of CD16/32 on AMs, and treatment with GM-CSF not only restored but also significantly increased the expression of CD16/32 on AMs. GM-CSF treatment increased uptake and digestion/removal of apoptotic cells by AMs. The latter was attributed to increased expression of Rab5 and Rab7. Increased efferocytosis of AMs was also tested in a disease condition. AMs from GM-CSF-treated, influenza-infected, SHS-exposed mice showed significantly better efferocytosis activity, and mice had significantly less morbidity compared with phosphate-buffered saline-treated group. GM-CSF-treated mice had increased amphiregulin levels in the lungs, which in addition to efferocytosis of AMs may have attributed to their protection against influenza. These results will have great implications for developing therapeutic approaches by harnessing mucosal innate immunity to treat lung and airway diseases and protect against pneumonia. C1 [Subramaniam, R.; Mukherjee, S.; Chen, H.; Shams, H.] Univ Texas Hlth Sci Ctr Tyler, CPIDC, Tyler, TX 75708 USA. [Keshava, S.] Univ Texas Hlth Sci Ctr Tyler, Dept Cellular & Mol Biol, Tyler, TX 75708 USA. [Neuenschwander, P.] Univ Texas Hlth Sci Ctr Tyler, Biomed Res, Tyler, TX 75708 USA. [Subramaniam, R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Subramaniam, R.] Harvard Univ, Sch Med, Boston, MA USA. RP Shams, H (reprint author), Univ Texas Hlth Sci Ctr Tyler, CPIDC, Tyler, TX 75708 USA. EM homayoun.shams@uthct.edu FU Flight Attendant Medical Research Institute [092015, 123020] FX We thank Dr Tvinnereim for her assistance in CT scanning and our vivarium staff for animal studies. This work was, in part, supported by grants to H.S. from the Flight Attendant Medical Research Institute (092015-Clinical Innovator Award and 123020-Clinical Innovator Award). NR 49 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 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2016 VL 9 IS 4 BP 873 EP 883 DI 10.1038/mi.2015.120 PG 11 WC Immunology SC Immunology GA DP2TW UT WOS:000378346800004 PM 26577570 ER PT J AU Renvall, V Witzel, T Wald, LL Polimeni, JR AF Renvall, Ville Witzel, Thomas Wald, Lawrence L. Polimeni, Jonathan R. TI Automatic cortical surface reconstruction of high-resolution T-1 echo planar imaging data SO NEUROIMAGE LA English DT Article DE fMRI registration; Tissue segmentation; Inversion recovery; Functional MRI; FreeSurfer; Surface-based analysis ID MAGNETIZATION-TRANSFER CONTRAST; HUMAN CEREBRAL-CORTEX; IN-VIVO; DISTORTION CORRECTION; GEOMETRIC DISTORTION; BRAIN IMAGES; SENSORY STIMULATION; 7 T; EPI; REGISTRATION AB Echo planar imaging (EPI) is the method of choice for the majority of functional magnetic resonance imaging ( fMRI), yet EPI is prone to geometric distortions and thus misaligns with conventional anatomical reference data. The poor geometric correspondence between functional and anatomical data can lead to severe misplacements and corruption of detected activation patterns. However, recent advances in imaging technology have provided EPI data with increasing quality and resolution. Here we present a framework for deriving cortical surface reconstructions directly from high-resolution EPI-based reference images that provide anatomical models exactly geometric distortion-matched to the functional data. Anatomical EPI data with 1 mm isotropic voxel size were acquired using a fast multiple inversion recovery time EPI sequence (MI-EPI) at 7 T, from which quantitative T-1 maps were calculated. Using these T1 maps, volumetric data mimicking the tissue contrast of standard anatomical data were synthesized using the Bloch equations, and these T-1-weighted data were automatically processed using FreeSurfer. The spatial alignment between T-2(*)-weighted EPI data and the synthetic T-1-weighted anatomical MI-EPI-based images was improved compared to the conventional anatomical reference. In particular, the alignment near the regions vulnerable to distortion due to magnetic susceptibility differences was improved, and sampling of the adjacent tissue classes outside of the cortex was reduced when using cortical surface reconstructions derived directly from the MI-EPI reference. The MI-EPI method therefore produces high-quality anatomical data that can be automatically segmented with standard software, providing cortical surface reconstructions that are geometrically matched to the BOLD fMRI data. (C) 2016 Elsevier Inc. All rights reserved. C1 [Renvall, Ville; Witzel, Thomas; Wald, Lawrence L.; Polimeni, Jonathan R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Renvall, Ville] Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, Espoo, Finland. [Renvall, Ville; Witzel, Thomas; Wald, Lawrence L.; Polimeni, Jonathan R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wald, Lawrence L.; Polimeni, Jonathan R.] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Renvall, V (reprint author), Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, Espoo, Finland. EM ville.renvall@aalto.fi RI Wald, Lawrence/D-4151-2009; Renvall, Ville/M-4165-2013 OI Renvall, Ville/0000-0002-4070-7030 FU NIH National Institute for Biomedical Imaging and Bioengineering [P41-EB015896, K01-EB011498, R01-EB019437]; Finnish Cultural Foundation Kalle and Dagmar Valimaa Fund; Swedish Cultural Foundation in Finland [11/7793-1166]; Instrumentarium Science Foundation; Academy of Finland [265917]; Athinoula A. Martinos Center for Biomedical Imaging; [S10-RR023401]; [S10-RR023043]; [S10-RR019371]; [S10-RR020948] FX We wish to thank Dr. Himanshu Bhat and Prof. Bruce Fischl for helpful discussions. Support for this research was provided in part by the NIH National Institute for Biomedical Imaging and Bioengineering (P41-EB015896, K01-EB011498, and R01-EB019437), Finnish Cultural Foundation Kalle and Dagmar Valimaa Fund, Swedish Cultural Foundation in Finland (11/7793-1166), Instrumentarium Science Foundation, and the Academy of Finland (grant #265917), and was made possible by the resources provided by Shared Instrumentation Grants S10-RR023401, S10-RR023043, S10-RR019371, and S10-RR020948 as well as the Athinoula A. Martinos Center for Biomedical Imaging. Some of the analysis scripts used in this work were developed by FBIRN (www.nbirn.net). Preliminary accounts of this work have been presented in the annual meetings of the International Society of Magnetic Resonance in Medicine (Renvall et al., 2014c) and the Organization for Human Brain Mapping (Renvall et al., 2014b). NR 74 TC 1 Z9 1 U1 3 U2 8 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 2016 VL 134 BP 338 EP 354 DI 10.1016/j.neuroimage.2016.04.004 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8PP UT WOS:000378045900033 PM 27079529 ER PT J AU Konukoglu, E Coutu, JP Salat, DH Fischl, B AF Konukoglu, Ender Coutu, Jean-Philippe Salat, David H. Fischl, Bruce CA ADNI TI Multivariate statistical analysis of diffusion imaging parameters using partial least squares: Application to white matter variations in Alzheimer's disease SO NEUROIMAGE LA English DT Article DE Multivariate analysis; Alzheimer's disease; Partial least squares; Diffusion tensor imaging ID MILD COGNITIVE IMPAIRMENT; INDEPENDENT COMPONENT ANALYSIS; MULTIMODAL FUSION; TRACT INTEGRITY; DISCRIMINATING SCHIZOPHRENIA; FRONTOTEMPORAL DEMENTIA; CONNECTIVITY NETWORKS; SPATIAL STATISTICS; RADIAL DIFFUSIVITY; VOXELWISE ANALYSIS AB Diffusion magnetic resonance imaging (dMRI) is a unique technology that allows the noninvasive quantification of microstructural tissue properties of the human brain in healthy subjects as well as the probing of disease-induced variations. Population studies of dMRI data have been essential in identifying pathological structural changes in various conditions, such as Alzheimer's and Huntington's diseases (Salat et al., 2010; Rosas et al., 2006). The most common form of dMRI involves fitting a tensor to the underlying imaging data (known as diffusion tensor imaging, or DTI), then deriving parametric maps, each quantifying a different aspect of the underlying microstructure, e.g. fractional anisotropy and mean diffusivity. To date, the statistical methods utilized in most DTI population studies either analyzed only one such map or analyzed several of them, each in isolation. However, it is most likely that variations in the microstructure due to pathology or normal variability would affect several parameters simultaneously, with differing variations modulating the various parameters to differing degrees. Therefore, joint analysis of the available diffusion maps can be more powerful in characterizing histopathology and distinguishing between conditions than the widely used univariate analysis. In this article, we propose a multivariate approach for statistical analysis of diffusion parameters that uses partial least squares correlation (PLSC) analysis and permutation testing as building blocks in a voxel-wise fashion. Stemming from the common formulation, we present three different multivariate procedures for group analysis, regressing-out nuisance parameters and comparing effects of different conditions. We used the proposed procedures to study the effects of non-demented aging, Alzheimer's disease and mild cognitive impairment on the white matter. Here, we present results demonstrating that the proposed PLSC-based approach can differentiate between effects of different conditions in the same region as well as uncover spatial variations of effects across the white matter. The proposed procedures were able to answer questions on structural variations such as: "are there regions in the white matter where Alzheimer's disease has a different effect than aging or similar effect as aging?" and "are there regions in the white matter that are affected by both mild cognitive impairment and Alzheimer's disease but with differing multivariate effects?" (C) 2016 Elsevier Inc. All rights reserved. C1 [Konukoglu, Ender; Coutu, Jean-Philippe; Salat, David H.; Fischl, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. [Coutu, Jean-Philippe] MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, Cambridge, MA 02139 USA. [Salat, David H.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Konukoglu, E (reprint author), 149 13th St, Charlestown, MA 02129 USA. EM enderk@nmr.mgh.harvard.edu FU National Institutes of Health grants [R01NR010827, NS042861, NS058793]; Center for Functional Neuroimaging Technologies [P41RR14075]; Biomedical Technology Program of the National Center for Research Resources (NCRR), National Institutes of Health; NCRR Shared Instrumentation Grant Program; High-End Instrumentation Grant Program; Fonds Quebecois de la Recherche - Sante; National Center for Research Resources [U24 RR021382]; National Institute for Biomedical Imaging and Bioengineering [P41EB015896, R01EB006758, R21EB018907, R01EB019956]; National Institute on Aging [AG022381, 5R01AG008122, R01 AG016495]; National Center for Alternativ Medicine [RC1 AT005728-01]; National Institute for Neurological Disorders and Stroke [R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, R01NS083534, 5U01NS086625]; Shared Instrumentation Grants [1S10RR023401, 1S10RR019307, 1S10RR023043]; Autism & Dyslexia Project - the Ellison Medical Foundation; NIH Blueprint for Neuroscience Research [5U01-MH093765]; multi-institutional Human Connectome Project; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; [S10RR021110]; [S10RR023401]; [S10RR019307]; [S10RR019254]; [S10RR023043] FX This study was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the National Institutes of Health grants R01NR010827, NS042861, NS058793 and by the Center for Functional Neuroimaging Technologies, P41RR14075, a P41 Regional Resource supported by the Biomedical Technology Program of the National Center for Research Resources (NCRR), National Institutes of Health. This work also involved the use of instrumentation supported by the NCRR Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant numbers S10RR021110, S10RR023401, S10RR019307, S10RR019254 and S10RR023043. Jean-Philippe Coutu was funded by the Fonds Quebecois de la Recherche - Sante.; Support for this research was provided in part by the National Center for Research Resources (U24 RR021382), the National Institute for Biomedical Imaging and Bioengineering (P41EB015896, R01EB006758, R21EB018907, R01EB019956), the National Institute on Aging (AG022381, 5R01AG008122, R01 AG016495), the National Center for Alternativ Medicine (RC1 AT005728-01), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, R01NS083534, 5U01NS086625), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation, and by the NIH Blueprint for Neuroscience Research (5U01-MH093765), part of the multi-institutional Human Connectome Project.; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare;; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern Rev December 5, 2013 California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 64 TC 0 Z9 0 U1 7 U2 7 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 2016 VL 134 BP 573 EP 586 DI 10.1016/j.neuroimage.2016.04.038 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8PP UT WOS:000378045900054 PM 27103138 ER PT J AU Chi, S Jiang, T Tan, L Yu, JT AF Chi, Song Jiang, Teng Tan, Lan Yu, Jin-Tai TI Distinct neurological disorders with C9orf72 mutations: genetics, pathogenesis, and therapy SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE C9orf72; Phenotypes; Neuropathology; Genetic; Pathogenesis; Therapy ID AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT EXPANSIONS; FRONTOTEMPORAL LOBAR DEGENERATION; G-QUADRUPLEX STRUCTURES; BAC TRANSGENIC MICE; ANTISENSE RNA FOCI; GGGGCC-REPEAT; NUCLEOCYTOPLASMIC TRANSPORT; PATHOLOGICAL FEATURES; CLINICOPATHOLOGICAL CORRELATIONS AB The G(4)C(2) repeat expansion within C9orf72 has been recently identified as the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. This mutation has also been detected in a variety of other neurological diseases with distinct clinical manifestations. The exact mechanisms of how this mutation leads to the wide spectrum of clinical syndromes remain unknown. A series of molecular changes together with some potential modifiers may play a key role. Nucleolar stress, nucleocytoplasmic transport defect, oxidative damage, inhibited stress granules assembly, activated endoplasmic reticulum stress, and inhibited proteasome activity are mechanisms that contribute to the pathogenesis of these diseases. Additional mutations, epigenetic modifiers, and repeat size are potential modifiers that modulate specific phenotypes on the basis of the molecular changes. Here, we summarize distinct C9orf72-related neurological disorders and their corresponding neuropathological changes. Then, we elucidate the existing molecular knowledge and the potential modifiers. Finally, we detail the main target of treatment aiming at controlling expanded RNA transcripts. (C) 2016 Published by Elsevier Ltd. C1 [Chi, Song] Qingdao Univ, Affiliated Hosp, Dept Neurol, Qingdao, Shandong, Peoples R China. [Chi, Song] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chi, Song; Tan, Lan; Yu, Jin-Tai] Qingdao Univ, Qingdao Municipal Hosp, Sch Med, Dept Neurol, Qingdao 266071, Shandong, Peoples R China. [Jiang, Teng] Nanjing Med Univ, Nanjing Hosp 1, Dept Neurol, Nanjing, Jiangsu, Peoples R China. RP Tan, L; Yu, JT (reprint author), Qingdao Univ, Qingdao Municipal Hosp, Sch Med, Dept Neurol, Qingdao 266071, Shandong, Peoples R China. EM Dr.tanlan@163.com; yu-jintag@163.com FU National Natural Science Foundation of China [81501092, 81471309, 81571245]; Natural Science Foundation of Jiangsu Province [BK20150091]; China Postdoctoral Science Foundation [2015M580448]; Qingdao Key Health Discipline Development Fund; Qingdao Outstanding Health Professional Development Fund; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders FX This work was supported by National Natural Science Foundation of China to T.J. (81501092), J.T.Y. (81471309), and L.T. (81571245); Natural Science Foundation of Jiangsu Province to T.J. (BK20150091); China Postdoctoral Science Foundation to T.J. (2015M580448); Qingdao Key Health Discipline Development Fund; Qingdao Outstanding Health Professional Development Fund; and Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders. NR 142 TC 0 Z9 0 U1 15 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD JUL PY 2016 VL 66 BP 127 EP 142 DI 10.1016/j.neubiorev.2016.03.033 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DP0KD UT WOS:000378177800010 PM 27139021 ER PT J AU Rosa, KC AF Rosa, Katherine C. TI Integrative Review on the Use of Newman Praxis Relationship in Chronic Illness SO NURSING SCIENCE QUARTERLY LA English DT Review DE chronic disease; healing; Newman's theory of health; nurse-patient relations ID EXPANDING CONSCIOUSNESS; PATTERN-RECOGNITION; AMERICAN WOMEN; LIFE PATTERNS; HEALTH; FAMILIES; CANCER; TRANSFORMATION; CHILDREN; CARE AB Over the past 20 years, many Newman scholars across the globe have investigated health as expanding consciousness with persons living with chronic illness. This integrative review examines the use of the concept, relationship, and its seven dimensionshealth, caring, consciousness, mutual process, patterning, presence, and meaning with persons with chronic illness when engaged in health as expanding consciousness praxis. A regular and sustained pattern of publication of studies that included the seven dimensions was found. Relationships among the dimensions of a Newman praxis relationship, chronic illness, and health as expanding consciousness are discussed. C1 [Rosa, Katherine C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rosa, KC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. FU Connell Nursing Research Scholars Program, Munn Center for Nursing Research, Institute for Patient Care at Massachusetts General Hospital FX Funding for completion of this project/research was supported in part by the Connell Nursing Research Scholars Program, Munn Center for Nursing Research, Institute for Patient Care, at Massachusetts General Hospital. NR 34 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0894-3184 EI 1552-7409 J9 NURS SCI QUART JI Nurs. Sci. Q. PD JUL PY 2016 VL 29 IS 3 BP 211 EP 218 DI 10.1177/0894318416647776 PG 8 WC Nursing SC Nursing GA DP3TY UT WOS:000378419700009 PM 27271134 ER PT J AU Cavallari, JM Fang, SC Eisen, EA Mittleman, MA Christiani, DC AF Cavallari, Jennifer M. Fang, Shona C. Eisen, Ellen A. Mittleman, Murray A. Christiani, David C. TI Environmental and occupational particulate matter exposures and ectopic heart beats in welders SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; AMBIENT AIR-POLLUTION; CARDIAC-ARRHYTHMIAS; VENTRICULAR-ARRHYTHMIAS; RATE-VARIABILITY; CARDIOVASCULAR-DISEASE; ASSOCIATION; EPIDEMIOLOGY; POPULATION; POLLUTANTS AB Objectives Links between arrhythmias and particulate matter exposures have been found among sensitive populations. We examined the relationship between personal particulate matter <= 2.5 mu m aerodynamic diameter (PM2.5) exposures and ectopy in a panel study of healthy welders. Methods Simultaneous ambulatory ECG and personal PM2.5 exposure monitoring with DustTrak Aerosol Monitor was performed on 72 males during work and non-work periods for 5-90 h (median 40 h). ECGs were summarised hourly for supraventricular ectopy (SVE) and ventricular ectopy (VE). PM2.5 exposures both work and non-work periods were averaged hourly with lags from 0 to 7 h. Generalised linear mixed-effects models with a random participant intercept were used to examine the relationship between PM2.5 exposure and the odds of SVE or VE. Sensitivity analyses were performed to assess whether relationships differed by work period and among current smokers. Results Participants had a mean (SD) age of 38 (11) years and were monitored over 2993 person-hours. The number of hourly ectopic events was highly skewed with mean (SD) of 14 (69) VE and 1 (4) SVE. We found marginally significant increases in VE with PM2.5 exposures in the sixth and seventh hour lags, yet no association with SVE. For every 100 mu g/m(3) increase in sixth hour lagged PM2.5, the adjusted OR (95% CI) for VE was 1.03 (1.00 to 1.05). Results persisted in work or non-work exposure periods and non-smokers had increased odds of VE associated with PM2.5 as compared with smokers. Conclusions A small increase in the odds of VE with short-term PM2.5 exposure was observed among relatively healthy men with environmental and occupational exposures. C1 [Cavallari, Jennifer M.] UConn Hlth Ctr, Div Occupat & Environm Med, Farmington, CT 06032 USA. [Cavallari, Jennifer M.; Fang, Shona C.; Christiani, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Eisen, Ellen A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Mittleman, Murray A.] Beth Israel Deaconess Med Ctr, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Mittleman, Murray A.] Harvard Univ, Sch Med, Boston, MA USA. [Mittleman, Murray A.; Christiani, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cavallari, JM (reprint author), UConn Hlth Ctr, Div Occupat & Environm Med, Farmington, CT 06032 USA. EM cavallari@uchc.edu FU Flight Attendant Medical Research Institute; National Institute of Environmental Health Sciences; National Institute for Occupational Safety and Health FX Flight Attendant Medical Research Institute; National Institute of Environmental Health Sciences; National Institute for Occupational Safety and Health. NR 34 TC 0 Z9 0 U1 7 U2 7 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 2016 VL 73 IS 7 BP 435 EP 441 DI 10.1136/oemed-2015-103256 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO9GV UT WOS:000378094300004 PM 27052768 ER PT J AU Underhill, ML Jones, T Habin, K AF Underhill, Meghan L. Jones, Tarsha Habin, Karleen TI Disparities in Cancer Genetic Risk Assessment and Testing SO ONCOLOGY NURSING FORUM LA English DT Editorial Material DE health disparities; genetic testing; risk assessment; breast cancer; ovarian cancer ID BREAST-CANCER; OVARIAN-CANCER; PERSONALIZED MEDICINE; HEREDITARY BREAST; POPULATION; HEALTH; WOMEN; INTERVENTIONS; AWARENESS; GENOMICS C1 [Underhill, Meghan L.; Jones, Tarsha] Dana Farber Canc Inst, Boston, MA 02115 USA. [Habin, Karleen] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Underhill, ML (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM meghanl_underhill@dfci.harvard.edu NR 30 TC 0 Z9 0 U1 2 U2 3 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X EI 1538-0688 J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD JUL PY 2016 VL 43 IS 4 BP 519 EP 523 DI 10.1188/16.ONF.519-523 PG 5 WC Oncology; Nursing SC Oncology; Nursing GA DO9EO UT WOS:000378087400018 PM 27314195 ER PT J AU Flanagan, J Tetler, D Winters, L Post, K Habin, K AF Flanagan, Jane Tetler, Devin Winters, Loren Post, Kathryn Habin, Karleen TI The Experience of Initiating Oral Adjuvant Treatment for Estrogen Receptor-Positive Breast Cancer SO ONCOLOGY NURSING FORUM LA English DT Article DE breast cancer; comorbidities; biologic-based therapies; nursing research; qualitative ID QUALITY-OF-LIFE; ENDOCRINE THERAPY; CLINICAL-PRACTICE; HORMONAL-THERAPY; SURVIVORS; WOMEN; ADHERENCE; SYMPTOMS; INTERVENTIONS; PERSPECTIVES AB Purpose/Objectives: To describe the experience of women with estrogen receptor-positive breast cancer who are initiating oral adjuvant therapy and to determine what they describe as facilitating and/or hindering this experience. Research Approach: Qualitative inquiry. Setting: Massachusetts General Hospital Cancer Center in Boston. Participants: 14 women aged 48-81 years. Methodologic Approach: Qualitative, descriptive study using content analysis. Findings: Five themes were identified: (a) feeling overwhelmed and abandoned despite highly skilled medical care, (b) processing the trauma and putting it in perspective, (c) keeping up the facade while feeling vulnerable, (d) needing to connect cautiously, and (e) moving toward healing and being aware. Conclusions: Each participant who was initiating oral adjuvant treatment described many unmet needs. Women who were caregivers, were older aged, had several chronic illnesses, and were on several medications reported more difficulty transitioning to oral adjuvant therapy. Interpretation: This study suggests that nurses need to collaborate with other members of the healthcare team to assess the needs of and provide comprehensive care to women initiating oral adjuvant therapy. This is particularly true for women who are older aged, selfreported caregivers, and on several medications, and who have chronic comorbid conditions. C1 [Flanagan, Jane] Boston Coll, Adult Gerontol, William F Connell Sch Nursing, Chestnut Hill, MA 02167 USA. [Tetler, Devin] Portland Community Hlth Ctr, Portland, ME USA. [Winters, Loren; Post, Kathryn; Habin, Karleen] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Flanagan, J (reprint author), Boston Coll, Adult Gerontol, William F Connell Sch Nursing, Chestnut Hill, MA 02167 USA. EM flanagjg@bc.edu NR 31 TC 0 Z9 0 U1 3 U2 3 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X EI 1538-0688 J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD JUL PY 2016 VL 43 IS 4 BP E143 EP E152 DI 10.1188/16.ONF.E143-E152 PG 10 WC Oncology; Nursing SC Oncology; Nursing GA DO9EO UT WOS:000378087400001 PM 27314197 ER PT J AU Abud, TB Amparo, F Saboo, US Di Zazzo, A Dohlman, TH Ciolino, JB Hamrah, P Dana, R AF Abud, Tulio B. Amparo, Francisco Saboo, Ujwala S. Di Zazzo, Antonio Dohlman, Thomas H. Ciolino, Joseph B. Hamrah, Pedram Dana, Reza TI A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease SO OPHTHALMOLOGY LA English DT Article ID FLOW-CYTOMETRIC ANALYSIS; SEVERE ALLERGIC CONJUNCTIVITIS; HLA-DR EXPRESSION; CYCLOSPORINE-A; KERATOCONJUNCTIVITIS SICCA; SURFACE DISEASE; CORNEAL TRANSPLANTATION; OPHTHALMIC SUSPENSION; INFLAMMATORY MARKER; IMPRESSION CYTOLOGY AB Purpose: To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD). Design: Phase 1/2 prospective, randomized, double-masked clinical trial. Participants: Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled. Methods: Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen. Main Outcome Measures: Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI). Results: After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04). Conclusions: Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids. (C) 2016 by the American Academy of Ophthalmology. C1 [Abud, Tulio B.; Amparo, Francisco; Saboo, Ujwala S.; Di Zazzo, Antonio; Ciolino, Joseph B.; Hamrah, Pedram; Dana, Reza] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, Boston, MA USA. [Abud, Tulio B.] Fed Univ Sao Paulo UNIFESP, Paulista Sch Med, Dept Ophthalmol & Visual Sci, Sao Paulo, Brazil. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, Cornea Serv,New England Eye Ctr,Dept Ophthalmol, Boston, MA 02111 USA. [Abud, Tulio B.; Amparo, Francisco; Di Zazzo, Antonio; Dohlman, Thomas H.; Dana, Reza] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst,Dept Ophthalmol, Boston, MA USA. RP Dana, R (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM reza_dana@meei.harvard.edu OI Hamrah, Pedram/0000-0002-9313-2939 FU Higher Level Personnel Improvement Commission (CAPES-Ministry of Education, Brazil); Allergan (Irvine, CA); GlaxoSmithKline (Philadelphia, PA); Alcon Laboratories, Inc (Fort Worth, TX); National Eye Institute, National Institutes of Health, Bethesda, Maryland [K24 EY019098]; Research to Prevent Blindness, Inc., New York, New York FX The author(s) have made the following disclosure(s): T.B.A.: Financial support - Higher Level Personnel Improvement Commission (CAPES-Ministry of Education, Brazil); P.H.: Consultant - AllerganInc. (Irvine, CA); Shire (Lexington, MA); Bausch & Lomb (Rochester, NY); Valeant, Laval, (Quebec, Canada); GlaxoSmithKline (Philadelphia, PA); Jade Therapeutics (Waltham, MA); Revision Optics (Lake Forest, CA); Financial support - Allergan (Irvine, CA); GlaxoSmithKline (Philadelphia, PA); Alcon Laboratories, Inc (Fort Worth, TX).; Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant no.: K24 EY019098); and Research to Prevent Blindness, Inc., New York, New York. The funding organizations had no role in the design or conduct of this research. NR 40 TC 1 Z9 1 U1 1 U2 2 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 2016 VL 123 IS 7 BP 1449 EP 1457 DI 10.1016/j.ophtha.2016.02.044 PG 9 WC Ophthalmology SC Ophthalmology GA DP3KC UT WOS:000378391100016 PM 27086024 ER PT J AU Qazi, Y Hurwitz, S Khan, S Jurkunas, UV Dana, R Hamrah, P AF Qazi, Yureeda Hurwitz, Shelley Khan, Sarosh Jurkunas, Ula V. Dana, Reza Hamrah, Pedram TI Validity and Reliability of a Novel Ocular Pain Assessment Survey (OPAS) in Quantifying and Monitoring Corneal and Ocular Surface Pain SO OPHTHALMOLOGY LA English DT Article ID DN4 DIAGNOSTIC QUESTIONNAIRE; DRY EYE SYMPTOMS; NEUROPATHIC PAIN; PSYCHOMETRIC PROPERTIES; SCREENING QUESTIONNAIRE; CULTURAL-ADAPTATION; LEEDS ASSESSMENT; NERVOUS-SYSTEM; DISEASE-INDEX; ID PAIN AB Purpose: To validate the Ocular Pain Assessment Survey (OPAS), specifically designed to measure ocular pain and quality of life for use by eye care practitioners and researchers. Design: A single-center cohort study was conducted among patients with and without corneal and ocular surface pain at initial and follow-up visits over a 6-month period. The content of the OPAS was guided by literature review, a body of experts, and incorporating conceptual frameworks from existing pain questionnaires. The Wong-Baker FACES Pain Rating Scale served as the gold standard for measuring the intensity of ocular pain. Participants: A total of 102 patients aged 18 to 80 years completed the OPAS at the initial visit. A total of 21 patients were followed up after treatment. Methods: Indices of validity and internal consistency (Spearman's rank-order, r(s), or Pearson's correlation coefficients, r(p)), and coefficient of reliability (Cronbach's alpha) were determined in addition to equivalence testing, exploratory factor analysis (EFA), and diagnostic analysis. Main Outcome Measures: Eye pain intensity was the primary outcome measure, and interference with quality of life (QoL), aggravating factors, associated factors, associated non-eye pain intensity, and self-reported symptomatic relief were the secondary outcome measures. Results: The OPAS had criterion validity at both initial (r(s) = 0.71; n = 102; P < 0.01) and follow-up visits (r(s) = 0.97; n = 21; P < 0.01). Equivalence tests yielded OPAS and gold standard equivalence for both the initial and follow-up visits. The EFA supported 6 subscales (eye pain intensity at 24 hours and 2 weeks, non-eye pain intensity, QoL, aggravating factors, and associated factors) confirming multidimensionality. Cronbach's alpha > 0.83 for all subscales established strong internal consistency, which correlated with the gold standard, including 24-hour eye pain intensity and QoL interference scores (r(p) = 0.81, 0.64, respectively P < 0.001). At follow-up, reduction in pain scores was accompanied by improvement in all dimensions of the OPAS. Percentage change in QoL correlated to percentage change in the gold standard (r(p) = 0.53; P < 0.05). The OPAS was sensitive (94%), specific (81%), and accurate (91%), with a diagnostic odds ratio >50. Conclusions: The OPAS is a valid, reliable, and responsive tool with strong psychometric and diagnostic properties in the multidimensional quantification of corneal and ocular surface pain intensity, and QoL. (C) 2016 by the American Academy of Ophthalmology. C1 [Qazi, Yureeda; Khan, Sarosh; Jurkunas, Ula V.; Dana, Reza; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, Boston, MA USA. [Hurwitz, Shelley] Harvard Univ, Brigham & Womens Hosp, Sch Med, Biostat Core,Ctr Clin Invest, Boston, MA 02115 USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Dept Ophthalmol, Cornea Serv,New England Eye Ctr,Tufts Med Ctr, 800 Washington St, Boston, MA 02111 USA. RP Hamrah, P (reprint author), Tufts Univ, Sch Med, Dept Ophthalmol, Cornea Serv,New England Eye Ctr,Tufts Med Ctr, 800 Washington St, Boston, MA 02111 USA. EM phamrah@tuftsmedicalcenter.org FU National Institutes of Health [K08-EY020575]; MEEI Foundation grant; Research to Prevent Blindness Career Development Award; Falk Medical Research Trust FX Funded by the National Institutes of Health K08-EY020575 (P.H.) and an MEEI Foundation grant (P.H.), a Research to Prevent Blindness Career Development Award (P.H.), and the Falk Medical Research Trust (P.H.). The sponsor or funding organization had no role in the design or conduct of this research. NR 72 TC 4 Z9 4 U1 1 U2 2 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 2016 VL 123 IS 7 BP 1458 EP 1468 DI 10.1016/j.ophtha.2016.03.006 PG 11 WC Ophthalmology SC Ophthalmology GA DP3KC UT WOS:000378391100017 PM 27089999 ER PT J AU Balaratnasingam, C Freund, KB Tan, AM Mrejen, S Hunyor, AP Keegan, DJ Dansingani, KK Dayani, PN Barbazetto, IA Sarraf, D Jampol, LM Yannuzzi, LA AF Balaratnasingam, Chandrakumar Freund, K. Bailey Tan, Anna M. Mrejen, Sarah Hunyor, Alex P. Keegan, David J. Dansingani, Kunal K. Dayani, Pouya N. Barbazetto, Irene A. Sarraf, David Jampol, Lee M. Yannuzzi, Lawrence A. TI Bullous Variant of Central Serous Chorioretinopathy Expansion of Phenotypic Features Using Multimethod Imaging SO OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; INDOCYANINE GREEN ANGIOGRAPHY; RETINAL-DETACHMENT; ORGAN-TRANSPLANTATION; NEOVASCULARIZATION; THERAPY AB Purpose: To define the phenotypic characteristics of the bullous variant of central serous chorioretinopathy (CSC) using multimethod imaging. Design: Retrospective, observational case series. Participants: Twenty-one eyes of 14 patients with bullous retinal detachment resulting from CSC (bullous CSC group) and 122 eyes of 84 patients with chronic CSC without bullous retinal detachment (nonbullous CSC group). Methods: We performed a retrospective review of clinical and multimethod imaging data of patients who sought treatment from the authors with bullous retinal detachment resulting from CSC between January 2010 and November 2015. Multimethod imaging comprised color photography, fluorescein angiography, fundus autofluorescence, and high-resolution optical coherence tomography. Consecutive cases of chronic CSC without bullous retinal detachment, seen during the same period, comprised a comparative group. Main Outcome Measures: Qualitative and quantitative characteristics of the choroid, retinal pigment epithelium, and retina were compared between the 2 groups. Results: Mean age of the bullous CSC group was 53.8 years. There was no difference in age, visual acuity, corticosteroid use, or the proportion of white patients and men between the 2 groups (all P > 0.132). Peripheral nonperfusion occurred only in eyes with bullous retinal detachment (38% of cases). Retinal pigment epithelial tears were seen in 95% of eyes in the bullous group and none of the eyes in the nonbullous CSC group. The bullous CSC group demonstrated a greater number of pigment epithelial detachments (PEDs) and more eyes demonstrated PEDs with internal hyperreflectivity (both P < 0.016). Mean subfoveal choroidal thickness in the bullous CSC group (463.1 +/- 83.1 mm) was not different compared with that of the nonbullous CSC group (400.6 +/- 100.6 mm; P = 0.993). More eyes in the bullous CSC group demonstrated hyperreflectivity around large choroidal vessels and at the level of the choriocapillaris on OCT (P < 0.001). Retinal folds and subretinal fibrin were identified in a greater proportion of eyes in the bullous CSC group (both P < 0.001). Conclusions: Bullous retinal detachment is a rare manifestation of chronic CSC and is characterized by a unique constellation of phenotypic and multimethod imaging features. (C) 2016 by the American Academy of Ophthalmology. C1 [Balaratnasingam, Chandrakumar; Freund, K. Bailey; Tan, Anna M.; Mrejen, Sarah; Dansingani, Kunal K.; Barbazetto, Irene A.; Yannuzzi, Lawrence A.] Manhattan Eye Ear & Throat Hosp, LuEsther T Mertz Retinal Res Ctr, New York, NY 10022 USA. [Balaratnasingam, Chandrakumar; Freund, K. Bailey; Tan, Anna M.; Mrejen, Sarah; Dansingani, Kunal K.; Barbazetto, Irene A.; Yannuzzi, Lawrence A.] Vitreous Retina Macula Consultants New York, New York, NY USA. [Balaratnasingam, Chandrakumar; Freund, K. Bailey; Barbazetto, Irene A.] NYU, Dept Ophthalmol, Sch Med, 550 1St Ave, New York, NY 10016 USA. [Balaratnasingam, Chandrakumar] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Lions Eye Inst, Perth, WA 6009, Australia. [Hunyor, Alex P.] Univ Sydney, Sydney Med Sch, Save Sight Inst, Sydney, NSW 2006, Australia. [Hunyor, Alex P.] Retina Associates, Chatswood, NSW, Australia. [Keegan, David J.] Mater Misericordiae Univ Hosp, Dublin, Ireland. [Dayani, Pouya N.] Retina Vitreous Associated Med Grp, Los Angeles, CA USA. [Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, Los Angeles, CA 90024 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Jampol, Lee M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Yannuzzi, LA (reprint author), Manhattan Eye Ear & Throat Hosp, LuEsther T Mertz Retinal Res Ctr, New York, NY 10022 USA. EM layannuzzi@gmail.com OI Freund, K. Bailey/0000-0002-7888-9773 FU LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York; Macula Foundation, Inc, New York, New York; RANZCO Eye Foundation, NSW, Australia FX Supported by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York; The Macula Foundation, Inc, New York, New York; and RANZCO Eye Foundation, NSW, Australia. The funding organizations had no role in the design or conduct of this research. NR 36 TC 0 Z9 0 U1 0 U2 4 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 2016 VL 123 IS 7 BP 1541 EP 1552 DI 10.1016/j.ophtha.2016.03.017 PG 12 WC Ophthalmology SC Ophthalmology GA DP3KC UT WOS:000378391100026 PM 27084564 ER PT J AU Seo, A Walsh, T Lee, MK Ho, PA Hsu, EK Sidbury, R King, MC Shimamura, A AF Seo, Aaron Walsh, Tom Lee, Ming K. Ho, Phoenix A. Hsu, Evelyn Kanyu Sidbury, Robert King, Mary-Claire Shimamura, Akiko TI FAM111B Mutation Is Associated With Inherited Exocrine Pancreatic Dysfunction SO PANCREAS LA English DT Article DE exocrine pancreatic dysfunction; inherited bone marrow failure syndromes; Shwachman-Diamond syndrome ID SHWACHMAN-DIAMOND-SYNDROME; CYSTIC-FIBROSIS GENE; IDENTIFICATION; FAILURE; SBDS AB Objectives: Few genetic causes of exocrine pancreatic dysfunction have been described to date. We identified a family with multiple affected members manifesting exocrine pancreatic dysfunction. Additional associated features included facial rash, sparse hair, hypohidrosis, and swelling of the extremities. The transmission pattern of these clinical features was consistent with an autosomal dominant mode of inheritance. The 2 proband siblings also had transient elevated liver transaminases with hepatic steatosis early in life. This study identifies the genetic cause of exocrine pancreatic dysfunction in this family. Methods: Whole exome sequencing was performed to identify the genetic cause of exocrine pancreatic dysfunction. Results: A heterozygous germline in-frame deletion in the gene FAM111B (c. 1261_1263delAAG, p.Lys421del) cosegregated with the phenotype: the variant was present in all affected relatives genotyped and absent in all unaffected relatives genotyped. The variant is also absent from public control sequence databases. Conclusions: Our findings implicate FAM111B in autosomal dominantly inheritable exocrine pancreatic dysfunction. C1 [Seo, Aaron; Walsh, Tom; Lee, Ming K.; King, Mary-Claire] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Seo, Aaron] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Walsh, Tom; Lee, Ming K.; King, Mary-Claire] Univ Washington, Div Med Genet, Seattle, WA 98195 USA. [Ho, Phoenix A.] Seattle Childrens Hosp, Pediat Hematol Oncol, Seattle, WA USA. [Hsu, Evelyn Kanyu] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Hsu, Evelyn Kanyu] Univ Washington, Pediat Gastroenterol & Hepatol, Seattle, WA 98195 USA. [Sidbury, Robert] Seattle Childrens Hosp, Dept Dermatol, Seattle, WA USA. [Shimamura, Akiko] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Shimamura, Akiko] Harvard Univ, Sch Med, Boston, MA USA. RP Shimamura, A (reprint author), Dana Farber & Boston Childrens Canc & Blood Disor, 300 Longwood Ave,Karp 08210, Boston, MA 02115 USA. EM Akiko.Shimamura@childrens.harvard.edu FU US National Institutes of Health [R24DK093425, R24DK099808]; Ghiglione Aplastic Anemia Fund; Julian's Dinosaur Guild from Seattle Children's Hospital; Medical Scientist Training Program Training grant [T32GM007266]; Developmental Biology Training Grant [T32HD007183]; ARCS Foundation Fellowship FX This work was supported by US National Institutes of Health grants R24DK093425 and R24DK099808 to A.S. and M.-C.K.; by the Ghiglione Aplastic Anemia Fund and Julian's Dinosaur Guild from Seattle Children's Hospital to A.S.; by Medical Scientist Training Program Training grant T32GM007266 and Developmental Biology Training Grant T32HD007183 to A.S.; by ARCS Foundation Fellowship to A.S. NR 14 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD JUL PY 2016 VL 45 IS 6 BP 858 EP 862 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DO9HJ UT WOS:000378095800018 PM 26495788 ER PT J AU Matsuzaka, S Karasaki, H Ono, Y Ogata, M Oikawa, K Tamakawa, S Chiba, S Muraki, M Yokochi, T Funakoshi, H Kono, T Nagashima, K Mizukami, Y AF Matsuzaka, Suguru Karasaki, Hidenori Ono, Yusuke Ogata, Munehiko Oikawa, Kensuke Tamakawa, Susumu Chiba, Shin-ichi Muraki, Miho Yokochi, Tomoki Funakoshi, Hiroshi Kono, Toru Nagashima, Kazuo Mizukami, Yusuke TI Tracking the Clonal Evolution of Adenosquamous Carcinoma, a Rare Variant of Intraductal Papillary Mucinous Neoplasm of the Pancreas SO PANCREAS LA English DT Article DE intraductal papillary mucinous neoplasm; adenosquamous carcinoma; next-generation sequencing ID CONSENSUS AB Adenosquamous carcinoma (ASC) is an uncommon variant of pancreatic neoplasm. We sought to trace the mode of tumor progression using specimens of ASC associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. A resected specimen of the primary pancreatic ASC, developed in a 72-year-old man, was subjected to mutation profiling using amplicon-targeted sequencing and digital polymerase chain reaction. DNA was isolated from each histological compartment including noninvasive IPMN, squamous cell carcinoma (SCC), and adenocarcinoma (AC). Histologically, an IPMN with a large mural nodule was identified. The invasive tumor predominantly consisted of SCC, and a smaller AC was found around the lesion. Squamous metaplasias were sporadically distributed within benign IPMNs. Mutation alleles KRAS(G12D) and GNASR(201C) were identified in all specimens of IPMN including the areas of squamous metaplasia. In addition, these mutations were found in SCC and AC. Clear transition from flat/low-papillary IPMN to SCC indicated a potent invasion front, and the SCC compartment was genetically unique, because the area has a higher frequency of mutation KRAS(G12D). The invasive tumors with distinct histological appearances shared the form of noninvasive IPMN as a common precursor, rather than de novo cancer, suggesting the significance of a genetic profiling scheme of tumors associated with IPMN. C1 [Matsuzaka, Suguru] Furano Kyoukai Hosp, Dept Surg, Furano, Hokkaido, Japan. [Karasaki, Hidenori; Ono, Yusuke; Ogata, Munehiko; Kono, Toru; Nagashima, Kazuo; Mizukami, Yusuke] Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Sapporo, Hokkaido, Japan. [Oikawa, Kensuke] Asahikawa Med Univ, Dept Pathol, Asahikawa, Hokkaido, Japan. [Tamakawa, Susumu] Natl Hosp Org Asahikawa Med Ctr, Asahikawa, Hokkaido, Japan. [Chiba, Shin-ichi; Funakoshi, Hiroshi] Asahikawa Med Univ, Ctr Adv Res & Educ, Asahikawa, Hokkaido, Japan. [Muraki, Miho] Life Technol Japan, Tokyo, Japan. [Yokochi, Tomoki] Chiba Tokushukai Hosp, Dept Clin Res, Funabashi, Chiba, Japan. [Mizukami, Yusuke] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Mizukami, Yusuke] Harvard Univ, Sch Med, Boston, MA USA. RP Mizukami, Y (reprint author), Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Lab Clin Bioinformat, Higashi Ku, 3-1 North 33,East 14, Sapporo, Hokkaido 0650033, Japan. EM ymizu_ccbr@tohtoku.jp FU Ministry of Education, Culture, Sports, Science and Technology [25461029]; Pancreas Research Foundation in Japan FX This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (25461029 to Y.M.), and Pancreas Research Foundation in Japan (to Y.M.). NR 13 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD JUL PY 2016 VL 45 IS 6 BP 915 EP 918 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DO9HJ UT WOS:000378095800027 PM 27295533 ER PT J AU Patel, SA Wo, JY Hong, TS AF Patel, Sagar A. Wo, Jennifer Y. Hong, Theodore S. TI Advancing Techniques of Radiation Therapy for Rectal dancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID PREOPERATIVE ENDORECTAL BRACHYTHERAPY; PHASE-III TRIAL; POSTOPERATIVE CHEMORADIOTHERAPY; SMALL-BOWEL; ENDOCAVITARY IRRADIATION; PELVIC RECURRENCE; RANDOMIZED-TRIAL; CANCER; RADIOTHERAPY; OXALIPLATIN AB Since the advent of radiation therapy for rectal cancer, there has been continual investigation of advancing technologies and techniques that allow for improved dose conformality to target structures while limiting irradiation of surrounding normal tissue. For locally advanced disease, intensity modulated and proton beam radiation therapy both provide more highly conformal treatment volumes that reduce dose to organs at risk, though the clinical benefit in terms of toxicity reduction is unclear. For early stage disease, endorectal contact therapy and high-dose rate brachytherapy may be a definitive treatment option for patients who are poor operative candidates or those with low-lying tumors that desire sphincter-preservation. Finally, there has been growing evidence that supports stereotactic body radiotherapy as a safe and effective salvage treatment for the minority of patients that locally recur following trimodality therapy for locally advanced disease. This review addresses these topics that remain areas of active clinical investigation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Patel, Sagar A.] Harvard Radiat Oncol Program, Boston, MA USA. [Wo, Jennifer Y.; Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM tshong1@partners.org NR 29 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2016 VL 26 IS 3 BP 220 EP 225 DI 10.1016/j.semradonc.2016.02.005 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DP0LU UT WOS:000378182100008 PM 27238474 ER PT J AU Jain, R Sharma, N Basu, S Iyer, G Ueta, M Sotozono, C Kannabiran, C Rathi, VM Gupta, N Kinoshita, S Gomes, JAP Chodosh, J Sangwan, VS AF Jain, Rajat Sharma, Namrata Basu, Sayan Iyer, Geetha Ueta, Mayumi Sotozono, Chie Kannabiran, Chitra Rathi, Varsha M. Gupta, Nidhi Kinoshita, Shigeru Gomes, Jose A. P. Chodosh, James Sangwan, Virender S. TI Stevens-Johnson syndrome: The role of an ophthalmologist SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE Stevens-Johnson syndrome; acute; dry eye; keratoprosthesis; stem cell transplantation: PROSE ID TOXIC EPIDERMAL NECROLYSIS; OCULAR SURFACE RECONSTRUCTION; AMNIOTIC MEMBRANE TRANSPLANTATION; STEM-CELL DEFICIENCY; MUCOSAL EPITHELIAL TRANSPLANTATION; OSTEO-ODONTO-KERATOPROSTHESIS; SCLERAL CONTACT-LENSES; NECROSIS-FACTOR-ALPHA; INDUCED HYPERSENSITIVITY REACTIONS; CUTANEOUS ADVERSE-REACTIONS AB Stevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. Acute SJS leads to the acute inflammation of the ocular surface and chronic conjunctivitis. If not properly treated, it causes chronic cicatricial conjunctivitis and cicatricial lid margin abnormalities. Persistent inflammation and ulceration of the ocular surface with cicatricial complications of the lids leads to chronic ocular sequelae, ocular surface damage, and corneal scarring. The destruction of the glands that secrete the tear film leads to a severe form of dry eye that makes the management of chronic SJS difficult. The option that is routinely used for corneal visual rehabilitation, keratoplasty, is best avoided in such cases. We describe the management strategies that are most effective during the acute and chronic stages of SJS. Although treatments for acute SJS involve immunosuppressive and immunomodulatory therapies, amniotic membrane transplantation is also useful. The options for visual rehabilitation in patients with chronic SJS are undergoing radical change. We describe the existing literature regarding the management of SJS and highlight recent advances in the management of this disorder. (C) 2016 Elsevier Inc. All rights reserved. C1 [Jain, Rajat] DrishtiCONE Eye Care, Dept Ophthalmol, Cornea Segment Serv, New Delhi, India. [Jain, Rajat] DrishtiCONE Eye Care, Dept Ophthalmol, Ocular Surface Segment Serv, New Delhi, India. [Jain, Rajat] DrishtiCONE Eye Care, Dept Ophthalmol, Anterior Segment Serv, New Delhi, India. [Sharma, Namrata] All India Inst Med Sci, Dr Rajendra Prasad Ctr Ophthalm Sci, Cornea Surg Serv, New Delhi 110029, India. [Sharma, Namrata] All India Inst Med Sci, Dr Rajendra Prasad Ctr Ophthalm Sci, Refract Surg Serv, New Delhi 110029, India. [Basu, Sayan] LV Prasad Eye Inst, Dept Ophthalmol, Cornea Segment Serv, Hyderabad, Telangana, India. [Basu, Sayan] LV Prasad Eye Inst, Dept Ophthalmol, Anterior Segment Serv, Hyderabad, Telangana, India. [Iyer, Geetha] Sankara Nethralaya, Dr G Sitalakshmi Mem Clin Ocular Surface Disorder, Dept Ophthalmol, CJ Shah Cornea Serv, Chennai, Tamil Nadu, India. [Ueta, Mayumi; Sotozono, Chie; Kinoshita, Shigeru] Kyoto Prefectural Univ Med, Dept Ophthalmol, Kyoto, Japan. [Ueta, Mayumi] Doshisha Univ, Dept Ophthalmol, Kyotanabe, Japan. [Kannabiran, Chitra] LVPEI, Kallam Anji Reddy Mol Genet Lab, Dept Ophthalmol, Hyderabad, Telangana, India. [Rathi, Varsha M.] LV Prasad Eye Inst, Dept Ophthalmol, Cornea Serv, Hyderabad, Telangana, India. [Gupta, Nidhi] Dr Shroff Char Eye Hosp, Dept Ophthalmol, Delhi, India. [Gomes, Jose A. P.] Univ Fed Sao Paulo, Escola Paulista Med UNIFESP EPM, Dept Ophthalmol, Cornea & External Dis Serv, Sao Paulo, Brazil. [Gomes, Jose A. P.] Univ Fed Sao Paulo, Escola Paulista Med UNIFESP EPM, Dept Ophthalmol, CASO, Sao Paulo, Brazil. [Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Sangwan, Virender S.] LV Prasad Eye Inst, Srujana Ctr Innovat, Dept Ophthalmol, Hyderabad, Telangana, India. RP Sangwan, VS (reprint author), LV Prasad Eye Inst, Ctr Ocular Regenerat CORE, Dept Ophthalmol, Kallam Anji Reddy Campus,LV Prasad Marg, Hyderabad 500034, Telangana, India. EM vsangwan@lvpei.org NR 238 TC 1 Z9 1 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JUL-AUG PY 2016 VL 61 IS 4 BP 369 EP 399 DI 10.1016/j.survophthal.2016.01.004 PG 31 WC Ophthalmology SC Ophthalmology GA DP4DB UT WOS:000378444500001 PM 26829569 ER PT J AU Taber, DJ Hamedi, M Rodrigue, JR Gebregziabher, MG Srinivas, TR Baliga, PK Egede, LE AF Taber, David J. Hamedi, Mahsa Rodrigue, James R. Gebregziabher, Mulugeta G. Srinivas, Titte R. Baliga, Prabhakar K. Egede, Leonard E. TI Quantifying the Race Stratified Impact of Socioeconomics on Graft Outcomes in Kidney Transplant Recipients SO TRANSPLANTATION LA English DT Article ID SOCIAL ADAPTABILITY INDEX; RENAL-ALLOGRAFT RECIPIENTS; EVENT TIME DATA; RACIAL DISPARITIES; AFRICAN-AMERICANS; RISK-FACTORS; SURVIVAL; DISEASE; MORTALITY; PREDICTS AB Background. Socioeconomic status (SES) is a significant determinant of health outcomes and may be an important component of the causal chain surrounding racial disparities in kidney transplantation. The social adaptability index (SAI) is a validated and quantifiable measure of SES, with a lack of studies analyzing this measure longitudinally or between races. Methods. Longitudinal cohort study in adult kidney transplantation transplanted at a single-center between 2005 and 2012. The SAI score includes 5 domains (employment, education, marital status, substance abuse and income), each with a minimum of 0 and maximum of 3 for an aggregate of 0 to 15 (higher score. better SES). Results. One thousand one hundred seventy-one patients were included; 624 (53%) were African American (AA) and 547 were non-AA. African Americans had significantly lower mean baseline SAI scores (AAs 6.5 vs non-AAs 7.8; P < 0.001). Cox regression analysis demonstrated that there was no association between baseline SAI and acute rejection in non-AAs (hazard ratio [HR], 0.92; 95% confidence interval [95% CI], 0.81-1.05), whereas it was a significant predictor of acute rejection in AAs (HR, 0.89; 95% CI, 0.80-0.99). Similarly, a 2-stage approach to joint modelling of time to graft loss and longitudinal SAI did not predict graft loss in non-AAs (HR, 1.01; 95% CI, 0.28-3.62), whereas it was a significant predictor of graft loss in AAs (HR, 0.23; 95% CI, 0.06-0.93). Conclusions. After controlling for confounders, SAI scores were associated with a lower risk of acute rejection and graft loss in AA kidney transplant recipients, whereas neither baseline nor follow-up SAI predicted outcomes in non-AA kidney transplant recipients. C1 [Taber, David J.; Baliga, Prabhakar K.] Med Univ S Carolina, Coll Med, Div Transplant Surg, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. [Taber, David J.] Ralph H Johnson VAMC, Dept Pharm, Charleston, SC USA. [Hamedi, Mahsa] Med Univ S Carolina, Coll Med, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. [Rodrigue, James R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Transplant Inst, Sch Med, Boston, MA 02215 USA. [Gebregziabher, Mulugeta G.] Med Univ S Carolina, Dept Publ Hlth Sci, Coll Med, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. [Srinivas, Titte R.] Med Univ S Carolina, Div Transplant Nephrol, Coll Med, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. [Egede, Leonard E.] Ralph H Johnson VAMC, Vet Affairs HSR&D Hlth Equ & Rural Outreach In, Charleston, SC USA. RP Taber, DJ (reprint author), Med Univ S Carolina, Div Transplant Surg, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. EM taberd@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU NIDDK NIH HHS [K23 DK099440, T35 DK007431] NR 35 TC 5 Z9 5 U1 2 U2 4 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 JUL PY 2016 VL 100 IS 7 BP 1550 EP 1557 DI 10.1097/TP.0000000000000931 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DP0AG UT WOS:000378149300030 PM 26425875 ER PT J AU Rose, C Nickerson, P Delmonico, F Randhawa, G Gill, J Gill, JS AF Rose, Caren Nickerson, Peter Delmonico, Francis Randhawa, Gurch Gill, Jagbir Gill, John S. TI Estimation of Potential Deceased Organ Donors in Canada SO TRANSPLANTATION LA English DT Article ID DONATION; KIDNEY; COHORT; RATES; DEATH AB Background. Development of strategies to increase deceased organ donation is dependent on timely, accurate information regarding the number of potential deceased organ donors. Our objective was to estimate the number of potential deceased organ donors in Canada. Methods. This was a retrospective analysis of information captured from hospital separations in Canadian provinces with the exception of Quebec between 2005 and 2009. We studied individuals 70 years or younger who died in hospital. Our primary outcome measure was potential deceased organ donors (identified by the presence of diagnostic codes compatible with donation, the absence of contraindications to donation defined by Canadian Standards, and the use of mechanical ventilation). Results. Among 335 793 hospital deaths, 8274 potential donors were identified. The study method was 81% sensitive and 93% specific for identification of potential donors, and overestimated potential donors by a factor of 1.6- to 2.1-fold when compared to information from chart audits. After accounting for this overestimation, there are conservatively 400 unrecognized potential deceased donors in Canada annually. Conclusions. These findings suggest there may be significant potential to increase deceased organ donations in Canada. Further studies to fully characterize the number of potential donors identified by the study method are needed. C1 [Rose, Caren; Gill, Jagbir; Gill, John S.] Univ British Columbia, Div Nephrol, Dept Med, Providence Bldg Ward,6a-1080 Burrard St, Vancouver, BC V6Z 1Y6, Canada. [Nickerson, Peter] Univ Manitoba, Renal Transplant Program, Winnipeg, MB, Canada. [Delmonico, Francis] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Randhawa, Gurch] Univ Bedfordshire, Inst Hlth Res, Luton, Beds, England. [Gill, Jagbir; Gill, John S.] Ctr Hlth Evaluat & Outcomes Sci, Vancouver, BC, Canada. RP Gill, JS (reprint author), Univ British Columbia, Dept Med, St Pauls Hosp, Providence Bldg Ward,6a-1080 Burrard St, Vancouver, BC V6Z 1Y6, Canada. EM jgill@providencehealth.bc.ca NR 30 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2016 VL 100 IS 7 BP 1558 EP 1563 DI 10.1097/TP.0000000000000947 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DP0AG UT WOS:000378149300031 PM 26479283 ER PT J AU Markmann, JF Bartlett, ST Johnson, P Korsgren, O Hering, BJ Scharp, D Kay, TWH Bromberg, J Odorico, JS Weir, GC Bridges, N Kandaswamy, R Stock, P Friend, P Gotoh, M Cooper, DKC Park, CG O'Connell, PJ Stabler, C Matsumoto, S Ludwig, B Choudhary, P Khovatchev, B Rickels, MR Sykes, M Wood, K Kraemer, K Hwa, A Stanley, E Ricordi, C Zimmerman, M Greenstein, J Montanya, E Otonkoski, T AF Markmann, James F. Bartlett, Stephen T. Johnson, Paul Korsgren, Olle Hering, Bernhard J. Scharp, David Kay, Thomas W. H. Bromberg, Jonathan Odorico, Jon S. Weir, Gordon C. Bridges, Nancy Kandaswamy, Raja Stock, Peter Friend, Peter Gotoh, Mitsukazu Cooper, David K. C. Park, Chung-Gyu O'Connell, Philip J. Stabler, Cherie Matsumoto, Shinichi Ludwig, Barbara Choudhary, Pratik Khovatchev, Boris Rickels, Michael R. Sykes, Megan Wood, Kathryn Kraemer, Kristy Hwa, Albert Stanley, Edward Ricordi, Camillo Zimmerman, Mark Greenstein, Julia Montanya, Eduard Otonkoski, Timo TI Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of beta-Cell Replacement SO TRANSPLANTATION LA English DT Review ID PORCINE ISLET XENOTRANSPLANTATION; MEDIATED INFLAMMATORY REACTION; NONHUMAN-PRIMATES; CYNOMOLOGUS MONKEYS; PIG ISLETS; REVERSAL; TRANSPLANTATION; SURVIVAL; IMMUNOSUPPRESSION; AUTOIMMUNITY AB The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation. C1 [Markmann, James F.] Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA. [Bartlett, Stephen T.; Bromberg, Jonathan] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA. [Johnson, Paul; Friend, Peter; Wood, Kathryn] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Johnson, Paul; Friend, Peter; Wood, Kathryn] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Korsgren, Olle] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Hering, Bernhard J.; Kandaswamy, Raja] Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA. [Scharp, David] Prodo Labs LLC, Irvine, CA USA. [Scharp, David] Scharp Lacy Res Inst, Irvine, CA USA. [Kay, Thomas W. H.] St Vincents Inst Med Res, 41 Victoria Parade, Fitzroy, Vic 3065, Australia. [Kay, Thomas W. H.] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia. [Odorico, Jon S.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Div Transplantat, Madison, WI USA. [Weir, Gordon C.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Weir, Gordon C.] Harvard Univ, Sch Med, Boston, MA USA. [Bridges, Nancy; Kraemer, Kristy] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Stock, Peter] Univ San Francisco, Med Ctr, Div Transplantat, San Francisco, CA 94117 USA. [Gotoh, Mitsukazu] Fukushima Med Univ, Dept Surg, Fukushima, Japan. [Cooper, David K. C.] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA. [Park, Chung-Gyu] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Xenotransplantat Res Ctr,Dept Microbiol & Immunol, Seoul, South Korea. [O'Connell, Philip J.] Univ Sydney, Westmead Hosp, Ctr Transplant & Renal Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Stabler, Cherie] Univ Florida, Dept Biomed Engn, Gainesville, FL USA. [Matsumoto, Shinichi] Otsuka Pharmaceut Factory Inc, Naruto, Japan. [Matsumoto, Shinichi] Natl Ctr Global Hlth & Med, Tokyo, Japan. [Ludwig, Barbara] Tech Univ Dresden, Dept Med 3, D-01062 Dresden, Germany. [Ludwig, Barbara] Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Ctr Munich, Paul Langerhans Inst Dresden, Dresden, Germany. [Ludwig, Barbara] DZD German Ctr Diabet Res, Dresden, Germany. [Choudhary, Pratik] Kings Coll London, Weston Educ Ctr, Diabet Res Grp, London WC2R 2LS, England. [Khovatchev, Boris] Univ Virginia, Ctr Diabet Technol, Charlottesville, VA USA. [Rickels, Michael R.] Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Sykes, Megan] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA. [Hwa, Albert] Juvenile Diabet Res Fdn, New York, NY USA. [Stanley, Edward] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Stanley, Edward] Monash Univ, Melbourne, Vic 3004, Australia. [Ricordi, Camillo] Univ Miami, Diabet Res Inst, Coral Gables, FL 33124 USA. [Zimmerman, Mark] BetaLogics, Raritan, NJ USA. [Greenstein, Julia] Juvenile Diabet Res Fdn, Discovery Res, New York, NY USA. [Montanya, Eduard] Univ Barcelona, Hosp Univ Bellvitge, CIBERDEM, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain. [Otonkoski, Timo] Univ Helsinki, Childrens Hosp, Helsinki, Finland. [Otonkoski, Timo] Univ Helsinki, Biomedicum Stem Cell Ctr, Helsinki, Finland. RP Markmann, JF (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WHT 517, Boston, MA 02114 USA. EM jmarkmann@partners.org RI Stabler, Cherie/E-8227-2011 NR 32 TC 3 Z9 3 U1 1 U2 6 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 JUL PY 2016 VL 100 IS 7 BP E25 EP E31 DI 10.1097/TP.0000000000001054 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DP0AG UT WOS:000378149300001 PM 27082827 ER PT J AU Gleason, CE Dowling, NM Benton, SF Kaseroff, A Gunn, W Edwards, DF AF Gleason, Carey E. Dowling, N. Maritza Benton, Susan Flowers Kaseroff, Ashley Gunn, Wade Edwards, Dorothy Farrar TI Common Sense Model Factors Affecting African Americans' Willingness to Consult a Healthcare Provider Regarding Symptoms of Mild Cognitive Impairment SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE timely diagnosis; mild cognitive impairment; common sense model; health disparities; structural equation modeling ID ALZHEIMERS ASSOCIATION WORKGROUPS; NURSING-HOME PLACEMENT; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; DEMENTIA DIAGNOSIS; TIMELY DIAGNOSIS; OLDER-ADULTS; DISEASE; SAMPLE; REPRESENTATIONS AB Objective: Although at increased risk for developing dementia compared with white patients, older African Americans are diagnosed later in the course of dementia. Using the common sense model (CSM) of illness perception, we sought to clarify processes promoting timely diagnosis of mild cognitive impairment (MCI) for African American patients. Design, Setting, Participants: In-person, cross-sectional survey data were obtained from 187 African American (mean age: 60.44 years). Data were collected at social and health-focused community events in three southern Wisconsin cities. Measurements: The survey represented a compilation of published surveys querying CSM constructs focused on early detection of memory disorders, and willingness to discuss concerns about memory loss with healthcare providers. Derived CSM variables measuring perceived causes, consequences, and controllability of MCI were included in a structural equation model predicting the primary outcome: Willingness to discuss symptoms of MCI with a provider. Results: Two CSM factors influenced willingness to discuss symptoms of MCI with providers: Anticipation of beneficial consequences and perception of low harm associated with an MCI diagnosis predicted participants' willingness to discuss concerns about cognitive changes. No association was found between perceived controllability and causes of MCI, and willingness to discuss symptoms with providers. Conclusions: These data suggest that allaying concerns about the deleterious effects of a diagnosis, and raising awareness of potential benefits, could influence an African American patient's willingness to discuss symptoms of MCI with a provider. The findings offer guidance to designers of culturally congruent MCI education materials, and healthcare providers caring for older African Americans. C1 [Gleason, Carey E.; Dowling, N. Maritza; Edwards, Dorothy Farrar] Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA. [Gleason, Carey E.; Edwards, Dorothy Farrar] Univ Wisconsin, Dept Med, Div Geriatr, Madison, WI USA. [Dowling, N. Maritza] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI USA. [Gleason, Carey E.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI USA. [Benton, Susan Flowers; Kaseroff, Ashley] Univ Wisconsin, Sch Educ, Dept Rehabil Psychol & Special Educ, Madison, WI USA. [Gunn, Wade; Edwards, Dorothy Farrar] Univ Wisconsin, Sch Educ, Kinesiol & Occupat Therapy, Madison, WI USA. RP Gleason, CE (reprint author), William S Middleton Mem VA Hosp, 2500 Overlook Terrace,GRECC 11G,D4223, Madison, WI 53705 USA. EM ceg@medicine.wisc.edu RI Edwards, Dorothy/L-6720-2016 FU Wisconsin ADRC Minority Recruitment Satellite Program; Education, Clinical, and Administrative Cores of the Wisconsin ADRC; Community-Academic Aging Research Network (CAARN); Wisconsin Partnership Program of the University of Wisconsin School of Medicine and Public Health; Wisconsin Alzheimer's Disease Research Center (ADRC; NIH-NIA) [P50-AG033514]; Madison VA Geriatric Research, Education, and Clinical Center (GRECC); Community-Academic Aging Research Network; National Institute on Aging [RC4AG038175]; NCATS via the UW Clinical and Translational Science Award (CTSA) [UL1TR000427] FX The authors acknowledge support from the Wisconsin ADRC Minority Recruitment Satellite Program, and the Education, Clinical, and Administrative Cores of the Wisconsin ADRC, and the Community-Academic Aging Research Network (CAARN). Finally, we are grateful for the dedication and support from our Community Partners, Charlestine Daniel, MS, and Paul Rusk from the Alzheimer's and Dementia Alliance; staff Ornella Hills, and Tyrone Dickson from the Wisconsin Alzheimer's Disease Research Center; project assistants Paul Izard and Brianna Harris; and our participants.; This project was funded by the Wisconsin Partnership Program of the University of Wisconsin School of Medicine and Public Health and the Wisconsin Alzheimer's Disease Research Center (ADRC; NIH-NIA grant P50-AG033514), and supported by the Madison VA Geriatric Research, Education, and Clinical Center (GRECC), and the Community-Academic Aging Research Network, award number RC4AG038175 from the National Institute on Aging. Additional support was provided by NCATS grant UL1TR000427 (PI: M. Drezner) via the UW Clinical and Translational Science Award (CTSA) and resources and use of facilities at the UW School of Medicine and Public Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging, the National Institutes of Health, or any other funding agency. This is GRECC manuscript number: 2014-027. NR 34 TC 0 Z9 0 U1 5 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2016 VL 24 IS 7 BP 537 EP 546 DI 10.1016/j.jagp.2015.08.005 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DO6BH UT WOS:000377866800005 PM 26809602 ER PT J AU Kaufmann, CN Mojtabai, R Hock, RS Thorpe, RJ Canham, SL Chen, LY Wennberg, AMV Chen-Edinboro, LP Spira, AP AF Kaufmann, Christopher N. Mojtabai, Ramin Hock, Rebecca S. Thorpe, Roland J., Jr. Canham, Sarah L. Chen, Lian-Yu Wennberg, Alexandra M. V. Chen-Edinboro, Lenis P. Spira, Adam P. TI Racial/Ethnic Differences in Insomnia Trajectories Among US Older Adults SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 01-05, 2013 CL Baltimore, MD SP Associated Profess Sleep Soc DE Disparities; Aging; Insomnia; Chronic health conditions ID SHORT-SLEEP DURATION; REGRESSION-ANALYSIS; RACIAL-DIFFERENCES; UNITED-STATES; SELF-REPORTS; HEALTH; POPULATION; SYMPTOMS; DISPARITIES; PREVALENCE AB Objectives: Insomnia is reported to be more prevalent in minority racial/ethnic groups. Little is known, however, about racial/ethnic differences in changes in insomnia severity over time, particularly among older adults. We examined racial/ethnic differences in trajectories of insomnia severity among middle-aged and older adults. Design: Data were drawn from five waves of the Health and Retirement Study (2002-2010), a nationally representative longitudinal biennial survey of adults aged > 50 years. Setting: Population-based. Participants: 22,252 participants from non-Hispanic white, non-Hispanic black, Hispanic, and other racial/ethnic groups. Measurements: Participants reported the severity of four insomnia symptoms; summed scores ranged from 4 (no insomnia) to 12 (severe insomnia). We assessed change in insomnia across the five waves as a function of race/ethnicity. Results: Across all participants, insomnia severity scores increased 0.19 points (95% CI: 0.14-0.24; t = 7.52; design df = 56; p < 0.001) over time after adjustment for sex, race/ethnicity, education, and baseline age. After adjusting for the number of accumulated health conditions and body mass index, this trend decreased substantially and even changed direction (B = -0.24; 95% CI: -0.29 to -0.19; t = -9.22; design df = 56; p < 0.001). The increasing trajectory was significantly more pronounced in Hispanics compared with non-Hispanic whites, even after adjustment for number of accumulated health conditions, body mass index, and number of depressive symptoms. Conclusions: Although insomnia severity increases with age-largely due to the accumulation of health conditions-this trend appears more pronounced among Hispanic older adults than in non-Hispanic whites. Further research is needed to determine the reasons for a different insomnia trajectory among Hispanics. C1 [Kaufmann, Christopher N.; Mojtabai, Ramin; Chen, Lian-Yu; Wennberg, Alexandra M. V.; Spira, Adam P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Thorpe, Roland J., Jr.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Hock, Rebecca S.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Hock, Rebecca S.] Harvard Univ, Sch Med, Boston, MA USA. [Canham, Sarah L.] Simon Fraser Univ, Gerontol Res Ctr, Vancouver, BC, Canada. [Chen-Edinboro, Lenis P.] Univ N Carolina, Sch Hlth & Appl Human Sci, Wilmington, NC 28401 USA. [Spira, Adam P.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. RP Kaufmann, CN (reprint author), 9500 Gilman Dr 0664, La Jolla, CA 92093 USA. EM cnkaufmann@ucsd.edu RI Wennberg, Alexandra/O-9563-2016 OI Wennberg, Alexandra/0000-0003-4906-1165 FU National Institutes of Health; National Institute on Aging [F31AG044052, K01AG033195]; National Institute of Mental Health [T32MH019934, T32MH093310, T32MH014592]; National Institute on Minority Health and Health Disparities [P60MD000214]; National Institute on Drug Abuse [T32DA007292] FX This work was supported by the National Institutes of Health. Drs. Kaufmann and Spira were supported by the National Institute on Aging (CNK: F31AG044052, APS: K01AG033195). Dr. Kaufmann currently receives funding from the National Institute of Mental Health (T32MH019934). Drs. Hock and Chen-Edinboro were supported by the National Institute of Mental Health (RSH: T32MH093310, LPC-E: T32MH014592). Dr. Thorpe was supported by the National Institute on Minority Health and Health Disparities (P60MD000214). Dr. Canham was supported by the National Institute on Drug Abuse (T32DA007292). All authors report no conflicts of interest. NR 28 TC 0 Z9 0 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2016 VL 24 IS 7 BP 575 EP 584 DI 10.1016/j.jagp.2016.02.049 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DO6BH UT WOS:000377866800008 PM 27212222 ER PT J AU Becerra, MB Becerra, BJ Hassija, CM Safdar, N AF Becerra, Monideepa B. Becerra, Benjamin J. Hassija, Christina M. Safdar, Nasia TI Unmet Mental Healthcare Need and Suicidal Ideation Among US Veterans SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSION; WAR VETERANS; RISK; AFGHANISTAN; SERVICES; DEATH; IRAQ; ASSOCIATION; SYMPTOMS AB Introduction: Suicide prevention remains a national priority, especially among vulnerable populations. With increasing trends in suicide among Veterans, understanding the underlying factors associated with such an outcome is imperative. In this study, the association between unmet mental healthcare need and suicidal ideation among U.S. Veterans was evaluated. Methods: The National Survey on Drug Use and Health, 2008-2013, was used to identify those with mental illness, resulting in a total sample of 2,015 Veterans. Data were analyzed in July 2015. Survey-weighted descriptive and logistic regression analyses were conducted with p<0.05 used to establish significance. Results: Sixteen percent of Veterans reported unmet mental healthcare need and 18% had past-year suicidal ideation. After adjusting for confounders, unmet mental healthcare need was associated with increased likelihood of suicidal ideation (AOR=4.11) in the study population. Other characteristics, such as participating in a governmental assistance program and alcohol dependency in the past year, demonstrated 66% and 103% increased odds of suicidal ideation, respectively. Conclusions: Unmet mental healthcare need is a critical aspect of suicidal ideation among Veterans. Improved access to care for such at-risk populations through means of integrated care is needed to ensure reduced burden of suicide among Veterans. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [Becerra, Monideepa B.] Calif State Univ San Bernardino, Dept Hlth Sci & Human Ecol, San Bernardino, CA 92407 USA. [Becerra, Monideepa B.; Becerra, Benjamin J.; Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Becerra, Benjamin J.] Loma Linda Univ, Sch Allied Hlth Profess, Loma Linda, CA 92350 USA. [Hassija, Christina M.] Calif State Univ San Bernardino, Dept Psychol, San Bernardino, CA 92407 USA. [Safdar, Nasia] Univ Wisconsin, Dept Med, Madison, WI USA. RP Becerra, MB (reprint author), 5500 Univ Pkwy, San Bernardino, CA 92407 USA. EM mbecerra@csusb.edu FU U.S. Department of Veterans Affairs (VA) Merit grant; VA National Center for Patient Safety FX Nasia Safdar is supported by a U.S. Department of Veterans Affairs (VA) Merit grant and by the VA National Center for Patient Safety. NR 33 TC 0 Z9 0 U1 8 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2016 VL 51 IS 1 BP 90 EP 94 DI 10.1016/j.amepre.2016.01.015 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DO8VR UT WOS:000378063800013 PM 26927480 ER PT J AU Coulon, SM Monroe, CM West, DS AF Coulon, Sandra M. Monroe, Courtney M. West, Delia S. TI A Systematic, Multi-domain Review of Mobile Smartphone Apps for Evidence-Based Stress Management SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH-CARE PROVIDERS; GOOD MEDICAL-ETHICS; SOCIOECONOMIC-STATUS; MENTAL-HEALTH; ANXIETY; DEPRESSION; ADHERENCE; QUALITY; TOOLS; PRINCIPLES AB Contex: Chronic stress presents a growing, pervasive burden in healthcare, and mobile smartphone applications (apps) have the potential to deliver evidence-based stress management strategies. This review identified and evaluated stress management apps across domains of (1) evidence-based content; (2) transparency in app development; and (3) functionality of the app interface. Evidence acquisition: The iOS App Store was systematically searched. Apps with descriptions indicating that they targeted the intended audience and included evidence-related terminology, at least one evidence-based stress management strategy, and behavior change components were downloaded and evaluated by two independent raters across the three domains of evidence-based content, transparency, and functionality. Evidence synthesis: A total of 902 apps were identified based on 21 searches. Of these, 60 met study criteria and were downloaded and evaluated between April and June 2015. Twenty (33%) ultimately did not deliver an evidence-based strategy. Of the delivered strategies, the most common were mindfulness and meditation (73%) and diaphragmatic breathing (25%). On average, apps addressed half of the transparency criteria, and nearly all (85%) were acceptable across usability criteria. A total of 32 apps included both evidence-based content and exhibited no problems with usability or functionality; apps affiliated with a non-profit, research-engaged institution comprised 31% of these. Conclusions: This review evaluated 60 iOS apps for stress management across domains of evidence-based content, transparency, and functionality; these apps have the potential to effectively supplement medical care. Findings further indicate that a comprehensive, multi-domain approach can distinguish apps that use evidence-based strategies from those that do not. (C) 2016 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Coulon, Sandra M.; Monroe, Courtney M.; West, Delia S.] Univ S Carolina, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. RP Coulon, SM (reprint author), Ralph H Johnson Vet Affairs Med Ctr, 109 Bee St,Mental Hlth Serv 116, Charleston, SC 29401 USA. EM coulon@mailbox.sc.edu FU Technology Center to Promote Healthy Lifestyles (TecHealth), Arnold School of Public Health, University of South Carolina FX This work was funded in part by the Technology Center to Promote Healthy Lifestyles (TecHealth), Arnold School of Public Health, University of South Carolina. SMC, CMM, and DSW contributed to the manuscript in its conception and writing. SMC and DSW developed the app screening and evaluation methods. SMC and CMM each evaluated the downloaded stress management apps. SMC screened app descriptions and CMM assessed the reliability of the screening. SMC developed data collection tools; extracted, cleaned, and analyzed the data; and wrote the initial drafts of the manuscript. CMM and DSW revised the drafts. The work was performed while SMC was at the University of South Carolina. All authors had full access to all of the data, and read and approved the final manuscript. NR 49 TC 1 Z9 1 U1 10 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2016 VL 51 IS 1 BP 95 EP 105 DI 10.1016/j.amepre.2016.01.026 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DO8VR UT WOS:000378063800014 PM 26993534 ER PT J AU Shahian, DM Normand, SLT Friedberg, MW Hutter, MM Pronovost, PJ AF Shahian, David M. Normand, Sharon-Lise T. Friedberg, Mark W. Hutter, Matthew M. Pronovost, Peter J. TI Rating the Raters: The Inconsistent Quality of Health Care Performance Measurement SO ANNALS OF SURGERY LA English DT Editorial Material ID OUTCOMES C1 [Shahian, David M.; Hutter, Matthew M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Shahian, David M.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Shahian, David M.; Friedberg, Mark W.; Hutter, Matthew M.] Harvard Univ, Sch Med, Boston, MA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Friedberg, Mark W.] RAND Corp, Boston, MA USA. [Friedberg, Mark W.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Armstrong Inst Patient Safety & Qual, Baltimore, MD USA. [Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 284, Boston, MA 02114 USA. EM dshahian@partners.org NR 17 TC 1 Z9 1 U1 3 U2 5 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 JUL PY 2016 VL 264 IS 1 BP 36 EP 38 DI 10.1097/SLA.0000000000001631 PG 3 WC Surgery SC Surgery GA DO4RB UT WOS:000377769600009 PM 26756770 ER PT J AU Patel, MS Chaikof, EL AF Patel, Madhukar S. Chaikof, Elliot L. TI Promoting Creativity and Innovation in a Structured Learning Environment SO ANNALS OF SURGERY LA English DT Editorial Material C1 [Patel, Madhukar S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Patel, Madhukar S.; Chaikof, Elliot L.] Beth Israel Deaconess Med Ctr, Dept Surg, 330 Brookline Ave, Boston, MA 02215 USA. [Patel, Madhukar S.; Chaikof, Elliot L.] Harvard Univ, Sch Med, Boston, MA USA. RP Chaikof, EL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, 110 Francis St,Suite 9F, Boston, MA 02115 USA. EM echaikof@bidmc.harvard.edu NR 8 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUL PY 2016 VL 264 IS 1 BP 39 EP 40 DI 10.1097/SLA.0000000000001658 PG 2 WC Surgery SC Surgery GA DO4RB UT WOS:000377769600010 PM 26835984 ER PT J AU Ghogawala, Z Schwartz, JS Benzel, EC Magge, SN Coumans, JV Harrington, JF Gelbs, JC Whitmore, RG Butler, WE Barker, FG AF Ghogawala, Zoher Schwartz, J. Sanford Benzel, Edward C. Magge, Subu N. Coumans, Jean Valery Harrington, J. Fred Gelbs, Jared C. Whitmore, Robert G. Butler, William E. Barker, Fred G., II TI Increased Patient Enrollment to a Randomized Surgical Trial Through Equipoise Polling of an Expert Surgeon Panel SO ANNALS OF SURGERY LA English DT Article DE clinical equipoise; clinical trial design; clinical trial recruitment; ethics trial discontinuation; outcomes expert panel; randomized clinical trial ID LUMBAR SPINAL STENOSIS; RISK AB Objective: To determine whether patients who learned the views of an expert surgeons' panel's assessment of equipoise between 2 alternative operative treatments had increased likelihood of consenting to randomization. Background: Difficulty obtaining patient consent to randomization is an important barrier to conducting surgical randomized clinical trials, the gold standard for generating clinical evidence. Methods: Observational study of the rate of patient acceptance of randomization within a 5-center randomized clinical trial comparing lumbar spinal decompression versus lumbar spinal decompression plus instrumented fusion for patients with symptomatic grade I degenerative lumbar spondylolisthesis with spinal stenosis. Eligible patients were enrolled in the trial and then asked to accept randomization. A panel of 10 expert spine surgeons was formed to review clinical information and images for individual patients to provide an assessment of suitability for randomization. The expert panel vote was disclosed to the patient by the patient's surgeon before the patient decided whether to accept randomization or not. Results: Randomization acceptance among eligible patients without expert panel review was 40% (19/48) compared with 81% (47/58) among patients undergoing expert panel review (P < 0.001). Among expert-reviewed patients, randomization acceptance was 95% when all experts or all except 1 voted for randomization, 75% when 2 experts voted against randomization, and 20% with 3 or 4 votes against (P < 0.001 for trend). Conclusions: Patients provided with an expert panel's assessment of their own suitability for randomization were twice as likely to agree to randomization compared with patients receiving only their own surgeon's recommendation. C1 [Ghogawala, Zoher; Magge, Subu N.; Whitmore, Robert G.] Lahey Hosp & Med Ctr, Alan & Jacqueline Stuart Spine Ctr, Dept Neurosurg, Burlington, MA USA. [Ghogawala, Zoher] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Ghogawala, Zoher; Gelbs, Jared C.] Greenwich Hosp, Wallace Trials Ctr, Greenwich, CT USA. [Schwartz, J. Sanford] Univ Penn, Wharton Sch Business, Perelman Sch Med, Philadelphia, PA 19104 USA. [Schwartz, J. Sanford] Univ Penn, Leonard Davis Inst, Philadelphia, PA 19104 USA. [Benzel, Edward C.] Cleveland Clin Fdn, Ctr Spine Hlth, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Benzel, Edward C.] Cleveland Clin Fdn, Dept Neurosurg, Cleveland, OH 44195 USA. [Coumans, Jean Valery; Butler, William E.; Barker, Fred G., II] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. [Coumans, Jean Valery; Butler, William E.; Barker, Fred G., II] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Harrington, J. Fred] Univ New Mexico, Dept Neurosurg, Albuquerque, NM 87131 USA. RP Ghogawala, Z (reprint author), Tufts Univ, Sch Med, Lahey Hosp & Med Ctr, Dept Neurosurg, 41 Mall Rd, Burlington, MA 01805 USA. EM zoher.ghogawala@lahey.org FU Wallace Foundation [GH-382]; Watson Foundation [GH-387]; Stryker FX This study was supported by private research funds from the Wallace Foundation (GH-382) and the Watson Foundation (GH-387). Z. G. and W. E. B. have disclosed intellectual property interest in a software algorithm that can administer an equipoise panel on a web platform (US Patent Application No 13/872,596). E. C. B. reported being inventor and developer of an arthroplasty device for AxioMed and is a consultant for AxioMed Spine. He also reports board membership for OrthoMEMS and grant funding from Stryker. NR 21 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUL PY 2016 VL 264 IS 1 BP 81 EP 86 DI 10.1097/SLA.0000000000001483 PG 6 WC Surgery SC Surgery GA DO4RB UT WOS:000377769600016 PM 26501698 ER PT J AU Patel, AP Peloso, GM Pirruccello, JP Johansen, CT Dube, JB Larach, DB Ban, MR Dallinge-Thie, GM Gupta, N Boehnke, M Abecasis, GR Kastelein, JJP Hovingh, GK Hegele, RA Rader, DJ Kathiresan, S AF Patel, Aniruddh P. Peloso, Gina M. Pirruccello, James P. Johansen, Christopher T. Dube, Joseph B. Larach, Daniel B. Ban, Matthew R. Dallinge-Thie, Geesje M. Gupta, Namrata Boehnke, Michael Abecasis, Gonalo R. Kastelein, John J. P. Hovingh, G. Kees Hegele, Robert A. Rader, Daniel J. Kathiresan, Sekar TI Targeted exonic sequencing of GWAS loci in the high extremes of the plasma lipids distribution SO ATHEROSCLEROSIS LA English DT Article DE Genetic techniques; Genomics; Lipids; Human genetics ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; SINGLE NUCLEOTIDE POLYMORPHISMS; CORONARY-HEART-DISEASE; APOLIPOPROTEIN-A-IV; MACULAR DEGENERATION; HIGH-RISK; RARE VARIANTS; POPULATION; TRIGLYCERIDES AB Objective: Genome-wide association studies (GWAS) for plasma lipid levels have mapped numerous genomic loci, with each region often containing many protein-coding genes. Targeted re-sequencing of exons is a strategy to pinpoint causal variants and genes. Methods: We performed solution-based hybrid selection of 9008 exons at 939 genes within 95 GWAS loci for plasma lipid levels and sequenced using next-generation sequencing technology individuals with extremely high as well as low to normal levels of low-density lipoprotein cholesterol (LDL-C, n = 311; mean low = 71 mg/dl versus high = 241 mg/dl), triglycerides (TG, n = 308; mean low = 75 mg/dl versus high = 1938 mg/dl), and high-density lipoprotein cholesterol (HDL-C, n = 684; mean low = 32 mg/dl versus high = 102 mg/dl). We identified 15,002 missense, nonsense, or splice site variants with a frequency <5%. We tested whether coding sequence variants, individually or aggregated within a gene, were associated with plasma lipid levels. To replicate findings, we performed sequencing in independent participants (n = 6424). Results: Across discovery and replication sequencing, we found 6 variants with significant associations with plasma lipids. Of these, one was a novel association: p. Ser147Asn variant in APOA4 (14.3% frequency, TG OR = 0.49, P = 7.1 x 10(-4)) with TG. In gene-level association analyses where rare variants within each gene are collapsed, APOC3 (P = 2.1 x 10(-5)) and LDLR (P = 5.0 x 10(-12)) were associated with plasma lipids. Conclusions: After sequencing genes from 95 GWAS loci in participants with extremely high plasma lipid levels, we identified one new coding variant associated with TG. These results provide insight regarding design of similar sequencing studies with respect to sample size, follow-up, and analysis methodology. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Patel, Aniruddh P.; Peloso, Gina M.; Pirruccello, James P.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Patel, Aniruddh P.; Peloso, Gina M.; Pirruccello, James P.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Patel, Aniruddh P.; Peloso, Gina M.; Pirruccello, James P.; Gupta, Namrata; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Patel, Aniruddh P.; Pirruccello, James P.; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Johansen, Christopher T.; Dube, Joseph B.; Ban, Matthew R.; Hegele, Robert A.] Univ Western Ontario, Dept Med, London, ON, Canada. [Larach, Daniel B.] Univ Michigan, Dept Anesthesiol, Sch Med, Ann Arbor, MI 48109 USA. [Dallinge-Thie, Geesje M.; Kastelein, John J. P.; Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Boehnke, Michael; Abecasis, Gonalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. RP Kathiresan, S (reprint author), 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM Sekar@broadinstitute.org RI Hegele, Robert/G-3301-2011 FU Stanley J. Sarnoff Cardiovascular Research Foundation; NHLBI [5RC1HL099793, T32HL007208]; British Heart Foundation; Massachusetts General Hospital [R01HL107816]; Fondation Leducq; Dutch Heart Foundation; Netherlands Organisation for Scientific Research (NWO) [91612122]; CardioVascular Research Initiative [CVON2011-19]; European Union [TransCard: FP7-603091-2] FX APP and JPP are recipients of research fellowships from the Stanley J. Sarnoff Cardiovascular Research Foundation. Funding for this study was provided by NHLBI grant 5RC1HL099793 to DJR. GMP is supported by award number T32HL007208 from the NHLBI. NJS holds a Chair supported by the British Heart Foundation. SK is supported by a Research Scholar award from the Massachusetts General Hospital, R01HL107816, and a grant from Fondation Leducq. JJPK is holder of a lifetime achievement award from the Dutch Heart Foundation. GKH is a recipient of a Veni grant (project number 91612122) from the Netherlands Organisation for Scientific Research (NWO). GKH is holder of a Veni grant (91612122) from the Netherlands Organisation for Scientific Research. This work is supported by the CardioVascular Research Initiative (CVON2011-19; Genius), European Union (TransCard: FP7-603091-2), and Fondation Leducq (Transatlantic Network, 2009-2014). NR 46 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2016 VL 250 BP 63 EP 68 DI 10.1016/j.atherosclerosis.2016.04.011 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DO7SH UT WOS:000377982800010 PM 27182959 ER PT J AU Pham, H Hui, HX Morvaridi, S Cai, JN Zhang, SQ Tan, J Wu, V Levin, N Knudsen, B Goddard, WA Pandol, SJ Abrol, R AF Hung Pham Hui, Hongxiang Morvaridi, Susan Cai, Jiena Zhang, Sanqi Tan, Jun Wu, Vincent Levin, Nancy Knudsen, Beatrice Goddard, William A., III Pandol, Stephen J. Abrol, Ravinder TI A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE GLP-1; Diabetes; Enteroendocrine L-cell; GPCR structure prediction; Virtual ligand screening; Gut receptors ID CHAIN FATTY-ACID; DIPEPTIDYL-PEPTIDASE-IV; GLUCAGON-LIKE PEPTIDE-1; GASTROINTESTINAL-TRACT; STC-1 CELLS; HUMAN COLON; GUT; SECRETION; EXPRESSION; GUSTDUCIN AB The bitter taste receptor TAS2R38 is a G protein coupled receptor (GPCR) that has been found in many extra-oral locations like the gastrointestinal (GI) system, respiratory system, and brain, though its function at these locations is only beginning to be understood. To probe the receptor's potential metabolic role, immunohistochemistry of human ileum tissues was performed, which showed that the receptor was co-localized with glucagon-like peptide 1 (GLP-1) in L-cells. In a previous study, we had modeled the structure of this receptor for its many taste-variant haplotypes (Tan et al. 2011), including the taster haplotype PAV. The structure of this haplotype was then used in a virtual ligand screening pipeline using a collection of similar to 2.5 million purchasable molecules from the ZINC database. Three compounds (Z7, Z3, Z1) were purchased from the top hits and tested along with PTU (known TAS2R38 agonist) in in vitro and in vivo assays. The dose-response study of the effect of PTU and Z7 on GLP-1 release using wild-type and TAS2R38 knockout HuTu-80 cells showed that the receptor TAS2R38 plays a major role in GLP-1 release due to these molecules. In vivo studies of PTU and the three compounds showed that they each increase GLP-1 release. PTU was also chemical linked to cellulose to slow its absorption and when tested in vivo, it showed an enhanced and prolonged GLP-1 release. These results suggest that the GI lumen location of TAS2R38 on the L-cell makes it a relatively safe drug target as systemic absorption is not needed for a TAS2R38 agonist drug to effect GLP-1 release. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hung Pham; Morvaridi, Susan; Knudsen, Beatrice; Pandol, Stephen J.; Abrol, Ravinder] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Hung Pham; Morvaridi, Susan; Knudsen, Beatrice; Pandol, Stephen J.; Abrol, Ravinder] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Hui, Hongxiang; Knudsen, Beatrice; Pandol, Stephen J.; Abrol, Ravinder] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Hui, Hongxiang; Cai, Jiena] Southern Med Univ, Int Ctr Metab Dis, Guangzhou, Guangdong, Peoples R China. [Zhang, Sanqi] Xi An Jiao Tong Univ, Dept Med Chem, Xian 710061, Peoples R China. [Tan, Jun; Goddard, William A., III; Abrol, Ravinder] CALTECH, Mat & Proc Simulat Ctr, Pasadena, CA 91125 USA. [Tan, Jun] Chongqing Univ, Bioengn Coll, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400030, Peoples R China. [Wu, Vincent; Pandol, Stephen J.] Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Levin, Nancy; Pandol, Stephen J.; Abrol, Ravinder] GIRx Metab Inc, Los Angeles, CA USA. RP Pandol, SJ; Abrol, R (reprint author), Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA.; Pandol, SJ; Abrol, R (reprint author), Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA.; Hui, HX; Pandol, SJ; Abrol, R (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA.; Hui, HX (reprint author), Southern Med Univ, Int Ctr Metab Dis, Guangzhou, Guangdong, Peoples R China. EM abrolr@csmc.edu FU Materials and Process Simulation Center at Caltech; Cedars-Sinai Medical Center; NIH [P01CA163200]; Department of Veterans Affairs FX RA acknowledges support in part from Materials and Process Simulation Center at Caltech when this project started and from start-up funds provided by Cedars-Sinai Medical Center. SJP acknowledges partial support for this project from NIH P01CA163200 and the Department of Veterans Affairs. NR 40 TC 2 Z9 2 U1 7 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 1 PY 2016 VL 475 IS 3 BP 295 EP 300 DI 10.1016/j.bbrc.2016.04.149 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DO6XH UT WOS:000377926300009 PM 27208775 ER PT J AU Ryan, J Montero, J Rocco, J Letai, A AF Ryan, Jeremy Montero, Joan Rocco, James Letai, Anthony TI iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry SO BIOLOGICAL CHEMISTRY LA English DT Article; Proceedings Paper CT EMBO Workshop on Mitochondria, Apoptosis and Cancer (MAC) CY SEP 10-12, 2015 CL Frankfurt, GERMANY SP EMBO DE apoptosis; BCL-2; cancer; chemotherapy; flow cytometry; mitochondria ID BCL-2 FAMILY; CELLS; CHEMOTHERAPY AB Dysregulation of the mitochondrial pathway of apoptosis, controlled by the BCL-2 family of proteins, leads to disease states including cancer. Rapid analysis of a cell's dependency on the BCL-2 family of proteins is hindered by the complex interactions of more than a dozen proteins. Transcript or even protein levels are therefore generally insufficient to predict a cell's response to perturbations like chemotherapy. Previously, we developed the JC-1 BH3 method to provide a same day functional assay to assess a cell's propensity to undergo apoptosis and demonstrated its utility in predicting response to chemotherapy. We have now improved upon these methods to create a robust assay amenable to high throughput platforms using cytochrome c retention in formaldehyde fixed cells to remove the time sensitivity of JC-1 potential measurements. BH3 profiling by intracellular staining (iBH3) is suitable for 96- and 384-well formats, and can be used to directly screen candidate BH3-mimetic compounds for activity. When used as the final component of dynamic BH3 profiling (DBP), which uses a drug pretreatment prior to iBH3 to assess the change in profile due to treatment, it can predict the response of cells to chemotherapy days before they show signs of death. C1 [Ryan, Jeremy; Montero, Joan; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,M430, Boston, MA 02210 USA. [Rocco, James] Ohio State Univ, Dept Otolaryngol, Wexner Med Ctr, Columbus, OH 43212 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,M430, Boston, MA 02210 USA. EM Anthony_Letai@dfci.harvard.edu OI Ryan, Jeremy/0000-0002-3327-1283 NR 14 TC 4 Z9 4 U1 2 U2 5 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 EI 1437-4315 J9 BIOL CHEM JI Biol. Chem. PD JUL PY 2016 VL 397 IS 7 BP 671 EP 678 DI 10.1515/hsz-2016-0107 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO6KQ UT WOS:000377892600010 PM 26910743 ER PT J AU Mahal, BA Muralidhar, V Chen, YW Choueiri, TK Hoffman, KE Hu, JC Sweeney, CJ Yu, JB Feng, FY Trinh, QD Nguyen, PL AF Mahal, Brandon A. Muralidhar, Vinayak Chen, Yu-Wei Choueiri, Toni K. Hoffman, Karen E. Hu, Jim C. Sweeney, Christopher J. Yu, James B. Feng, Felix Y. Quoc-Dien Trinh Nguyen, Paul L. TI Gleason score 5+3=8 prostate cancer: much more like Gleason score 9? SO BJU INTERNATIONAL LA English DT Article DE prostatic neoplasms; Gleason score; cancer mortality; outcomes research ID RADICAL PROSTATECTOMY; DISEASE RECURRENCE; RADIATION-THERAPY; FOLLOW-UP; PATTERN 5; RISK; PROGRESSION; PREDICTOR; DURATION AB Objective To determine whether patients with Gleason score 5 + 3 = 8 prostate cancer have outcomes more similar to other patients with Gleason score 8 disease or to patients with Gleason score 9 disease. Patients and Methods The Surveillance, Epidemiology and End Results (SEER) database was used to study 40 533 men diagnosed with N0M0 Gleason score 8 or 9 prostate cancer from 2004 to 2011. Using Gleason score 4 + 4 = 8 as the referent, Fine and Gray competing risks regression analyses modelled the association between Gleason score and prostate cancer-specific mortality (PCSM). Results The 5-year PCSM rates for patients with Gleason score 4 + 4 = 8, 3 + 5 = 8, 5 + 3 = 8, and 9 disease were 6.3%, 6.6%, 13.5%, and 13.9%, respectively (P < 0.001). Patients with Gleason score 5 + 3 = 8 or 9 disease had up to a two-fold increased risk of PCSM (adjusted hazard ratio [AHR] 1.89, 95% confidence interval [CI] 1.50-2.38, P < 0.001; and AHR 2.17, 95% CI 1.99-2.36, P < 0.001, respectively) compared with the referent group of patients (Gleason score 4 + 4 = 8). There was no difference in PCSM between patients with Gleason score 5 + 3 = 8 vs 9 disease (P = 0.25). Conclusions Gleason score 8 disease represents a heterogeneous entity with PCSM outcomes distinguishable by the primary Gleason pattern. The PCSM of Gleason score 3 + 5 = 8 and Gleason 4 + 4 = 8 disease are similar, but patients with Gleason score 5 + 3 = 8 have a risk of PCSM that is twice as high as other patients with Gleason score 8 disease and should be considered to have a similar poor prognosis as patients with Gleason score 9 disease. Such patients should be allowed onto trials seeking the highest-risk patients in which to test novel aggressive treatment strategies. C1 [Mahal, Brandon A.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Muralidhar, Vinayak] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Chen, Yu-Wei] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Choueiri, Toni K.; Sweeney, Christopher J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Choueiri, Toni K.; Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Hu, Jim C.] Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. [Yu, James B.] Yale Univ, Dept Therapeut Radiol Radiat Oncol, New Haven, CT USA. [Feng, Felix Y.] Univ Michigan Hlth Syst, Dept Radiat Oncol, Ann Arbor, MI USA. [Quoc-Dien Trinh] Brigham & Womens Hosp, Div Urol, 75 Francis St, Boston, MA 02115 USA. [Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu FU Prostate Cancer Foundation; Fitz's Cancer Warriors; Hugh Simons in Honour of Frank and Anne Simons; Scott Forbes/Gina Ventre Fund; Anonymous Family Foundation FX This work is supported by David and Cynthia Chapin, the Prostate Cancer Foundation, Fitz's Cancer Warriors, Hugh Simons in Honour of Frank and Anne Simons, the Scott Forbes/Gina Ventre Fund, and a grant from an Anonymous Family Foundation. NR 25 TC 7 Z9 7 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD JUL PY 2016 VL 118 IS 1 BP 95 EP 101 DI 10.1111/bju.13239 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DO8OK UT WOS:000378042700017 PM 26207642 ER PT J AU Keay, SK Zhang, CO AF Keay, Susan K. Zhang, Chen-Ou TI Abnormal Akt signalling in bladder epithelial cell explants from patients with interstitial cystitis/bladder pain syndrome can be induced by antiproliferative factor treatment of normal bladder cells SO BJU INTERNATIONAL LA English DT Article DE bladder epithelial cells; Akt; Wnt/frizzled; antiproliferative factor; interstitial cystitis/bladder pain syndrome ID EPIDERMAL-GROWTH-FACTOR; SYNDROME/INTERSTITIAL CYSTITIS; GENE-EXPRESSION; URINE MARKERS; PATHWAY; PROTEIN; CANCER; DIFFERENTIATION; UROTHELIUM; ACTIVATION AB Objectives To determine whether protein kinase B (Akt) signalling and secretion of specific downstream effector proteins are abnormal in specific cell fractions of bladder epithelial cells from patients with interstitial cystitis/bladder pain syndrome (IC/BPS), as explanted bladder epithelial cells from patients with IC/BPS produce a frizzled 8-related glycopeptide antiproliferative factor (APF) that inhibits normal bladder epithelial cell proliferation and expression of several proteins known to be regulated by Akt signalling. A related secondary objective was to determine whether treatment of normal bladder epithelial cells with active synthetic asialo-antiproliferative factor (as-APF) induces similar changes in Akt signalling and specific downstream effector proteins/mRNAs. Patients and Methods Cell proteins were extracted into four subcellular fractions from primary bladder epithelial explants of six patients who fulfilled modified National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria for IC/BPS and six age-and gender-matched controls. Total and/or phosphorylated cellular Akt, glycogen synthase kinase 3 beta (GSK3 beta), and beta-catenin; total cellular JunB; and secreted matrix metalloproteinase 2 (MMP2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) levels were determined by Western blot. MMP2, JunB, p53, uroplakin 3 (UPK3), and beta-actin mRNAs were quantified by quantitative reverse transcriptase-polymerase chain reaction. Akt activity was determined by nonradioactive assay. Results IC/BPS cells had lower Akt activity, along with lower Akt ser473- and GSK3 beta ser9-phosphorylation and higher beta-catenin ser33,37/thr41-phosphorylation in specific fractions as compared with matched control cells. IC/BPS explants also had evidence of additional downstream abnormalities compared with control cells, including lower nuclear JunB; lower secreted MMP2 and HB-EGF; plus lower MMP2, JunB, and UPK3 mRNAs but higher p53 mRNA relative to beta-actin. Each of these IC/BPS cell abnormalities was also induced in normal cells by as-APF. Conclusion These findings indicate that IC/BPS cells have abnormal Akt activity with downstream protein expression abnormalities including decreased MMP2 and HB-EGF secretion. They also support the hypothesis that APF plays a role in the pathogenesis of IC/BPS via its effects on cell Akt signalling and HB-EGF production. C1 [Keay, Susan K.] Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. [Keay, Susan K.] US Dept Vet Affairs, Med Ctr, Med Serv, Baltimore, MD USA. [Zhang, Chen-Ou] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. RP Keay, SK (reprint author), Vet Affairs Maryland Hlth Care Syst, Room 3B-184,10 N Green St, Baltimore, MD 21201 USA. EM susan.keay2@va.gov FU Office of Research and Development (Medical Research Service), Department of Veterans Affairs; NIH [R01 DK52596] FX The authors thank Toby Chai, MD, for providing the patient biopsies from which the explanted cells were originally propagated. This work was supported by the Office of Research and Development (Medical Research Service), Department of Veterans Affairs, and by NIH R01 DK52596. Chen-Ou Zhang carried out major experiments and prepared the figures for these studies. Susan K. Keay designed the research, supervised performance of the experiments and interpretation of the data, and prepared the manuscript, which was reviewed by Chen-Ou Zhang before submission. NR 54 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD JUL PY 2016 VL 118 IS 1 BP 161 EP 172 DI 10.1111/bju.13457 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA DO8OK UT WOS:000378042700026 PM 26919663 ER PT J AU Kagan, VE Jiang, J Huang, Z Tyurina, YY Desbourdes, C Cottet-Rousselle, C Dar, HH Verma, M Tyurin, VA Kapralov, AA Cheikhi, A Mao, G Stolz, D Croix, CMS Watkins, S Shen, Z Li, Y Greenberg, ML Tokarska-Schlattner, M Boissan, M Lacombe, ML Epand, RM Chu, CT Mallampalli, RK Bayir, H Schlattner, U AF Kagan, V. E. Jiang, J. Huang, Z. Tyurina, Y. Y. Desbourdes, C. Cottet-Rousselle, C. Dar, H. H. Verma, M. Tyurin, V. A. Kapralov, A. A. Cheikhi, A. Mao, G. Stolz, D. Croix, C. M. St. Watkins, S. Shen, Z. Li, Y. Greenberg, M. L. Tokarska-Schlattner, M. Boissan, M. Lacombe, M-L Epand, R. M. Chu, C. T. Mallampalli, R. K. Bayir, H. Schlattner, U. TI NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID NUCLEOSIDE-DIPHOSPHATE-KINASE; SACCHAROMYCES-CEREVISIAE; ESSENTIAL REQUIREMENT; SELECTIVE AUTOPHAGY; INTERMEMBRANE SPACE; HEART MITOCHONDRIA; MAMMALIAN-CELLS; FUNCTIONAL-ROLE; MEMBRANE; PROTEIN AB Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation. C1 [Kagan, V. E.; Jiang, J.; Huang, Z.; Tyurina, Y. Y.; Dar, H. H.; Tyurin, V. A.; Kapralov, A. A.; Cheikhi, A.; Mao, G.] Univ Pittsburgh, Ctr Free Radical & Antioxidant Hlth, Dept Environm & Occupat Hlth, 100 Technol Dr,Suite 350, Pittsburgh, PA 15219 USA. [Desbourdes, C.; Cottet-Rousselle, C.; Tokarska-Schlattner, M.; Schlattner, U.] Univ Grenoble Alpes UJF, LBFA, BP 53, F-38041 Grenoble 9, France. [Desbourdes, C.; Cottet-Rousselle, C.; Tokarska-Schlattner, M.; Schlattner, U.] Univ Grenoble Alpes UJF, SFR Environm & Syst Biol BEeSy, U1055, BP 53, F-38041 Grenoble 9, France. [Desbourdes, C.; Cottet-Rousselle, C.; Tokarska-Schlattner, M.; Schlattner, U.] INSERM, U1055, Grenoble, France. [Verma, M.; Chu, C. T.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Stolz, D.; Croix, C. M. St.; Watkins, S.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. [Shen, Z.; Li, Y.; Greenberg, M. L.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Boissan, M.; Lacombe, M-L] Univ Paris 06, Sorbonne Univ, St Antoine Res Ctr, INSERM,UMR S 938, Paris, France. [Boissan, M.] Hop Tenon, AP HP, Serv Biochim & Hormonol, F-75970 Paris, France. [Epand, R. M.] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. [Mallampalli, R. K.] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA USA. [Mallampalli, R. K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. [Bayir, H.] Univ Pittsburgh, Dept Crit Care Med, 3434 Fifth Ave, Pittsburgh, PA 15260 USA. RP Kagan, VE (reprint author), Univ Pittsburgh, Ctr Free Radical & Antioxidant Hlth, Dept Environm & Occupat Hlth, 100 Technol Dr,Suite 350, Pittsburgh, PA 15219 USA.; Schlattner, U (reprint author), Univ Grenoble Alpes UJF, LBFA, BP 53, F-38041 Grenoble 9, France.; Schlattner, U (reprint author), Univ Grenoble Alpes UJF, SFR Environm & Syst Biol BEeSy, U1055, BP 53, F-38041 Grenoble 9, France.; Bayir, H (reprint author), Univ Pittsburgh, Dept Crit Care Med, 3434 Fifth Ave, Pittsburgh, PA 15260 USA. EM Kagan@pitt.edu; hub22@pitt.edu; uwe.schlattner@ujf-grenoble.fr OI Kapralov, Oleksandr/0000-0002-3006-916X; Tyurin, Vladimir/0000-0002-3474-1697 FU National Institutes of Health [P01HL114453, U19AI068021, NS076511, NS061817, ES020693, NS065789, AG026389, HL117880]; National Institute of Occupational Safety and Health [OH008282]; Human Frontier Science Program [HFSP-RGP0013/2014]; Barth Syndrome Foundation of Canada; Barth Syndrome Foundation of United States; Fondation pour la Recherche Medicale (FRM) [DPM20121125557]; CMIRA Explo'ra doc fellowship of the Region Rhone Alpes; GEFLUC; Natural Sciences and Engineering Council of Canada [9848] FX This study was supported in part by the National Institutes of Health P01HL114453, U19AI068021, NS076511, NS061817, ES020693, NS065789, AG026389, HL117880, National Institute of Occupational Safety and Health OH008282, Human Frontier Science Program HFSP-RGP0013/2014, and the Barth Syndrome Foundation of Canada and United States. This work was also supported by the Fondation pour la Recherche Medicale (FRM; DPM20121125557), a CMIRA Explo'ra doc fellowship of the Region Rhone Alpes, GEFLUC and the Natural Sciences and Engineering Council of Canada, grant 9848. NR 63 TC 7 Z9 7 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2016 VL 23 IS 7 BP 1140 EP 1151 DI 10.1038/cdd.2015.160 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DO6YN UT WOS:000377929500006 PM 26742431 ER PT J AU Falkenberg, KJ Newbold, A Gould, CM Luu, J Trapani, JA Matthews, GM Simpson, KJ Johnstone, RW AF Falkenberg, K. J. Newbold, A. Gould, C. M. Luu, J. Trapani, J. A. Matthews, G. M. Simpson, K. J. Johnstone, R. W. TI A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; HEDGEHOG SIGNALING PATHWAY; NEGATIVE BREAST-CANCER; B-CELL LYMPHOMA; GROWTH IN-VITRO; EXPRESSION ANALYSIS; HDAC INHIBITORS; OVARIAN-CANCER; DRUG TARGET; MOUSE MODEL AB Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostat-resistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 small-molecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy. C1 [Falkenberg, K. J.; Newbold, A.; Matthews, G. M.; Johnstone, R. W.] Peter MacCallum Canc Ctr, Canc Therapeut Program, St Andrews Pl, East Melbourne, Vic 3002, Australia. [Gould, C. M.; Luu, J.; Simpson, K. J.] Peter MacCallum Canc Ctr, Victorian Ctr Funct Genom, St Andrews Pl, East Melbourne, Vic 3002, Australia. [Trapani, J. A.] Peter MacCallum Canc Ctr, Canc Immunol Program, St Andrews Pl, East Melbourne, Vic 3002, Australia. [Trapani, J. A.; Matthews, G. M.; Simpson, K. J.; Johnstone, R. W.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Falkenberg, K. J.] Res Inst Mol Pathol IMP, Vienna, Austria. [Gould, C. M.] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. [Matthews, G. M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Johnstone, RW (reprint author), Peter MacCallum Canc Ctr, Gene Regulat Lab, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia. EM ricky.johnstone@petermac.org OI Simpson, Kaylene/0000-0001-9136-1781 FU Merck Research Laboratories; Australian National Health and Medical Research Council (NHMRC) [APP1028871]; Australian Postgraduate Award; Cancer Council Victoria Postdoctoral Research Fellowship; NHMRC; Cancer Council Victoria; Leukemia Foundation of Australia; Victorian Cancer Agency; Australian Cancer Research Foundation (ACRF); Victorian Department of Industry, Innovation and Regional Development (DIIRD); Australian Phenomics Network (APN) from the Australian Government's Education Investment Fund through the Super Science Initiative; Australasian Genomics Technologies Association (AMATA); Brockhoff Foundation; Peter MacCallum Cancer Centre Foundation FX We thank Richard Tothill, Maria Doyle and Jason Ellul for constructive discussions about NGS methodologies and analysis. For technical support, we also thank Yanny Handoko and Daniel Thomas (Victorian Centre for Functional Genomics), Andrea Newbold and Timothy Semple, Timothy Holloway and Aga Borcz (Molecular Genomics Facility). This work was supported by Merck Research Laboratories, and an Australian National Health and Medical Research Council (NHMRC) project grant APP1028871 (to RWJ). KJF was a recipient of an Australian Postgraduate Award and later a Cancer Council Victoria Postdoctoral Research Fellowship. RWJ is a Senior Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia and supported by NHMRC Program and Project Grants, Cancer Council Victoria, the Leukemia Foundation of Australia and the Victorian Cancer Agency. The VCFG (KJS) is funded by the Australian Cancer Research Foundation (ACRF), the Victorian Department of Industry, Innovation and Regional Development (DIIRD), the Australian Phenomics Network (APN) supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative, the Australasian Genomics Technologies Association (AMATA), the Brockhoff Foundation and the Peter MacCallum Cancer Centre Foundation. NR 61 TC 2 Z9 2 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2016 VL 23 IS 7 BP 1209 EP 1218 DI 10.1038/cdd.2015.175 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DO6YN UT WOS:000377929500012 PM 26868908 ER PT J AU Patel, NR Tamara, LA Lee, H AF Patel, Niraj R. Tamara, Luis A. Lee, Ho TI Tc-99m Sestamibi Thyroid Scan in Amiodarone-Induced Thyrotoxicosis Type I SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE Tc-99m sestamibi; amiodarone-induced thyrotoxicosis; Graves disease; hyperthyroidism AB Amiodarone-induced thyrotoxicosis (AIT) type I describes inducement of clinical hyperthyroidism by excessive thyroidal iodine in the setting of latent Graves disease, and therapy differs from that used for AIT type II. A 65-year-old man previously on amiodarone for atrial fibrillation developed clinical hyperthyroidism. Diagnosis of AIT was made, but the type was not clear. Tc-99m sestamibi thyroid scan showed diffusely increased uptake and retention in an enlarged thyroid gland, a pattern consistent with AIT type I. Methimazole was initiated and controlled the thyrotoxicosis. I-123 iodide thyroid scan and uptake study performed later was consistent with Graves disease. C1 Baylor Coll Med, Div Nucl Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Patel, NR (reprint author), 2002 Holcombe Blvd, Houston, TX 77030 USA. EM Niraj.Patel2@va.gov NR 7 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD JUL PY 2016 VL 41 IS 7 BP 566 EP 567 DI 10.1097/RLU.0000000000001243 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3QJ UT WOS:000377695800018 PM 27163459 ER PT J AU Fu, ZL Zhang, J Liu, M Li, Z Li, Q AF Fu, Zhanli Zhang, Jin Liu, Meng Li, Ziao Li, Qian TI Extramedullary Involvement of Mast Cell Leukemia Detected by F-18-FDG PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE F-18-FDG; mast cell leukemia; PET/CT ID ACUTE MYELOID-LEUKEMIA; FDG-PET/CT AB Mast cell leukemia (MCL) is a very rare subtype of systemic mastocytosis, characterized by the leukemic expansion of immature mast cells. We present a case of MCL with extramedullary involvement of cervical lymph node and lung demonstrated by the initial F-18-FDG PET/CT scan. After a transient complete remission by induction chemotherapy and allogeneic hematopoietic stem cell transplantation, the follow-up PET/CT showed extensive extramedullary relapse involving multiple lymph nodes and small bowel. F-18-FDG PET/CT may be a useful tool to comprehensively stage and follow-up MCL. C1 [Fu, Zhanli; Liu, Meng; Li, Ziao] Peking Univ, Hosp 1, Dept Nucl Med, 8 Xishiku St, Beijing 100034, Peoples R China. [Zhang, Jin] Beijing Univ Chinese Med, Dongzhimen Hosp, Dept Nucl Med, Beijing, Peoples R China. [Li, Qian] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fu, ZL (reprint author), Peking Univ, Hosp 1, Dept Nucl Med, 8 Xishiku St, Beijing 100034, Peoples R China. EM fuzhanli2002@163.com NR 8 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD JUL PY 2016 VL 41 IS 7 BP 578 EP 579 DI 10.1097/RLU.0000000000001207 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3QJ UT WOS:000377695800024 PM 26975014 ER PT J AU Liu, M Chen, GQ Fu, ZL Li, Z Li, Q AF Liu, Meng Chen, Guoqian Fu, Zhanli Li, Ziao Li, Qian TI Occult Mediastinal Yolk Sac Tumor Producing alpha-Fetoprotein Detected by F-18-FDG PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE F-18-FDG; alpha-fetoprotein (AFP); mediastinum; PET/CT; yolk sac tumor (YST) AB Malignant mediastinal yolk sac tumor (YST), especially adult onset, is rare. Herein, we report a case of occult mediastinal YST with alpha-fetoprotein production revealed by F-18-FDG PET/CT in a young adult, in which the intense tracer uptake was demonstrated in the anterior mediastinum. This case indicates F-18-FDG PET/CT may be a useful tool for detecting the occult primaries of YST. C1 [Liu, Meng; Fu, Zhanli; Li, Ziao] Peking Univ, Dept Nucl Med, Hosp 1, 8 Xishiku St, Beijing 100034, Peoples R China. [Chen, Guoqian] Wenzhou Med Univ, Affiliated Hosp 1, Dept Neurol, Wenzhou, Peoples R China. [Li, Qian] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fu, ZL (reprint author), Peking Univ, Dept Nucl Med, Hosp 1, 8 Xishiku St, Beijing 100034, Peoples R China. EM fuzhanli2002@163.com NR 11 TC 0 Z9 0 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD JUL PY 2016 VL 41 IS 7 BP 585 EP 586 DI 10.1097/RLU.0000000000001238 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3QJ UT WOS:000377695800027 PM 27088388 ER PT J AU Yu, VWC Scadden, DT AF Yu, Vionnie W. C. Scadden, David T. TI Heterogeneity of the bone marrow niche SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE bone marrow niche; hematopoietic stem cell; megakaryocyte; mesenchymal stem cell; mobilization; osteolineage cell; perivascular cells; quiescence ID HEMATOPOIETIC STEM-CELL; PROGENITORS; MICROENVIRONMENT; ERYTHROPOIESIS; OSTEOBLASTS; QUIESCENCE; DEFICIENCY; RELEASE AB Purpose of review The bone marrow niche is increasingly recognized as heterogeneous with specific subtypes of mesenchymal niche cells governing the development or homeostasis of selective parenchymal hematopoietic subsets. The present review outlines recent efforts in dissecting these microniches regulated by unique cell pairings within the bone marrow and provides an overview of how the bone marrow orchestrates multiple facets of hematopoiesis. Recent findings Recent advancement in technologies has significantly improved our understanding of the cellular and molecular constituents that contribute to regulation of hematopoiesis and to maintenance of the hematopoietic stem cells (HSCs). Transgenic mouse models that enable endogenous cell deletion or lineage tracing, coupled with advanced intravital microscopy has identified several mesenchymal cell types, including the osteolineage cells, megakaryocytes, macrophages, perivascular cells, and Schwann cells, to be indispensible regulators of hematopoiesis. These niche cells, when perturbed, each caused very specific hematopoietic consequences including impairment in B-cell maturation, T lineage development, erythropoiesis, and impact different aspects of HSC behavior such as quiescence, mobilization, and response to acute stress signals. Summary The emerging concept is that the bone marrow environment is composed of multiple microniches, each consisting of unique pairing of distinct supportive stromal cells with distinct hematopoietic subtypes to regulate a particular branch of hematopoietic cell process. The bone marrow can be viewed as a carrier with subcompartments tailored to support different hematopoietic activities. C1 [Yu, Vionnie W. C.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Yu, Vionnie W. C.; Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Yu, Vionnie W. C.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Yu, Vionnie W. C.] Novartis Inst BioMed Res, Cambridge, MA USA. RP Scadden, DT (reprint author), 185 Cambridge St, Boston, MA 02115 USA. EM david_scadden@harvard.edu FU Novartis Institutes for BioMedical Research; National Institutes of Health; Gerald and Darlene Jordan Professorship FX This work was supported by Novartis Institutes for BioMedical Research, the National Institutes of Health, and the Gerald and Darlene Jordan Professorship to D.T.S. NR 29 TC 6 Z9 6 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2016 VL 23 IS 4 BP 331 EP 338 DI 10.1097/MOH.0000000000000265 PG 8 WC Hematology SC Hematology GA DO8FH UT WOS:000378017500006 PM 27177311 ER PT J AU Ng, SY Abramson, JS AF Ng, Samuel Y. Abramson, Jeremy S. TI Chemotherapy-sparing treatment strategies for follicular lymphoma: current options and future directions SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE follicular lymphoma; immunotherapy; targeted therapy ID MONOCLONAL-ANTIBODY THERAPY; NON-HODGKINS-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; LENALIDOMIDE PLUS RITUXIMAB; RELAPSED INDOLENT LYMPHOMA; B-CELL MALIGNANCIES; PHASE-II TRIAL; TYROSINE KINASE; LUNG-CANCER; NIVOLUMAB AB Purpose of review The accelerating development of targeted therapy offers the possibility of avoiding the many toxic side effects of cytotoxic chemotherapy often experienced during treatment of patients with malignancies. As a currently incurable disease that typically follows an indolent course, follicular lymphoma is a disease for which chemotherapy-free treatment may offer substantial benefit. Recent findings We review chemotherapy-free treatment regimens, including those targeting cell-surface proteins and intracellular signaling pathways currently in use for the treatment of follicular lymphoma, paying particular attention to the unique toxicity profiles of these agents. Additionally, the safety profiles and efficacy of selected novel-targeted therapies in earlier phase studies, including immunotherapeutics, will be explored. Summary Novel-targeted therapies are rapidly changing the landscape of follicular lymphoma and decreasing reliance upon traditional chemotherapeutics. Although the toxicities of chemotherapy are well known to clinicians, the unique adverse events associated with novel agents may be less familiar, and requires attention to identification, management, and prophylaxis of toxicity associated with emerging chemotherapy-sparing treatments. C1 [Ng, Samuel Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Yawkey 9A,32 Fruit St, Boston, MA 02114 USA. RP Abramson, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Yawkey 9A,32 Fruit St, Boston, MA 02114 USA. EM jabramson@mgh.harvard.edu NR 37 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 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2016 VL 23 IS 4 BP 371 EP 376 DI 10.1097/MOH.0000000000000263 PG 6 WC Hematology SC Hematology GA DO8FH UT WOS:000378017500011 PM 27213499 ER PT J AU Manier, S Kawano, Y Bianchi, G Roccaro, AM Ghobrial, IM AF Manier, Salomon Kawano, Yawara Bianchi, Giada Roccaro, Aldo M. Ghobrial, Irene M. TI Cell autonomous and microenvironmental regulation of tumor progression in precursor states of multiple myeloma SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE bone marrow microenvironment in multiple myeloma; genomic alterations in multiple myeloma; molecular mechanisms of disease progression from monoclonal gammopathy of undetermined significance to multiple myeloma ID BONE-MARROW ANGIOGENESIS; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; IGH TRANSLOCATIONS; PROGNOSTIC VALUE; ZOLEDRONIC ACID; POOR-PROGNOSIS; IN-VIVO; DISEASE; ABNORMALITIES AB Purpose of review Multiple myeloma is a plasma cell malignancy evolving in the bone marrow and leading to end organ damage such as bone lesions, cytopenias, and kidney failure. This review delineates recent advances in the molecular mechanisms leading to tumor progression in multiple myeloma. Two different aspects enable tumor expansion: cell autonomous through genomic alterations in the tumor clone and noncell autonomous deregulations in the bone marrow tumor microenvironment. These alterations provide the framework for the continuous progression of multiple myeloma from early precursor conditions such as monoclonal gammopathy of undetermined significance and smoldering multiple myeloma to overt multiple myeloma. Recent findings In this review, we discuss recent findings in the genomic alterations that occur in the tumor clone such as somatic genomic mutations, copy number variation and chromosomal translocation, and delineate noncell autonomous deregulations in which tumor cells take advantage of a permissive microenvironment to further proliferate. The latter compartment includes interaction with bone marrow stromal cells, osteoblasts, osteoclasts, and immune escape. Summary Understanding the mechanisms that lead tumor progression from early stages to overt multiple myeloma could guide to more effective therapies and therefore prevent disease progression. C1 [Manier, Salomon; Kawano, Yawara; Bianchi, Giada; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Oncol, 44 Binney St, Boston, MA 02115 USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, Med Oncol, HIM 237,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu FU Leukemia and Lymphoma Society; International Myeloma Foundation; [R01 CA181683-01A1] FX This work is supported in part by R01 CA181683-01A1, and by the Leukemia and Lymphoma Society and the International Myeloma Foundation. NR 80 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2016 VL 23 IS 4 BP 426 EP 433 DI 10.1097/MOH.0000000000000259 PG 8 WC Hematology SC Hematology GA DO8FH UT WOS:000378017500018 PM 27101529 ER PT J AU Lee, GO Lichterfeld, M AF Lee, Guinevere O. Lichterfeld, Mathias TI Diversity of HIV-1 reservoirs in CD4(+) T-cell subpopulations SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE CD4(+) T cells; HIV-1; persistence; reservoirs ID ANTIRETROVIRAL THERAPY; LATENT RESERVOIR; TH17 CELLS; MEMORY; PERSISTENCE; INFECTION; IDENTIFICATION; PROLIFERATION; TRANSCRIPTION; REPLICATION AB Purpose of review HIV-1 is able to create lasting reservoirs of virally infected cells that persist life-long and are extremely difficult to eradicate, thus necessitating indefinite antiretroviral therapy. Large numbers of studies suggest that CD4(+) T cells represent the major, and possibly the only cell type supporting HIV-1 long-term persistence. However, the ability to serve as long-term viral reservoirs may be confined to certain subpopulations of CD4(+) T cells with specific functional and developmental characteristics that HIV-1 can selectively exploit to propagate long-term viral survival within the host. Identification of CD4(+) T-cell subtypes that serve as hotspots for viral persistence may be critical for designing strategies to purge the immune system of persisting viral reservoirs. Recent findings Developmentally immature, long-lasting CD4(+) memory T-cell populations seem to contain the majority of latently HIV-1-infected cells that persist despite antiretroviral therapy in the peripheral blood. Emerging data suggest that functional polarization toward a T helper 17 (Th17), a T follicular helper cell or a regulatory T-cell lineage may also be associated with an increased ability to serve as a viral reservoir site. Atypical T cells such a gamma delta CD4(+) T cells or tissue-resident memory CD4(+) T cells may be predestined to serve as sites for HIV-1 persistence in specific tissues, but will require additional exploration in future studies. Summary Recent advances have increased awareness for the profound diversity and complexity of CD4 T-cell subpopulations serving as sites for HIV-1 persistence. Continuous technological and methodological improvements to interrogate viral reservoirs in distinct CD4(+) T-cell subpopulations may allow to define a more complete landscape of the HIV-1 reservoir composition in different T-cell subpopulations. C1 [Lee, Guinevere O.; Lichterfeld, Mathias] Brigham & Womens Hosp, Div Infect Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. [Lee, Guinevere O.; Lichterfeld, Mathias] Massachusetts Gen Hosp, Cambridge, MA USA. [Lichterfeld, Mathias] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Lee, Guinevere O.; Lichterfeld, Mathias] Harvard Univ, Sch Med, Boston, MA USA. RP Lichterfeld, M (reprint author), Brigham & Womens Hosp, Div Infect Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. EM mlichterfeld@partners.org FU NIH [AI120008, AI114235, AI 106468, AI098487, AI117841] FX M.L. is supported by NIH grants AI120008, AI114235, AI 106468, AI098487, AI117841. NR 45 TC 4 Z9 4 U1 4 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JUL PY 2016 VL 11 IS 4 BP 383 EP 387 DI 10.1097/COH.0000000000000281 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO6XB UT WOS:000377925700005 PM 27023286 ER PT J AU Salinsky, M Storzbach, D Goy, E Kellogg, M Boudreau, E AF Salinsky, Martin Storzbach, Daniel Goy, Elizabeth Kellogg, Marissa Boudreau, Eilis TI Health care utilization following diagnosis of psychogenic nonepileptic seizures SO EPILEPSY & BEHAVIOR LA English DT Article DE Psychogenic nonepileptic seizures; Epilepsy; Health care utilization; Veterans ID VIDEO-EEG; VETERANS; EPILEPSY; ADMISSION AB Objectives: The long-term outcome of patients with psychogenic nonepileptic seizures (PNES) is of importance given the disabling symptoms and tendency to affect patients early in their productive years. Health care utilization (HCU) is an important outcome measure reflecting overall health status and costs. There is little information regarding long-term HCU following diagnosis of PNES. Methods: We retrospectively reviewed records of Veterans diagnosed with PNES during epilepsy monitoring unit (EMU) evaluation. For the three-year period following diagnosis of PNES, we reviewed emergency department (ED) visits, hospitalizations, outpatient clinic visits, and radiology procedures. We compared the three years following PNES diagnosis with the three years preceding diagnosis. We also compared patients with PNES and patients with epileptic seizures (ES). Results: Emergency department visits and hospitalizations were more frequent in patients with PNES compared with those in patients with ES (p = 0.01). There was no overall improvement in HCU during the three-year interval following diagnosis of PNES. A transient decrease during the year following diagnosis was not sustained over three-year follow-up. Pain complaints rather than seizures were the most common reason for presentation, whereas the opposite was true for patients with ES (p < 0.01). There was a sharp decrease in neurology outpatient visits (p < 0.001) and a decrease in primary care visits (p < 0.05) after PNES was diagnosed. Total outpatient visits were unchanged. Conclusions: Overall HCU did not improve during the three years following diagnosis of PNES, compared with three years preceding diagnosis. The results add to studies documenting poor seizure outcomes following diagnosis of PNES and underscore the need for more effective and comprehensive treatments, addressing comorbid symptoms. Published by Elsevier Inc. C1 [Salinsky, Martin; Boudreau, Eilis] Portland VA Med Ctr, Portland, OR USA. [Salinsky, Martin; Storzbach, Daniel; Goy, Elizabeth; Kellogg, Marissa; Boudreau, Eilis] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Kellogg, Marissa] Stanford Univ, Med Ctr, Dept Neurol, Stanford, CA 94305 USA. RP Salinsky, M (reprint author), Portland VAMC Epilepsy Ctr, 3710 SW US Vet Hosp Rd P3ECOE, Portland, OR 97239 USA. EM Salinsky@ohsu.edu FU Department of Veterans Affairs [5101CX00071] FX This study was supported by grant # 5101CX00071 from the Department of Veterans Affairs. NR 30 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 EI 1525-5069 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD JUL PY 2016 VL 60 BP 107 EP 111 DI 10.1016/j.yebeh.2016.04.007 PG 5 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA DO7WA UT WOS:000377992500018 PM 27206227 ER PT J AU Shaaya, EA Grocott, OR Laing, O Thibert, RL AF Shaaya, Elias A. Grocott, Olivia R. Laing, Olivia Thibert, Ronald L. TI Seizure treatment in Angelman syndrome: A case series from the Angelman Syndrome Clinic at Massachusetts General Hospital SO EPILEPSY & BEHAVIOR LA English DT Article DE Angelman syndrome; Antiepileptic drug; LGIT; Epilepsy; Seizures ID EPILEPSY; QUESTIONNAIRE; DELETION; CHILDREN; EXPRESSION; 15Q11-13 AB Epilepsy is a common feature of Angelman syndrome (similar to 80-90%), with the most common seizure types including myoclonic, atonic, atypical absence, focal, and generalized tonic-clonic. Seizure types are similar among the various genetic subtypes, but epilepsy in those with maternal deletions is more frequent and more refractory to medication. Treatment with older antiepileptic drugs such as valproic acid and clonazepam is effective, but these medications tend to have less favorable side effect profiles in Angelman syndrome compared with those in newer medications. This study aimed to assess the use of newer antiepileptic drug therapies in individuals with Angelman syndrome followed at the Angelman Syndrome Clinic at the Massachusetts General Hospital. Many of the subjects in this study were on valproic acid therapy prior to their initial evaluation and exhibited increased tremor, decreased balance, and/or regression of motor skills, which resolved after tapering off of this medication. Newer antiepileptic drugs such as levetiracetam, lamotrigine, and clobazam, and to a lesser extent topiramate, appeared to be as effective - if not more so - as valproic acid and clonazepam while offering more favorable side effect profiles. The low glycemic index treatment also provided effective seizure control with minimal side effects. The majority of subjects remained on combination therapy with levetiracetam, lamotrigine, and clobazam being the most commonly used medications, indicating a changing trend when compared with prior studies. (C) 2016 Elsevier Inc. All rights reserved. C1 [Shaaya, Elias A.; Grocott, Olivia R.; Laing, Olivia; Thibert, Ronald L.] Massachusetts Gen Hosp, Dept Neurol, Angelman Syndrome Clin, Boston, MA 02114 USA. RP Thibert, RL (reprint author), 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM rthibert@mgh.harvard.edu NR 23 TC 2 Z9 2 U1 4 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 EI 1525-5069 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD JUL PY 2016 VL 60 BP 138 EP 141 DI 10.1016/j.yebeh.2016.04.030 PG 4 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA DO7WA UT WOS:000377992500023 PM 27206232 ER PT J AU Andrikopoulou, E AlJaroudi, WA Farag, A Lester, D Patel, H Iskandrian, AE Hage, FG AF Andrikopoulou, Efstathia AlJaroudi, Wael A. Farag, Ayman Lester, Davis Patel, Hiren Iskandrian, Ami E. Hage, Fadi G. TI The reproducibility and prognostic value of serial measurements of heart rate response to regadenoson during myocardial perfusion imaging SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Heart rate response; Regadenoson; Vasodilator stress; Myocardial perfusion imaging; Coronary artery disease ID POSITRON-EMISSION-TOMOGRAPHY; CORONARY-ARTERY-DISEASE; DIABETES-MELLITUS; ASYMPTOMATIC PATIENTS; NUCLEAR CARDIOLOGY; DEFECT SIZE; STRESS; ADENOSINE; RISK; ISCHEMIA AB The heart rate response (HRR, percentage change from baseline) to regadenoson during myocardial perfusion imaging (MPI) can provide incremental prognostic value in patients with known or suspected coronary artery disease. Our purpose was to evaluate the variability and prognostic value of HRR on serial measurements. We studied 648 consecutive patients (61 +/- 11 years, 48 % with diabetes) who underwent two regadenoson MPI studies (16 +/- 9 months between studies). HRR < 30 % was defined as abnormal. All-cause mortality was determined by chart review and verified using the US Social Security Death Master File. HRR was well correlated between the two studies (intraclass correlation coefficient 0.72, 95 % CI 0.67 -aEuro parts per thousand 0.76) with no systematic bias (mean difference 0.88 %, p = 0.2) or proportional bias (p = 0.5) by Bland-Altman analysis in all patients and in those with normal MPI on both studies. Of the 308 patients (48 %) with normal baseline HRR (HRR-1), 33 % had developed a blunted HRR on the second MPI study (HRR-2). Older age, male gender, end-stage renal disease, and abnormal baseline left ventricular ejection fraction were independent predictors of a new-onset abnormal HRR. During a mean follow-up of 2.4 +/- 1.2 years, 55 patients (8.5 %) died. Patients with a blunted HRR-1 had increased mortality risk irrespective of their HRR-2 (p = 0.9, log-rank test). Among patients with normal HRR-1, a blunted HRR-2 was an independent predictor of all-cause mortality beyond clinical and traditional MPI data (hazard ratio 2.83, 95 % CI 1.14 -aEuro parts per thousand 7.03). Finally, patients with a normal HRR-1 and HRR-2 had the lowest event rate, while those with any abnormal HRR had an increased risk of death (hazard ratio 2.5, 95 % CI 1.2 -aEuro parts per thousand 5.4). There was good correlation in the HRR to regadenoson on serial measurements without systematic or proportional biases. Patients with consistently normal HRR had the best prognosis. C1 [Andrikopoulou, Efstathia; Farag, Ayman; Lester, Davis; Patel, Hiren; Iskandrian, Ami E.; Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Andrikopoulou, Efstathia; Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL 35233 USA. [AlJaroudi, Wael A.] Clemenceau Med Ctr, Div Cardiovasc Med, Beirut, Lebanon. [Hage, Fadi G.] Univ Alabama Birmingham, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA.; Hage, FG (reprint author), Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL 35233 USA.; Hage, FG (reprint author), Univ Alabama Birmingham, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 32 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUL PY 2016 VL 43 IS 8 BP 1493 EP 1502 DI 10.1007/s00259-016-3380-y PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO8AS UT WOS:000378005000015 PM 27079736 ER PT J AU Rosenfeld, EA Marx, J Terry, MA Stall, R Pallatino, C Borrero, S Miller, E AF Rosenfeld, Elian A. Marx, John Terry, Martha A. Stall, Ronald Pallatino, Chelsea Borrero, Sonya Miller, Elizabeth TI Intimate partner violence, partner notification, and expedited partner therapy: a qualitative study SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE Intimate partner violence; sexually transmitted infections; treatment; sexual violence; partner notification; expedited partner therapy ID SEXUALLY-TRANSMITTED INFECTIONS; FEMALE ADOLESCENTS; DOMESTIC VIOLENCE; SERVICES; GIRLS; RISK AB Over one-third of women experience intimate partner violence (IPV) in their lifetime. IPV increases the risk of infection and re-infection with sexually transmitted infections (STIs). The extent to which health care providers consider IPV when recommending partner notification and expedited partner therapy is unknown. The objective of this qualitative study was to understand health care providers' views on IPV and STIs when recommending partner treatment to patients with chlamydia. Using a purposive sampling strategy to include health care providers who treat young women at risk for chlamydia, 23 semi-structured, in-depth interviews were conducted. While some health care providers expressed concern for their patients' safety and believed assessing for IPV was needed before provision of expedited partner therapy, nearly a third had not considered the links between IPV and STIs. Strategies used by health care providers to assess for IPV did not include inquiry about specific behaviours related to IPV, STI risk, and sexual coercion. Many health care providers understand the risk for IPV in the setting of STI treatment, yet a significant portion of those interviewed failed to recognise the link between IPV and STIs. Provider education is necessary to increase knowledge and implement more effective inquiry and counselling about IPV to more safely recommend expedited partner therapy. C1 [Rosenfeld, Elian A.] VA Pittsburgh Healthcare Syst, VA Womens Hlth, Univ Dr C 151C Bldg 30, Pittsburgh, PA 15240 USA. [Marx, John; Terry, Martha A.; Stall, Ronald; Pallatino, Chelsea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA USA. [Borrero, Sonya] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Borrero, Sonya] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Miller, Elizabeth] Univ Pittsburgh, Childrens Hosp Pittsburgh, UPMC, Div Adolescent Med, Pittsburgh, PA 15213 USA. RP Rosenfeld, EA (reprint author), VA Pittsburgh Healthcare Syst, VA Womens Hlth, Univ Dr C 151C Bldg 30, Pittsburgh, PA 15240 USA. EM elian.rosenfeld@va.gov FU University of Pittsburgh FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study received funding from the Myrna Silverman Award and William Green Award from the University of Pittsburgh. NR 26 TC 1 Z9 1 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0956-4624 EI 1758-1052 J9 INT J STD AIDS JI Int. J. STD AIDS PD JUL PY 2016 VL 27 IS 8 BP 656 EP 661 DI 10.1177/0956462415591938 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO4RZ UT WOS:000377772100009 PM 26088259 ER PT J AU Katagira, W Walter, ND Den Boon, S Kalema, N Ayakaka, I Vittinghoff, E Worodria, W Cattamanchi, A Huang, L Davis, JL AF Katagira, Winceslaus Walter, Nicholas D. Den Boon, Saskia Kalema, Nelson Ayakaka, Irene Vittinghoff, Eric Worodria, William Cattamanchi, Adithya Huang, Laurence Davis, John Lucian TI Empiric TB Treatment of Severely Ill Patients With HIV and Presumed Pulmonary TB Improves Survival SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE pulmonary tuberculosis; treatment; danger signs; survival; HIV; sub-Saharan Africa ID SMEAR-NEGATIVE TUBERCULOSIS; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; IMMUNODEFICIENCY; DIAGNOSIS; ALGORITHM; COHORT; UGANDA AB Rationale: In 2007, World Health Organization (WHO) issued emergency recommendations on empiric treatment of sputum acid-fast bacillus smear-negative patients with possible tuberculosis (TB) in HIV-prevalent areas, and called for operational research to evaluate their effectiveness. We sought to determine if early, empiric TB treatment of possible TB patients with abnormal chest radiography or severe illness as suggested by the 2007 WHO guidelines, is associated with improved survival. Methods: We prospectively enrolled consecutive HIV-seropositive inpatients at Mulago Hospital in Kampala, Uganda, from 2007 to 2011 with cough for >= 2 weeks. We retrospectively examined the effect of empiric TB treatment before discharge on 8-week survival among those with and without a WHO-defined "danger sign," including fever >39 degrees C, tachycardia >120 beats per minute, or tachypnea >30 breaths per minute. We modeled the interaction between empiric TB treatment and danger signs, and their combined effect on 8-week survival, and adjusted for relevant covariates. Results: Among 631 sputum smear-negative patients, 322 (51%) had danger signs. Cumulative 8-week survival of patients with danger signs was significantly higher with empiric TB treatment (80%) than without treatment (64%, P < 0.001). After adjusting for duration of cough and concurrent hypoxemia, patients with danger signs who received empiric TB treatment had a 44% reduction in 8-week mortality (risk ratio 0.56, 95% confidence interval: 0.34-0.91, P = 0.020). Conclusions: Empiric TB treatment of HIV-seropositive, smear-negative, presumed pulmonary TB patients with 1 or more danger signs is associated with improved 8-week survival. Enhanced implementation of the 2007 WHO empiric treatment recommendations should be encouraged whenever and wherever rapid and highly sensitive diagnostic tests for TB are unavailable. C1 [Katagira, Winceslaus; Walter, Nicholas D.; Den Boon, Saskia; Kalema, Nelson; Ayakaka, Irene; Worodria, William; Cattamanchi, Adithya] Makerere Univ Univ Calif San Francisco MU UCSF Re, Kampala, Uganda. [Walter, Nicholas D.; Huang, Laurence] Denver Vet Affairs Med Ctr, Pulm Sect, Denver, CO USA. [Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Worodria, William] Makerere Univ, Dept Med, Coll Hlth Sci, Kampala, Uganda. [Cattamanchi, Adithya] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Huang, Laurence] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div HIV AIDS, San Francisco, CA USA. [Davis, John Lucian] Yale Univ, Dept Epidemiol Microbial Dis, Sch Publ Hlth, New Haven, CT USA. [Davis, John Lucian] Yale Univ, Sch Med, Pulm Crit Care & Sleep Med Sect, New Haven, CT USA. RP Davis, JL (reprint author), Yale Univ, Sch Publ Hlth, Epidemiol Microbial Dis, 60 Coll St, New Haven, CT 06520 USA. EM Lucian.Davis@yale.edu FU NIH [K24HL087713, R01HL090335, K23HL094141, R21AI101714]; NIH/NHLBI [K12 HL090147-04, CDA1IK2CX000914-01A1, K23AI080147] FX Supported by NIH K24HL087713 (L.H.), R01HL090335 (L.H.), K23HL094141 (A.C.), NIH/NHLBI K12 HL090147-04 (N.D.W.), CDA1IK2CX000914-01A1 (N.D.W.), K23AI080147 (J.L.D.), and NIH R21AI101714 (J.L.D.). NR 27 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2016 VL 72 IS 3 BP 297 EP 303 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO8UM UT WOS:000378059800016 PM 26918546 ER PT J AU Treasure, GC Aga, E Bosch, RJ Mellors, JW Kuritzkes, DR Para, M Gandhi, RT Li, JZ AF Treasure, Graham C. Aga, Evgenia Bosch, Ronald J. Mellors, John W. Kuritzkes, Daniel R. Para, Michael Gandhi, Rajesh T. Li, Jonathan Z. TI Relationship Among Viral Load Outcomes in HIV Treatment Interruption Trials SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; treatment interruption; set point; viral rebound; outcome ID PLACEBO-CONTROLLED TRIAL; ANTIRETROVIRAL THERAPY; REPLICATION; INFECTION; IMMUNIZATION; INITIATION; DYNAMICS; VACCINE; DECAY; DNA AB Viral load (VL) rebound timing and set point were analyzed in 235 participants undergoing analytic treatment interruption (ATI) in 6 AIDS Clinical Trials Group studies. There was no significant association between rebound timing and ATI VL set point for those who rebounded <12 weeks. VL set points were lower in participants with rebound >12 weeks (P < 0.001) and participants treated during early infection (P < 0.001). Pre-antiretroviral therapy VL correlated with set point, though 68% of participants had a set point lower than pre-antiretroviral therapy VL. These results illustrate complex relationships between post-ATI virologic outcomes and the potential presence of biological factors mediating rebound timing and set point. C1 [Treasure, Graham C.; Kuritzkes, Daniel R.; Li, Jonathan Z.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Treasure, Graham C.] Univ N Carolina, Chapel Hill, NC USA. [Aga, Evgenia; Bosch, Ronald J.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. [Para, Michael] Ohio State Univ, Columbus, OH 43210 USA. [Gandhi, Rajesh T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Gandhi, Rajesh T.] Harvard Univ, Sch Med, Ragon Inst, Boston, MA USA. RP Li, JZ (reprint author), Brigham & Womens Hosp, Div Infect Dis, 65 Landsdowne St,Rm 421, Cambridge, MA 02139 USA. EM jli22@partners.org FU Harvard University Center for AIDS Research [NIAID 5P30AI060354-08]; National Institutes of Health (NIH) [AI100699, UM1 AI068634, UM1 AI068636]; Gilead Sciences; Bristol-Myers Squibb; Gilead; Merck; ViiV Healthcare; Roche; EBSCO FX Supported in part by a grant from the Harvard University Center for AIDS Research (J.Z.L. and R.T.G., NIAID 5P30AI060354-08), National Institutes of Health (NIH) grants AI100699 (to Dr. Li), UM1 AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), UM1 AI068636 (AIDS Clinical Trials Group), and a subcontract from UM1 AI068636 to the Harvard Virology Support Laboratory (D.R.K.).; J.Z.L. has received research support from Gilead Sciences and served as a consultant for Quest Diagnostics and Merck. J.W.M. is a consultant to and has received grant support from Gilead Sciences, and is share owner of Co-Crystal, Inc. D.R.K. has served as a consultant to and/or has received research grant support from Bristol-Myers Squibb, Gilead, Merck, and ViiV Healthcare; he has also received speaking honoraria from Gilead and ViiV. R.T.G. has received educational grants from Gilead, Roche and EBSCO. The other authors have no conflicts of interest to disclose. NR 21 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2016 VL 72 IS 3 BP 310 EP 313 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DO8UM UT WOS:000378059800018 PM 26910502 ER PT J AU Bustamante, ND Macias-Konstantopoulos, WL AF Bustamante, Nirma D. Macias-Konstantopoulos, Wendy L. TI RETAINED LUMBAR BULLET: A CASE REPORT OF CHRONIC LEAD TOXICITY AND REVIEW OF THE LITERATURE SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE chelation therapy; lead toxicity; plumbism; retained bullet ID ABDOMINAL-PAIN; BURTONS LINE; TISSUE LEAD; MANIFESTATIONS; ARTHROPATHY; FRAGMENTS; ADULT; BONE AB Background: Lead toxicity from retained bullet fragments is difficult to both predict and diagnose, but important to treat early, given the potential severity of disease. Blood lead levels > 25 mu g/dL and 40 mu g/dL are considered toxic in children and adults, respectively. Symptoms may range from nonspecific constitutional symptoms to seizures and coma. Chelation is the mainstay therapy for lead poisoning and levels to treat depend on patient age, blood lead levels, and the presence of symptoms. Case Report: We present the case of a woman with symptoms of severe lead toxicity from 20-year-old retained bullet fragments. She had been seen by multiple providers for evaluation of each symptom, but a unifying diagnosis had not been found. After identifying this complication, she was treated appropriately and more serious complications were prevented. Why Should an Emergency Physician Be Aware of This?: We present this case to increase awareness among emergency physicians of lead toxicity in patients with a seemingly unrelated constellation of symptoms and a history of a previous gunshot wound with retained bullet or bullet fragments. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bustamante, Nirma D.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Bustamante, Nirma D.; Macias-Konstantopoulos, Wendy L.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Macias-Konstantopoulos, Wendy L.] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. RP Macias-Konstantopoulos, WL (reprint author), Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. NR 38 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JUL PY 2016 VL 51 IS 1 BP 45 EP 49 DI 10.1016/j.jemermed.2016.02.025 PG 5 WC Emergency Medicine SC Emergency Medicine GA DO7VQ UT WOS:000377991500007 PM 27071317 ER PT J AU Callans, KM Bleiler, C Flanagan, J Carroll, DL AF Callans, Kevin Mary Bleiler, Carolyn Flanagan, Jane Carroll, Diane L. TI The Transitional Experience of Family Caring for Their Child With a Tracheostomy SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Article DE Technology-dependent children; Family experience; Tracheostomy ID CARE AB Purpose: The purpose of this qualitative study was to describe the family experience of caring for their child with a tracheostomy due to a compromised airway during the transition from hospital to home, and to identify types of support that families request to be successful caregivers. Design and methods: This study used a qualitative descriptive design with focus groups to answer semi-structured interview questions. The investigators followed basic content analysis to interpret descriptive data using three-person consensus. Results: Eighteen family members participated. Four themes emerged: "This is not the life I had planned: coming to accept the new reality;" "Don't make the hospital your home; don't make your home a hospital;" " Caregivers engage with providers that demonstrate competence, confidence, attentiveness, and patience;" and " Participants value the opportunity to give back and help others." Conclusions: Growth in the family caregiver role leads to personal transformation demonstrated by increased confidence, finding joy from their child, becoming an advocate for their child, and a resource for others. Family members described the transition to being 'in charge,'the relationship with the provider, and being able to advocate for getting the resources they needed in the home. Practice implications: Relationships are as critical as teaching skills to families during hospitalization. Family members see considerable value in connecting with care providers. In addition, there is a desire to share their experience with other families that are beginning a similar journey. Participants requested a support approach that included competent providers, Web-based video education for skills training, family-to-family connection, and continued family group support after discharge. (C) 2016 Elsevier Inc. All rights reserved. C1 [Callans, Kevin Mary] Massachusetts Gen Hosp, Clin Care Management Unit, Boston, MA 02114 USA. [Callans, Kevin Mary] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Bleiler, Carolyn] Massachusetts Gen Hosp, Patient Care Serv, Boston, MA 02114 USA. [Flanagan, Jane; Carroll, Diane L.] Massachusetts Gen Hosp, Yvonne L Munn Ctr Nursing Res, Boston, MA 02114 USA. [Flanagan, Jane] Boston Coll, Chestnut Hill, MA 02167 USA. RP Callans, KM (reprint author), Massachusetts Gen Hosp, Clin Care Management Unit, Boston, MA 02114 USA.; Callans, KM (reprint author), Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM kcallans@partners.org NR 16 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD JUL-AUG PY 2016 VL 31 IS 4 BP 397 EP 403 DI 10.1016/j.pedn.2016.02.002 PG 7 WC Nursing; Pediatrics SC Nursing; Pediatrics GA DO8WD UT WOS:000378065200010 PM 27040188 ER PT J AU Fairbairn, NG Ng-Glazier, J Meppelink, AM Randolph, MA Valerio, IL Fleming, ME Kochevar, IE Winograd, JM Redmond, RW AF Fairbairn, Neil G. Ng-Glazier, Joanna Meppelink, Amanda M. Randolph, Mark A. Valerio, Ian L. Fleming, Mark E. Kochevar, Irene E. Winograd, Jonathan M. Redmond, Robert W. TI Light-Activated Sealing of Acellular Nerve Allografts following Nerve Gap Injury SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Article DE nerve gap; allograft; sutureless repair ID CELL BASAL LAMINA; PERIPHERAL-NERVE; CLINICAL-APPLICATIONS; SKELETAL-MUSCLE; UPPER EXTREMITY; SINGLET OXYGEN; HUMAN AMNION; REGENERATION; REPAIR; RAT AB Introduction Photochemical tissue bonding (PTB) uses visible light to create sutureless, watertight bonds between two apposed tissue surfaces stained with photoactive dye. In phase 1 of this two-phase study, nerve gaps repaired with bonded isografts were superior to sutured isografts. When autograft demand exceeds supply, acellular nerve allograft (ANA) is an alternative although outcomes are typically inferior. This study assesses the efficacy of PTB when used with ANA. Methods Overall 20 male Lewis rats had 15-mm left sciatic nerve gaps repaired using ANA. ANAs were secured using epineurial suture (group 1) or PTB (group 2). Outcomes were assessed using sciatic function index (SFI), gastrocnemius muscle mass retention, and nerve histomorphometry. Historical controls from phase 1 were used to compare the performance of ANA with isograft. Statistical analysis was performed using analysis of variance and Bonferroni all-pairs comparison. Results All ANAs had signs of successful regeneration. Mean values for SFI, muscle mass retention, nerve fiber diameter, axon diameter, and myelin thickness were not significantly different between ANA + suture and ANA + PTB. On comparative analysis, ANA + suture performed significantly worse than isograft + suture from phase 1. However, ANA + PTB was statistically comparable to isograft + suture, the current standard of care. Conclusion Previously reported advantages of PTB versus suture appear to be reduced when applied to ANA. The lack of Schwann cells and neurotrophic factors may be responsible. PTB may improve ANA performance to an extent, where they are equivalent to autograft. This may have important clinical implications when injuries preclude the use of autograft. C1 [Fairbairn, Neil G.; Ng-Glazier, Joanna; Meppelink, Amanda M.; Randolph, Mark A.; Winograd, Jonathan M.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Valerio, Ian L.] Walter Reed Natl Mil Med Ctr, Plast Surg Serv, Bethesda, MD USA. [Fleming, Mark E.] Walter Reed Natl Mil Med Ctr, Dept Orthopaed, Bethesda, MD USA. [Kochevar, Irene E.; Redmond, Robert W.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Redmond, RW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM redmond@helix.mgh.harvard.edu FU U.S. Army Medical Research Acquisition Activity [W81XWH-12-1-0511] FX The authors are grateful for excellent histological support from the Photopathology core at the Wellman Center for Photomedicine. This study was funded by the U.S. Army Medical Research Acquisition Activity W81XWH-12-1-0511. The content of this article does not necessarily reflect the position or the policy of the U.S. Government, and no official endorsement should be inferred. NR 43 TC 0 Z9 0 U1 0 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X EI 1098-8947 J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD JUL PY 2016 VL 32 IS 6 BP 421 EP 430 DI 10.1055/s-0035-1571247 PG 10 WC Surgery SC Surgery GA DO9DM UT WOS:000378084500001 PM 26878685 ER PT J AU Giannatempo, P Pond, GR Sonpavde, G Albany, C Loriot, Y Sweeney, CJ Salvioni, R Colecchia, M Nicolai, N Raggi, D Rice, KR Flack, CK El Mouallem, NR Feldman, H Fizazi, K Einhorn, LH Foster, RS Necchi, A Cary, C AF Giannatempo, Patrizia Pond, Gregory R. Sonpavde, Guru Albany, Costantine Loriot, Yohann Sweeney, Christopher J. Salvioni, Roberto Colecchia, Maurizio Nicolai, Nicola Raggi, Daniele Rice, Kevin R. Flack, Chandra K. El Mouallem, Nemer R. Feldman, Hope Fizazi, Karim Einhorn, Lawrence H. Foster, Richard S. Necchi, Andrea Cary, Clint TI Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International Collaboration SO JOURNAL OF UROLOGY LA English DT Article DE testicular neoplasms; teratoma; cell transformation, neoplastic; neoplasms, germ cell and embryonal; drug therapy ID GERM-CELL TUMORS; PRIMITIVE NEUROECTODERMAL TUMOR; SARCOMATOUS COMPONENTS; CHEMOTHERAPY; FEATURES; TESTIS AB Purpose: We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. Materials and Methods: Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. Results: Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p < 0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. Conclusions: Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy. C1 [Giannatempo, Patrizia; Salvioni, Roberto; Colecchia, Maurizio; Nicolai, Nicola; Raggi, Daniele; Necchi, Andrea] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Via Venezian 1, I-20133 Milan, Italy. [Pond, Gregory R.] McMaster Univ, Hamilton, ON, Canada. [Sonpavde, Guru; El Mouallem, Nemer R.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Albany, Costantine; Rice, Kevin R.; Flack, Chandra K.; Einhorn, Lawrence H.; Foster, Richard S.; Cary, Clint] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Loriot, Yohann; Fizazi, Karim] Univ Paris Sud, Inst Gustave Roussy, Villejuif, France. [Sweeney, Christopher J.; Feldman, Hope] Dana Farber Canc Inst, Boston, MA 02115 USA. [Feldman, Hope] Albert Einstein Coll Med, New York, NY USA. RP Necchi, A (reprint author), Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Via G Venezian 1, I-20133 Milan, Italy. EM andrea.necchi@istitutotumori.mi.it RI Colecchia, Maurizio/C-2745-2017; Nicolai, Nicola/D-1091-2017; OI Colecchia, Maurizio/0000-0003-1914-0743; Nicolai, Nicola/0000-0002-5718-2699; Necchi, Andrea/0000-0002-3007-2756 NR 19 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2016 VL 196 IS 1 BP 95 EP 100 DI 10.1016/j.juro.2015.12.082 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DO7HY UT WOS:000377954400031 PM 26748165 ER PT J AU Eisner, BH AF Eisner, Brian H. TI Systemic Inflammatory Response Syndrome after Percutaneous Nephrolithotomy: A Randomized Single-Blind Clinical Trial Evaluating the Impact of Irrigation Pressure EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Eisner, Brian H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Urol, Cambridge, MA 02138 USA. RP Eisner, BH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Urol, Cambridge, MA 02138 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 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2016 VL 196 IS 1 BP 114 EP 114 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DO7HY UT WOS:000377954400044 PM 27107551 ER PT J AU Graber, CJ Goetz, MB AF Graber, Christopher J. Goetz, Matthew Bidwell TI Next steps for antimicrobial stewardship SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material C1 [Goetz, Matthew Bidwell] VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90073 USA. RP Goetz, MB (reprint author), VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA 90073 USA. EM matthew.goetz@va.gov NR 8 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2016 VL 16 IS 7 BP 764 EP 765 DI 10.1016/S1473-3099(16)00099-2 PG 3 WC Infectious Diseases SC Infectious Diseases GA DP2LH UT WOS:000378319600012 PM 26947616 ER PT J AU Hall, KT Jablonski, KA Chen, L Harden, M Tolkin, BR Kaptchuk, TJ Bray, GA Ridker, PM Florez, JC Mukamal, KJ Chasman, DI AF Hall, Kathryn T. Jablonski, Kathleen A. Chen, Ling Harden, Maegan Tolkin, Benjamin R. Kaptchuk, Ted J. Bray, George A. Ridker, Paul M. Florez, Jose C. Mukamal, Kenneth J. Chasman, Daniel I. CA Diabet Prevention Program Res Grp TI Catechol-O-methyltransferase association with hemoglobin A1c SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE COMT; Type 2 diabetes; Hemoglobin A1C; Women's Health Study (WHS); Diabetes Prevention Program (DPP) ID GLUCOSE-METABOLISM; CARDIOVASCULAR-DISEASE; POLYMORPHISMS; EPINEPHRINE; COMT; METFORMIN; INSIGHTS; OBESITY; UPDATE; GENES AB Aims. Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. Methods. We tested whether COMT polymorphisms were associated with baseline HbA(1c) in the Women's Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. Results. COMT rs4680 high-activity G-allele was associated with lower HbA(1c) in WGHS (beta = -0.032% [0.012], p = 0.008) and borderline significant in MAGIC (beta = -0.006% [0.003], p = 0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR = 0.98 [0.96-0.998], p = 0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR = 0.81 [0.65-1.00], p = 0.05). Conclusions. COMT rs4680 high-activity G-allele was associated with lower HbA(1c) and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hall, Kathryn T.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave, Boston, MA 02215 USA. [Hall, Kathryn T.; Kaptchuk, Ted J.; Ridker, Paul M.; Florez, Jose C.; Mukamal, Kenneth J.; Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA USA. [Jablonski, Kathleen A.] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Chen, Ling] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Chen, Ling] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Harden, Maegan] Broad Inst, Genom Platform, Cambridge, MA USA. [Tolkin, Benjamin R.; Kaptchuk, Ted J.; Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Hall, KT (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave, Boston, MA 02215 USA. EM khall0@partners.org FU National Heart, Lung, and Blood Institute [HL043851, HL69757]; National Cancer Institute [CA 047988]; Donald W. Reynolds Foundation; Amgen; Harvard Catalyst Faculty Fellowship; NHLBI [1K01HL130625]; NCCAM-NIH [R01AT004662, K24AT004095, R21AT002860, 3R01AT004662-02S1]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Office of Research on Women's Health; Centers for Disease Control and Prevention; American Diabetes Association; McKesson BioServices; Matthews Media Group; Henry M. Jackson Foundation; [R01 DK072041] FX The WGHS is supported by HL043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, and the Donald W. Reynolds Foundation, with collaborative scientific support and funding for genotyping provided by Amgen. KTH is funded by Harvard Catalyst Faculty Fellowship and NHLBI 1K01HL130625. TJK is supported by NCCAM-NIH grants R01AT004662, K24AT004095, R21AT002860 and 3R01AT004662-02S1. Data from the Diabetes Prevention Program (DPP) was contributed by the DPP Research Group: a complete list of centers, investigators, and staff can be found in the online Appendix. The DPP investigators gratefully acknowledge the commitment and dedication of the participants of the DPP. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the coordinating center for the design and conduct of the study; collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Office of Research on Women's Health, the Centers for Disease Control and Prevention, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slim Fast Food, and Quaker Oats donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices, Matthews Media Group, and the Henry M. Jackson Foundation provided support services under subcontract with the coordinating center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. Genetic studies in the DPP are funded by R01 DK072041 to JCF and KAJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 0 Z9 0 U1 2 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 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD JUL PY 2016 VL 65 IS 7 BP 961 EP 967 DI 10.1016/j.metabol.2016.04.001 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO6VW UT WOS:000377922600003 PM 27282867 ER PT J AU Meier, SM Agerbo, E Maier, R Pedersen, CB Lang, M Grove, J Hollegaard, MV Demontis, D Trabjerg, BB Hjorthoj, C Ripke, S Degenhardt, F Nothen, MM Rujescu, D Maier, W Werge, T Mors, O Hougaard, DM Borglum, AD Wray, NR Rietschel, M Nordentoft, M Mortensen, PB Mattheisen, M AF Meier, S. M. Agerbo, E. Maier, R. Pedersen, C. B. Lang, M. Grove, J. Hollegaard, M. V. Demontis, D. Trabjerg, B. B. Hjorthoj, C. Ripke, S. Degenhardt, F. Noethen, M. M. Rujescu, D. Maier, W. Werge, T. Mors, O. Hougaard, D. M. Borglum, A. D. Wray, N. R. Rietschel, M. Nordentoft, M. Mortensen, P. B. Mattheisen, M. CA MooDS SCZ Consortium TI High loading of polygenic risk in cases with chronic schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article ID CENTRAL RESEARCH REGISTER; GENOME-WIDE ASSOCIATION; FAMILY-HISTORY; DANISH; DISORDERS; NATIONWIDE; MORTALITY; TRAITS; COHORT AB Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R-2 and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R-2 values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (P-target = 0.017, P-replication = 0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvement(target) = 50%; improvement(replication) = 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness. C1 [Meier, S. M.; Agerbo, E.; Pedersen, C. B.; Trabjerg, B. B.; Mortensen, P. B.] Aarhus Univ, Natl Ctr Register Based Res, DK-8000 Aarhus C, Denmark. [Meier, S. M.; Agerbo, E.; Pedersen, C. B.; Grove, J.; Demontis, D.; Trabjerg, B. B.; Hjorthoj, C.; Werge, T.; Mors, O.; Borglum, A. D.; Nordentoft, M.; Mortensen, P. B.; Mattheisen, M.] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Copenhagen, Denmark. [Meier, S. M.; Lang, M.; Rietschel, M.] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Agerbo, E.; Pedersen, C. B.; Mortensen, P. B.] Aarhus Univ, Ctr Integrated Register Based Res, DK-8000 Aarhus C, Denmark. [Maier, R.; Wray, N. R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Grove, J.; Demontis, D.; Borglum, A. D.; Mattheisen, M.] Aarhus Univ, Dept Biomed, DK-8000 Aarhus C, Denmark. [Grove, J.] Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus C, Denmark. [Grove, J.; Demontis, D.; Borglum, A. D.; Mortensen, P. B.; Mattheisen, M.] Aarhus Univ, Ctr Integrat Sequencing iSEQ, DK-8000 Aarhus C, Denmark. [Hollegaard, M. V.; Hougaard, D. M.] Statens Serum Inst, Dept Congenital Disorders, Danish Ctr Neonatal Screening, DK-2300 Copenhagen, Denmark. [Hjorthoj, C.; Werge, T.; Nordentoft, M.] Univ Copenhagen, Mental Hlth Ctr Copenhagen, Mental Hlth Serv Capital Reg Denmark, Copenhagen, Denmark. [Hjorthoj, C.] Univ Copenhagen, Fac Hlth Sci, Inst Clin Med, Copenhagen, Denmark. [Ripke, S.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, S.] Harvard Univ, Sch Med, Boston, MA USA. [Ripke, S.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Degenhardt, F.; Noethen, M. M.; Mattheisen, M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Degenhardt, F.; Noethen, M. M.; Mattheisen, M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Rujescu, D.; Nordentoft, M.] Univ Halle Wittenberg, Dept Psychiat Psychotherapy & Psychosomat, D-06108 Halle, Germany. [Maier, W.] Univ Bonn, Dept Psychiat, Bonn, Germany. [Mors, O.; Borglum, A. D.] Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark. RP Meier, SM (reprint author), Aarhus Univ, Natl Ctr Register Based Res, DK-8000 Aarhus C, Denmark. EM smeier@econ.au.dk RI Pedersen, Carsten Bocker/B-8441-2013; Agerbo, Esben/A-2645-2012; OI Pedersen, Carsten Bocker/0000-0003-2077-8533; Agerbo, Esben/0000-0002-2849-524X; Mattheisen, Manuel/0000-0002-8442-493X; Grove, Jakob/0000-0003-2284-5744; Nothen, Markus/0000-0002-8770-2464 FU Stanley Center for Psychiatric Research; Broad Institute; Lundbeck Foundation within Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH; Stanley Medical Research Institute; European Community [279227]; German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme [01ZX1314A, 01ZX1314G]; Australian National Health and Medical Research Council [1078901, 1047956] FX We are indebted to all individuals who have participated in, or helped with, our research. The Danish replication samples were genotyped at the Broad Institute and funded by Stanley Center for Psychiatric Research, Broad Institute and the Lundbeck Foundation, within the context of the Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH. We acknowledge Kimberly Chambert and Christine Stevens for laboratory sample management. Dr Mortensen received further funding from the Stanley Medical Research Institute. The German SCZ GWAS sample received funding from the European Community's Seventh Framework Programme (FP7) under grant agreement no 279227 (Crestar) and the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Programme (grant 01ZX1314A to MMN, grant 01ZX1314G to MR). Dr Wray is funded by Australian National Health and Medical Research Council grants (1078901, 1047956). We thank the Schizophrenia Working Group of the Psychiatric Genomics Consortium for kindly providing us with the summary statistics of their data. NR 34 TC 3 Z9 3 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 2016 VL 21 IS 7 BP 969 EP 974 DI 10.1038/mp.2015.130 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DO9DX UT WOS:000378085600013 PM 26324100 ER PT J AU Rennekamp, AJ Huang, XP Wang, Y Patel, S Lorello, PJ Cade, L Gonzales, APW Yeh, JRJ Caldarone, BJ Roth, BL Kokel, D Peterson, RT AF Rennekamp, Andrew J. Huang, Xi-Ping Wang, You Patel, Samir Lorello, Paul J. Cade, Lindsay Gonzales, Andrew P. W. Yeh, Jing-Ruey Joanna Caldarone, Barbara J. Roth, Bryan L. Kokel, David Peterson, Randall T. TI sigma(1) receptor ligands control a switch between passive and active threat responses SO NATURE CHEMICAL BIOLOGY LA English DT Article ID ZEBRAFISH DANIO-RERIO; FORCED SWIMMING TEST; DEPRESSIVE-LIKE; KNOCKOUT MICE; SCHIZOPHRENIA; FEAR; MODULATION; AGONISTS; AMYGDALA; BIOLOGY AB Humans and many animals show 'freezing' behavior in response to threatening stimuli. In humans, inappropriate threat responses are fundamental characteristics of several mental illnesses. To identify small molecules that modulate threat responses, we developed a high-throughput behavioral assay in zebrafish (Danio rerio) and evaluated 10,000 compounds for their effects on freezing behavior. We found three classes of compounds that switch the threat response from freezing to escape-like behavior. We then screened these for binding activity across 45 candidate targets. Using target profile clustering, we identified the sigma-1 (sigma(1)) receptor as having a role in the mechanism of behavioral switching and confirmed that known ligands also disrupt freezing behavior. Furthermore, mutation of the gene encoding sigma(1) prevented the behavioral effect of escape-inducing compounds. One compound, which we call finazine, potently bound mammalian sigma(1) and altered threat-response behavior in mice. Thus, pharmacological and genetic interrogation of the freezing response revealed sigma(1) as a mediator of threat responses in vertebrates. C1 [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Peterson, Randall T.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Yeh, Jing-Ruey Joanna; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Rennekamp, Andrew J.; Wang, You; Patel, Samir; Cade, Lindsay; Gonzales, Andrew P. W.; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Neurobehav Lab, Harvard NeuroDiscovery Ctr, 75 Francis St, Boston, MA 02115 USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Roth, Bryan L.] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Kokel, David] Univ Calif San Francisco, Dept Physiol, Box 0444, San Francisco, CA USA. RP Peterson, RT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA.; Peterson, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA.; Peterson, RT (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA.; Peterson, RT (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA.; Peterson, RT (reprint author), Broad Inst, Cambridge, MA USA. EM peterson@cvrc.mgh.harvard.edu OI Rennekamp , Andrew /0000-0001-6174-7253 FU US National Institutes of Health (NIH) Psychoactive Drug Screening Program [HHSN-271-2008-025C]; NIH [T32 HL 007208, R01 MH 086867, R01 GM 088040, U01 MH 105027]; Charles and Ann Sanders MGH Research Scholar Award; Harvard NeuroDiscovery Center FX We thank C. Brady, J.J. Colund, I.T. Helenius, Y.N. Jin and A. Nath for helpful comments. Receptor binding profiles and Ki data were provided by the US National Institutes of Health (NIH) Psychoactive Drug Screening Program, contract HHSN-271-2008-025C. This work was supported by NIH grants T32 HL 007208 (A.J.R.), R01 MH 086867 (R.T.P.), R01 GM 088040 (R.T.P.) and U01 MH 105027 (D.K. and J.-R.J.Y.); the Charles and Ann Sanders MGH Research Scholar Award (R.T.P.); and the Harvard NeuroDiscovery Center. NR 37 TC 3 Z9 3 U1 5 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUL PY 2016 VL 12 IS 7 BP 552 EP + DI 10.1038/NCHEMBIO.2089 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO9EP UT WOS:000378087500016 PM 27239788 ER PT J AU Bruni, G Rennekamp, AJ Velenich, A McCarroll, M Gendelev, L Fertsch, E Taylor, J Lakhani, P Lensen, D Evron, T Lorello, PJ Huang, XP Kolczewski, S Carey, G Caldarone, BJ Prinssen, E Roth, BL Keiser, MJ Peterson, RT Kokel, D AF Bruni, Giancarlo Rennekamp, Andrew J. Velenich, Andrea McCarroll, Matthew Gendelev, Leo Fertsch, Ethan Taylor, Jack Lakhani, Parth Lensen, Dennis Evron, Tama Lorello, Paul J. Huang, Xi-Ping Kolczewski, Sabine Carey, Galen Caldarone, Barbara J. Prinssen, Eric Roth, Bryan L. Keiser, Michael J. Peterson, Randall T. Kokel, David TI Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PSYCHIATRIC DRUG DISCOVERY; LARVAL ZEBRAFISH; SMALL MOLECULES; CNS DISORDERS; IN-VIVO; CLOZAPINE; PHENCYCLIDINE; SCHIZOPHRENIA; SEROTONIN; DOPAMINE AB Many psychiatric drugs act on multiple targets and therefore require screening assays that encompass a wide target space. With sufficiently rich phenotyping and a large sampling of compounds, it should be possible to identify compounds with desired mechanisms of action on the basis of behavioral profiles alone. Although zebrafish (Danio rerio) behavior has been used to rapidly identify neuroactive compounds, it is not clear what types of behavioral assays would be necessary to identify multitarget compounds such as antipsychotics. Here we developed a battery of behavioral assays in larval zebrafish to determine whether behavioral profiles can provide sufficient phenotypic resolution to identify and classify psychiatric drugs. Using the antipsychotic drug haloperidol as a test case, we found that behavioral profiles of haloperidol-treated zebrafish could be used to identify previously uncharacterized compounds with desired antipsychotic-like activities and multitarget mechanisms of action. C1 [Bruni, Giancarlo; Rennekamp, Andrew J.; Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Bruni, Giancarlo; Velenich, Andrea; Lensen, Dennis; Evron, Tama; Carey, Galen] Teleos Therapeut, Medford, MA USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Charlestown, MA USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Syst Biol, Charlestown, MA USA. [Rennekamp, Andrew J.; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [McCarroll, Matthew; Fertsch, Ethan; Taylor, Jack; Lakhani, Parth; Kokel, David] Univ Calif San Francisco, Dept Physiol, Box 0444, San Francisco, CA USA. [McCarroll, Matthew; Gendelev, Leo; Fertsch, Ethan; Taylor, Jack; Lakhani, Parth; Keiser, Michael J.; Kokel, David] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. [Gendelev, Leo; Keiser, Michael J.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Gendelev, Leo; Keiser, Michael J.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Neurobehav Lab, Harvard NeuroDiscovery Ctr, 75 Francis St, Boston, MA 02115 USA. [Lorello, Paul J.; Caldarone, Barbara J.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Chapel Hill, NC USA. [Kolczewski, Sabine; Prinssen, Eric] Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Basel, Switzerland. RP Kokel, D (reprint author), Univ Calif San Francisco, Dept Physiol, Box 0444, San Francisco, CA USA.; Kokel, D (reprint author), Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. EM david.kokel@ucsf.edu OI Keiser, Michael/0000-0002-1240-2192; Bruni, Giancarlo/0000-0003-2850-4633; Rennekamp , Andrew /0000-0001-6174-7253 FU US National Institutes of Health (NIH) [K01MH091449, U01MH105027, R01AA022583, R44GM093456, T32EB009383, T32GM008284, R01MH086867, R21MH085205]; Charles and Ann Sanders MGH Research Scholar Award; Glenn Foundation Award for Research in Biological Mechanisms of Aging FX We thank members of our research groups for helpful advice. This work was supported by US National Institutes of Health (NIH) grants K01MH091449, U01MH105027 and R01AA022583 (D.K.); R44GM093456 (M.J.K.), T32EB009383 and T32GM008284 (L.G.) and R01MH086867 and R21MH085205 (R.T.P.); the Charles and Ann Sanders MGH Research Scholar Award (R.T.P.); and the Glenn Foundation Award for Research in Biological Mechanisms of Aging (D.K. and M.J.K.). NR 52 TC 3 Z9 3 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUL PY 2016 VL 12 IS 7 BP 559 EP + DI 10.1038/NCHEMBIO.2097 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO9EP UT WOS:000378087500017 PM 27239787 ER PT J AU Flannick, J Johansson, S Njolstad, PR AF Flannick, Jason Johansson, Stefan Njolstad, Pal R. TI Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Review ID SEVERE INSULIN-RESISTANCE; LARGE-SCALE ASSOCIATION; DISEASE GENE-DISCOVERY; OF-FUNCTION MUTATIONS; LOW-FREQUENCY; SUSCEPTIBILITY LOCI; SEQUENCE VARIANTS; BETA-CELL; METABOLIC PHENOTYPES; MOLECULAR-GENETICS AB Insights into the genetic basis of type 2 diabetes mellitus (T2DM) have been difficult to discern, despite substantial research. More is known about rare forms of diabetes mellitus, several of which share clinical and genetic features with the common form of T2DM. In this Review, we discuss the extent to which the study of rare and low-frequency mutations in large populations has begun to bridge the gap between rare and common forms of diabetes mellitus. We hypothesize that the perceived division between these diseases might be due, in part, to the historical ascertainment bias of genetic studies, rather than a clear distinction between disease pathophysiologies. We also discuss possible implications of a new model for the genetic basis of diabetes mellitus subtypes, where the boundary between subtypes becomes blurred. C1 [Flannick, Jason] Broad Inst Harvard & MIT, Program Med & Populat Genet, 415 Main St, Cambridge, MA 02142 USA. [Flannick, Jason] Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. [Johansson, Stefan; Njolstad, Pal R.] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Jonas Lies Veg 87, N-5020 Bergen, Norway. [Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, Jonas Lies Veg 65, N-5021 Bergen, Norway. [Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, Jonas Lies Veg 65, N-5021 Bergen, Norway. RP Njolstad, PR (reprint author), Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Jonas Lies Veg 87, N-5020 Bergen, Norway.; Njolstad, PR (reprint author), Haukeland Hosp, Dept Pediat, Jonas Lies Veg 65, N-5021 Bergen, Norway. EM pal.njolstad@uib.no RI Johansson, Stefan/C-4394-2011 OI Johansson, Stefan/0000-0002-2298-7008 FU Novo Nordisk Foundation [15OC0016108]; European Research Council (AdG) [293574]; Research Council of Norway [240413]; KG Jebsen Foundation (Translational Research Center); University of Bergen (Diabetes Group); Helse Vest (Strategic Fund) FX Stefan Johansson has received a grant from the Novo Nordisk Foundation (# 15OC0016108). Pal R. Njolstad has received grants from the European Research Council (AdG; # 293574), the Research Council of Norway (# 240413), the KG Jebsen Foundation (Translational Research Center), the University of Bergen (Diabetes Group), and the Helse Vest (Strategic Fund). NR 127 TC 2 Z9 2 U1 5 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD JUL PY 2016 VL 12 IS 7 BP 394 EP 406 DI 10.1038/nrendo.2016.50 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO6LU UT WOS:000377895800005 PM 27080136 ER PT J AU Macht, R Rosen, A Horn, G Carmine, B Hess, D AF Macht, Ryan Rosen, Amy Horn, Garrick Carmine, Brian Hess, Donald TI An Exploration of System-Level Factors and the Geographic Variation in Bariatric Surgery Utilization SO OBESITY SURGERY LA English DT Article DE Bariatric surgery; Surgeon supply; Geographic variation; Obesity treatment disparities; System-level factors ID ACCESS; CARE AB There is wide geographic variation in bariatric surgery rates, although higher regional rates of obesity are not correlated with higher rates of surgery. In this study, four system-level factors were explored as contributors to this geographic variation. Geographic utilization rates of bariatric surgery showed no correlation to the number of bariatric surgeons, number of accredited centers, and the percentage of patients with a recent primary care visit. The total number of surgical discharges was weakly correlated with bariatric surgery rates (r = 0.26, p = < 0.001). As surgeon supply, accredited bariatric centers, overall surgical volume, and access to primary care do not appear to heavily influence bariatric surgery rates, future studies are needed to identify additional factors that may explain the underutilization of bariatric surgery. C1 [Macht, Ryan; Rosen, Amy; Carmine, Brian; Hess, Donald] Boston Univ, Sch Med, Dept Surg, Collamore C-500,88 East Newton St, Boston, MA 02118 USA. [Macht, Ryan; Rosen, Amy; Carmine, Brian; Hess, Donald] Boston Med Ctr, Collamore C-500,88 East Newton St, Boston, MA 02118 USA. [Rosen, Amy] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res CHOIR, Boston, MA USA. [Horn, Garrick] Boston Univ, Sch Med, Collamore C-500,88 East Newton St, Boston, MA 02118 USA. RP Macht, R (reprint author), Boston Univ, Sch Med, Dept Surg, Collamore C-500,88 East Newton St, Boston, MA 02118 USA.; Macht, R (reprint author), Boston Med Ctr, Collamore C-500,88 East Newton St, Boston, MA 02118 USA. EM ryan.macht@bmc.org; akrosen@bu.edu; garrick@bu.edu; brian.carmine@bmc.org; donald.hess@bmc.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 EI 1708-0428 J9 OBES SURG JI Obes. Surg. PD JUL PY 2016 VL 26 IS 7 BP 1635 EP 1638 DI 10.1007/s11695-016-2164-6 PG 4 WC Surgery SC Surgery GA DO7CG UT WOS:000377939200043 PM 27034061 ER PT J AU Concha-Benavente, F Srivastava, R Ferrone, S Ferris, RL AF Concha-Benavente, Fernando Srivastava, Raghvendra Ferrone, Soldano Ferris, Robert L. TI Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells SO ORAL ONCOLOGY LA English DT Article DE HLA class I; APM; CTL; Immunoescape ID PRIMARY MELANOMA LESIONS; TAP1 DOWN-REGULATION; HIGH-FREQUENCY; IMMUNE ESCAPE; NECK-CANCER; MOLECULAR-MECHANISMS; NATURAL-KILLER; COLORECTAL CARCINOMAS; LARYNGEAL CARCINOMAS; PRESENTING MACHINERY AB Experimental as well as clinical studies demonstrate that the immune system plays a major role in controlling generation and progression of tumors. The cancer immunoediting theory supports the notion that tumor cell immunogenicity is dynamically shaped by the immune system, as it eliminates immunogenic tumor cells in the early stage of the disease and then edits their antigenicity. The end result is the generation of a tumor cell population able to escape from immune recognition and elimination by tumor infiltrating lymphocytes. Two major mechanisms, which affect the target cells and the effector phase of the immune response, play a crucial role in the editing process. One is represented by the downregulation of tumor antigen (TA) processing and presentation because of abnormalities in the HLA class I antigen processing machinery (APM). The other one is represented by the anergy of effector immune infiltrates in the tumor microenvironment caused by aberrant inhibitory signals triggered by immune checkpoint receptor (ICR) ligands, such as programmed death ligand-1 (PD-L1). In this review, we will focus on tumor immune escape mechanisms caused by defects in HLA class I APM component expression and/or function in different types of cancer, with emphasis on head and neck cancer (HNC). We will also discuss the immunological implications and clinical relevance of these HLA class I APM abnormalities. Finally, we will describe strategies to counteract defective TA presentation with the expectation that they will enhance tumor recognition and elimination by tumor infiltrating effector T cells. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Concha-Benavente, Fernando; Ferris, Robert L.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Srivastava, Raghvendra; Ferris, Robert L.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Ferrone, Soldano] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Ferris, Robert L.] Univ Pittsburgh, Canc Immunol Program, Inst Canc, Pittsburgh, PA USA. RP Ferris, RL (reprint author), Hillman Canc Ctr Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM ferrisrl@upmc.edu FU NCI NIH HHS [P30 CA047904, P50 CA097190, R01 CA110249, R01 CA206517]; NIDCR NIH HHS [R01 DE019727] NR 84 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2016 VL 58 BP 52 EP 58 DI 10.1016/j.oraloncology.2016.05.008 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DO7AV UT WOS:000377935500014 PM 27264839 ER PT J AU Kang, WS Nguyen, K McKenna, CE Sewell, WF McKenna, MJ Jung, DH AF Kang, Woo Seok Nguyen, Kim McKenna, Charles E. Sewell, William F. McKenna, Michael J. Jung, David H. TI Measurement of Ototoxicity Following Intracochlear Bisphosphonate Delivery SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Bisphosphonates; Fluorescence imaging; Inner ear drug delivery; Otosclerosis; Ototoxicity ID DRUG-DELIVERY; GUINEA-PIGS; OTOSCLEROSIS; BONE; MECHANISMS; PERILYMPH; COCHLEA AB Hypothesis: Assessing the maximum safe dose for local bisphosphonate delivery to the cochlea enables efficient delivery without ototoxicity. Background: Otosclerosis is a disease of abnormal bone metabolism affecting the otic capsule, which can cause conductive hearing loss. Larger otosclerotic lesions involving the cochlear endosteum and spiral ligament can result in sensorineural hearing loss. Bisphosphonates are used to treat patients with metabolic bone diseases, including otosclerosis. Local delivery is the most efficient way of delivery to the cochlea while avoiding systemic side effects. To attain intracochlear bisphosphonate delivery without ototoxicity, the maximum safe dose of bisphosphonates requires definition. In the present study, we tested increasing concentrations of zoledronate, a third-generation bisphosphonate in an intracochlear delivery system. We measured ototoxicity by monitoring distortion product otoacoustic emissions and compound action potentials. Methods: Artificial perilymph and increasing molar concentrations of zoledronate were administered to the cochlea in guinea pigs via a cochleostomy. Hearing was measured at multiple time points. A fluorescently labeled zoledronate derivative (6-FAM-ZOL) was coadministered as an internal control for drug delivery. Specimens embedded in the resin blocks were ground to a mid-modiolar section and fluorescent photomicrographs were taken. Results: No significant shift in hearing was observed in animals treated either with artificial perilymph or with 4% of the human systemic zoledronate dose. However, compound action potentials thresholds increased during infusion of 8% of the human systemic zoledronate dose, improved 4 hours later, and then increased again 4 weeks later. Using fluorescent photomicrography, intracochlear bisphosphonate delivery up to the apical cochlear turn was confirmed by visualizing 6-FAM-ZOL. Conclusion: These findings provide reference values for intracochlear bisphosphonate delivery in the treatment of cochlear otosclerosis and describe a useful method for tracking cochlear drug delivery. C1 [Kang, Woo Seok] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Otolaryngol, Seoul, South Korea. [Kang, Woo Seok; McKenna, Michael J.; Jung, David H.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Kang, Woo Seok; Sewell, William F.; McKenna, Michael J.; Jung, David H.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Kang, Woo Seok; Sewell, William F.; McKenna, Michael J.; Jung, David H.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Nguyen, Kim; McKenna, Charles E.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. RP Jung, DH (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM david_jung@meei.harvard.edu FU NIDCD [R01 DC009837] FX This work was primarily supported by NIDCD grant R01 DC009837. NR 21 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD JUL PY 2016 VL 37 IS 6 BP 621 EP 626 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DO8VX UT WOS:000378064500006 PM 27153329 ER PT J AU Kamakura, T Nadol, JB AF Kamakura, Takefumi Nadol, Joseph B., Jr. TI Cochlear Histopathology as Observed in Two Patients With a Cochlear Implant Electrode With Positioner SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear implant; Fibrous sheath; Histopathology; Human; Insertion trauma; Osseous spiral lamina; Positioner ID HUMAN TEMPORAL BONES; MENINGITIS; RISK; RECONSTRUCTION; SUBJECT; TRAUMA; ARRAY AB Hypothesis: This study reports the cochlear histopathology of two patients who during life underwent cochlear implantation with a positioner. Background: A silastic positioner introduced by the Advanced Bionics Corporation in 1999 was designed to position the electrode of the cochlear implant close to the modiolus. The positioner was recalled in the United States in July 2002 because of an apparent higher incidence of bacterial meningitis in patients in whom the positioner had been placed. Methods: Four celloidin-embedded temporal bones from two patients with cochlear implants with a positioner from the temporal bone collection of the Massachusetts Eye and Ear Infirmary were included in the study. In a previous study, we reported histopathologic findings in Patient 1, and in this report, we present the findings in a second case in a 94-year-old woman (Patient 2), and the similarities and differences between the two patients. All four specimens were prepared for histologic study by conventional techniques and 2-D reconstruction. Results: Evidence of insertion trauma was observed in all three implanted specimens. More significant trauma was found in Patient 2 than in Patient 1 including disruption of the osseous spiral lamina and the basilar membrane. In addition, there was more new fibrous tissue and bone in Patient 2 than in Patient 1. There was a large fluid space in all three implanted temporal bones around the electrode and positioner. Conclusion: The findings observed in the two patients may help to explain the increased risk of meningitis in patients implanted with a positioner. C1 [Kamakura, Takefumi; Nadol, Joseph B., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Human Otopathol Lab, 243 Charles St, Boston, MA 02114 USA. [Kamakura, Takefumi; Nadol, Joseph B., Jr.] Harvard Univ, Sch Med, Boston, MA USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Human Otopathol Lab, 243 Charles St, Boston, MA 02114 USA. EM joseph_nadol@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD) [R01-DC000152] FX This work was supported by grant R01-DC000152 from the National Institute on Deafness and Other Communication Disorders (NIDCD). NR 23 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD JUL PY 2016 VL 37 IS 6 BP 642 EP 646 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DO8VX UT WOS:000378064500009 PM 27273406 ER PT J AU Watkins, LE Han, SZ Harpaz-Rotem, I Mota, NP Southwick, SM Krystal, JH Gelernter, J Pietrzak, RH AF Watkins, Laura E. Han, Shizhong Harpaz-Rotem, Ilan Mota, Natalie P. Southwick, Steven M. Krystal, John H. Gelernter, Joel Pietrzak, Robert H. TI FKBP5 polymorphisms, childhood abuse, and PTSD symptoms: Results from the National Health and Resilience in Veterans Study SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Posttraumatic stress disorder; FKBP5; Childhood abuse; Gene environment interaction; HPA axis ID POSTTRAUMATIC-STRESS-DISORDER; DSM-IV; ASSOCIATION; VALIDATION; CHILDREN; ADULTS; RISK AB Polymorphisms in the FK506 Binding Protein 5 (FKBP5) gene may interact with childhood abuse to increase risk of developing posttraumatic stress disorder (PTSD) symptoms. The objective of this study was to examine the relationship of four previously identified FKBP5 putative risk SNP5 (rs9296158, rs3800373, rs1360780, rs947008), childhood abuse, and lifetime PTSD symptoms, including contemporary phenotypic models of PTSD symptoms, in two nationally representative samples of European-American (EA) U.S. military veterans. The main sample included 1585 EA veterans who participated in the National Health and Resilience in Veterans Study (NHRVS), and the replication sample included 577 EA veterans who participated in a second baseline cohort survey of the NHRVS. Outcome variables were lifetime PTSD symptom severity and a 4-factor phenotypic model of PTSD symptoms that included re-experiencing, avoidance, emotional numbing/negative cognitions and mood, and hyperarousal/alterations in arousal and reactivity symptoms. Results revealed that the four FKBP5 SNPs were associated with PTSD symptom severity in both samples (p values ranged from 0.001 to 0.012). Further, SNP rs9470080 in the main sample, and all four SNP5 in the replication sample interacted with childhood abuse to predict PTSD severity (p values ranged from 0.002 to 0.006). In both samples, all four FKBP5 SNPs predicted hyperarousal/alterations in arousal and reactivity (p values ranged from <0.001 to 0.002). Results of this study suggest that FKBP5 polymorphisms, directly and interactively with childhood abuse, predict severity of lifetime PTSD symptoms, most notably hyperarousal symptoms, in two nationally representative samples of EA veterans. They further indicate that FKBP5 polymorphisms and childhood abuse may contribute to vulnerability for PTSD symptoms and may be most strongly associated with trauma-related hyperarousal symptoms that comprise this phenotype. Published by Elsevier Ltd. C1 [Watkins, Laura E.; Harpaz-Rotem, Ilan; Southwick, Steven M.; Krystal, John H.; Gelernter, Joel; Pietrzak, Robert H.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, VA Connecticut Healthcare Syst, West Haven, CT USA. [Watkins, Laura E.; Harpaz-Rotem, Ilan; Southwick, Steven M.; Krystal, John H.; Gelernter, Joel; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, 950 Campbell Ave 151D, New Haven, CT USA. [Han, Shizhong] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Mota, Natalie P.] Univ Manitoba, Dept Clin Hlth Psychol, Winnipeg, MB, Canada. RP Watkins, LE (reprint author), US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, VA Connecticut Healthcare Syst, West Haven, CT USA.; Watkins, LE (reprint author), Yale Univ, Sch Med, Dept Psychiat, 950 Campbell Ave 151D, New Haven, CT USA. EM laura.watkins@yale.edu FU U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder FX The National Health and Resilience in Veterans Study was supported by the U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder. NR 27 TC 2 Z9 2 U1 4 U2 11 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 2016 VL 69 BP 98 EP 105 DI 10.1016/j.psyneuen.2016.04.001 PG 8 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DO4CH UT WOS:000377728900012 PM 27078785 ER PT J AU Fan, VS Gylys-Colwell, I Locke, E Sumino, K Nguyen, HQ Thomas, RM Magzamen, S AF Fan, Vincent S. Gylys-Colwell, Ina Locke, Emily Sumino, Kaharu Nguyen, Huong Q. Thomas, Rachel M. Magzamen, Sheryl TI Overuse of short-acting beta-agonist bronchodilators in COPD during periods of clinical stability SO RESPIRATORY MEDICINE LA English DT Article DE Pulmonary disease, chronic obstructive; Metered dose inhaler; Telemedicine; Adrenergic beta-2 receptor agonists; Adherence; Medication ID CALCULATING CORRELATION-COEFFICIENTS; OBSTRUCTIVE PULMONARY-DISEASE; LUNG-DISEASE; AUDIT-C; ASTHMA; EXACERBATIONS; QUESTIONNAIRE; VALIDATION; KNOWLEDGE; DEVICES AB Background: Overuse of short-acting beta-agonists (SABA) is described in asthma, but little is known about overuse of SABA in chronic obstructive pulmonary disease (COPD). Methods: Prospective 3-month cohort study of patients with moderate-to-severe COPD who were provided a portable electronic inhaler sensor to monitor daily SABA use. Subjects wore a pedometer for 3 seven-day periods and were asked to complete a daily diary of symptoms and inhaler use. Overuse was defined as >8 actuations of their SABA per day while clinically stable. Results: Among 32 participants, 15 overused their SABA inhaler at least once (mean 8.6 +/- 5.0 puffs/day), and 6 overused their inhaler more than 50% of monitored days. Compared to those with no overuse, overusers had greater dyspnea (modified Medical Research Council Dyspnea Scale: 2.7 vs. 1.9, p = 0.02), were more likely to use home oxygen (67% vs. 29%, p = 0.04), and were more likely to be on maximal inhaled therapy (long-acting beta-agonist, long-acting antimuscarinic agent, and an inhaled steroid: 40% vs. 6%, p = 0.03), and most had completed pulmonary rehabilitation (67% vs. 0%, p < 0.001). However, 27% of overusers of SABA were not on guideline-concordant COPD therapy. Conclusions: Overuse of SABA was common and associated with increased disease severity and symptoms, even though overusers were on more COPD-related inhalers and more had completed pulmonary rehabilitation. More research is needed to understand factors associated with inhaler overuse and how to improve correct inhaler use. Published by Elsevier Ltd. C1 [Fan, Vincent S.; Gylys-Colwell, Ina; Locke, Emily; Thomas, Rachel M.] VA Puget Sound Hlth Care Syst, S-152,1660 S Columbian Way, Seattle, WA 98108 USA. [Fan, Vincent S.] Univ Washington, Seattle, WA 98195 USA. [Sumino, Kaharu] St Louis VA Med Ctr, St Louis, MO USA. [Sumino, Kaharu] Washington Univ, Sch Med, St Louis, MO USA. [Nguyen, Huong Q.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Magzamen, Sheryl] Colorado State Univ, Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Fan, VS (reprint author), VA Puget Sound Hlth Care Syst, S-152,1660 S Columbian Way, Seattle, WA 98108 USA. EM vincent.fan@va.gov FU United States Department of Veterans Affairs Health Services Research and Development (VA HSRD) Program [PPO 10-299] FX Hong T.K. Nguyen and Carol Simons participated in recruitment, data collection and data management for the study. Leslie Taylor and Eric Gunnink assisted with data analysis and assistance with plots. This research was supported by grant from the United States Department of Veterans Affairs Health Services Research and Development (VA HSR&D PPO 10-299) Program. NR 27 TC 0 Z9 0 U1 2 U2 4 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD JUL PY 2016 VL 116 BP 100 EP 106 DI 10.1016/j.rmed.2016.05.011 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DO6LI UT WOS:000377894500015 PM 27296828 ER PT J AU Millard, SP Shofer, J Braff, D Calkins, M Cadenhead, K Freedman, R Green, MF Greenwood, TA Gur, R Gur, R Lazzeroni, LC Light, GA Olincy, A Nuechterlein, K Seidman, L Siever, L Silverman, J Stone, WS Sprock, J Sugar, CA Swerdlow, NR Tsuang, M Turetsky, B Radant, A Tsuang, D AF Millard, Steven P. Shofer, Jane Braff, David Calkins, Monica Cadenhead, Kristin Freedman, Robert Green, Michael F. Greenwood, Tiffany A. Gur, Raquel Gur, Ruben Lazzeroni, Laura C. Light, Gregory A. Olincy, Ann Nuechterlein, Keith Seidman, Larry Siever, Larry Silverman, Jeremy Stone, William S. Sprock, Joyce Sugar, Catherine A. Swerdlow, Neal R. Tsuang, Ming Turetsky, Bruce Radant, Allen Tsuang, DebbyW. TI Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Endophenotype; Logistic regression; Random forest; Sensitivity; Specificity; Accuracy; ROC curve; Multiple imputation ID ANTISACCADE PERFORMANCE; NEUROPHYSIOLOGICAL ENDOPHENOTYPES; NEUROCOGNITIVE ENDOPHENOTYPES; 1ST-DEGREE RELATIVES; PREPULSE INHIBITION; CONSORTIUM; HERITABILITY; MULTISITE; DISORDER; RISK AB Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially. Published by Elsevier B.V. C1 [Millard, Steven P.; Shofer, Jane] VA Puget Sound Hlth Care Syst, VISN Mental Illness Res Educ & Clin Ctr 20, Seattle, WA 98108 USA. [Millard, Steven P.; Shofer, Jane; Radant, Allen; Tsuang, DebbyW.] VA Puget Sound Hlth Care Syst, VISN Geriatr Res Educ & Clin Ctr 20, Seattle, WA 98108 USA. [Braff, David; Light, Gregory A.; Sprock, Joyce] VA San Diego Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 22, San Diego, CA USA. [Braff, David; Cadenhead, Kristin; Greenwood, Tiffany A.; Light, Gregory A.; Sprock, Joyce; Swerdlow, Neal R.; Tsuang, Ming] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Calkins, Monica; Gur, Raquel; Gur, Ruben; Turetsky, Bruce] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Freedman, Robert; Olincy, Ann] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Green, Michael F.; Nuechterlein, Keith; Sugar, Catherine A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Green, Michael F.; Sugar, Catherine A.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Lazzeroni, Laura C.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Seidman, Larry; Stone, William S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Publ Psychiat Div,Med Sch,Dept Psychiat, Boston, MA 02215 USA. [Siever, Larry; Silverman, Jeremy] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Siever, Larry; Silverman, Jeremy] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 3, New York, NY USA. [Sugar, Catherine A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA USA. [Radant, Allen] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Tsuang, D (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,GRECC S182, Seattle, WA 98108 USA. EM dwt1@uw.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Greenwood, Tiffany/0000-0002-6080-6503 FU NIMH grants [R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, R01 MH65558] FX This material is the result of work supported in part with resources and the use of facilities at the VA Puget Sound Health Care System, Seattle, WA; VA San Diego Healthcare System, San Diego, CA; VA Greater Los Angeles Health Care System, Los Angeles, CA; and James J. Peters VA Medical Center, New York, NY. The study was supported by NIMH grants R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, and R01 MH65558. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and the contents do not represent the views of the funders, the U.S. Department of Veterans Affairs, or the United States Government. NR 56 TC 0 Z9 0 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2016 VL 174 IS 1-3 BP 1 EP 9 DI 10.1016/j.schres.2016.04.011 PG 9 WC Psychiatry SC Psychiatry GA DO7AO UT WOS:000377934800001 PM 27132484 ER PT J AU Deighton, S Buchy, L Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, S Bearden, CE Mathalon, D Addington, J AF Deighton, Stephanie Buchy, Lisa Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, ScottW. Bearden, Carrie E. Mathalon, Daniel Addington, Jean TI Traumatic brain injury in individuals at clinical high risk for psychosis SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Clinical high risk; Psychosis; Traumatic brain injury ID ULTRA-HIGH-RISK; SCHIZOPHRENIA; EXPERIENCES; DISORDER AB Background: Recent research suggests that a traumatic brain injury (TBI) can significantly increase the risk of later development of psychosis. However, it is unknown whether people at clinical high risk (CHR) of psychosis have experienced TBI at higher rates, compared to otherwise healthy individuals. This study evaluated the prevalence of mild TBI, whether it was related to past trauma and the relationship of mild TBI to later transition to psychosis. Methods: Seven-hundred forty-seven CHR and 278 healthy controls (HC) were assessed on past history of mild TBI, age at first and last injury, severity of worst injury and number of injuries using the Traumatic Brain Injury Interview. Attenuated psychotic symptoms were assessed with the Scale of Psychosis-risk Symptoms. IQ was estimated using the Wechsler Abbreviated Scale of Intelligence and past trauma and bullying were recorded using the Childhood Trauma and Abuse Scale. Results: CHR participants experienced a mild TBI more often than the HC group. CHR participants who had experienced a mild TBI reported greater total trauma and bullying scores than those who had not, and those who experienced a mild TBI and later made the transition to psychosis were significantly younger at the age at first and most recent injury than those who did not. Conclusion: A history of mild TBI is more frequently observed in CHR individuals than in HC. Inclusion or study of CHR youth with more severe TBI may provide additional insights on the relationship between TBI and later transition to psychosis in CHR individuals. (C) 2016 Elsevier B.V. All rights reserved. C1 [Deighton, Stephanie; Buchy, Lisa; Addington, Jean] Univ Calgary, Dept Psychiat, Hotchkiss Brain Inst, Calgary, AB T2N 4Z6, Canada. [Cadenhead, Kristin S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Cannon, Tyrone D.; Tsuang, Ming T.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [McGlashan, Thomas H.; Woods, ScottW.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Psychiat, Sch Med, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Mathalon, Daniel] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Addington, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health [U01MH081984, U01 MH081928, P50 MH080272, SCDMH82101008006, R01 MH60720, U01 MH082022, K24 MH76191, U01MH081902, P50 MH066286, U01MH082004, U01MH081988, U01MH082022, UO1 MH081857-05] FX This study was supported by the National Institute of Mental Health (grant U01MH081984 to Dr Addington; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to Dr Seidman; grants R01 MH60720, U01 MH082022 and K24 MH76191 to Dr Cadenhead; grant U01MH081902 to Dr Cannon; P50 MH066286 (Prodromal Core) to Dr Bearden; grant U01MH082004 to Dr Perkins; grant U01MH081988 to Dr Walker; grant U01MH082022 to Dr Woods; and UO1 MH081857-05 grant to Dr Cornblatt. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 29 TC 0 Z9 0 U1 5 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2016 VL 174 IS 1-3 BP 77 EP 81 DI 10.1016/j.schres.2016.04.041 PG 5 WC Psychiatry SC Psychiatry GA DO7AO UT WOS:000377934800013 PM 27165121 ER PT J AU Isitt, JJ Nadipelli, VR Kouassi, A Fava, M Heidbreder, C AF Isitt, John J. Nadipelli, Vijay R. Kouassi, Alex Fava, Maurizio Heidbreder, Christian TI Health-related quality of life in acute schizophrenia patients treated with RBP-7000 once monthly risperidone: An 8-week, randomized, double-blind, placebo-controlled, multicenter phase 3 study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Antipsychotic agents; Randomized controlled trials; Health-related quality of life ID POPULATION PHARMACOKINETICS; MEDICATION SATISFACTION; PSYCHOMETRIC EVALUATION; INJECTABLE RISPERIDONE; ANTIPSYCHOTIC-DRUGS; FORMULATION; REMISSION; IMPROVEMENT; PREDICTION; RELEASE AB Background: There is increased interest in the impact of new long-acting treatments on health-related quality of life (HRQoL) in patients with schizophrenia. The aim of this study was to evaluate the impact of treatment with subcutaneous injections of RBP-7000, a news ustained-release formulation of risperidone, compared with placebo on health status, subjective well-being, treatment satisfaction, and preference of medicine in subjects with acute schizophrenia. Methods: HRQoL data were derived froman 8-week double-blind, randomized, placebo-controlled, phase 3 study that assessed efficacy, safety, and tolerability of once monthly RBP-7000 (90 mg and 120 mg) compared with placebo in subjects with acute schizophrenia (n = 337). HRQoL was measured with the EuroQol EQ-5D-5L, well-being using the Neuroleptic Treatment-Short Version (SWN-S), satisfaction using the Medication Satisfaction Questionnaire (MSQ), and preference using the Preference of Medicine Questionnaire (POM). Results: The EQ-5D-5L VAS increased significantly in the RBP-7000 120 mg group compared to Placebo (p = 0.0212). In RBP-7000 120 mg, subjects reported significant improvements in SWN-S physical functioning (p=0.0093), social integration (p=0.0368), and total score (p=0.0395). Subjects were significantly more satisfied with RBP-7000 versus placebo (90 mg p= 0.0009, 120 mg p= 0.0006) and preferred RBP-7000 over their previous medication (90 mg p < 0.0001, 120 mg p = 0.0619). Conclusions: Significantly greater improvements in HRQoL and overall well-being were demonstrated in patients randomized to RBP-7000 compared to placebo. The effect was more pronounced in the RBP-7000 120 mg group. Patient satisfaction improved significantly and patient preference for their medicine favored RBP-7000 90 mg and 120 mg versus Placebo. (C) 2016 Elsevier B.V. All rights reserved. C1 [Isitt, John J.; Nadipelli, Vijay R.; Kouassi, Alex; Heidbreder, Christian] Indivior Inc, 10710 Midlothian Turnpike,Suite 430, Richmond, VA 23235 USA. [Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. RP Isitt, JJ (reprint author), Indivior Inc, 10710 Midlothian Turnpike,Suite 430, Richmond, VA 23235 USA. EM john.isitt@indivior.com FU Indivior Inc. FX This work was sponsored and supported by Indivior Inc. NR 27 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2016 VL 174 IS 1-3 BP 126 EP 131 DI 10.1016/j.schres.2016.03.020 PG 6 WC Psychiatry SC Psychiatry GA DO7AO UT WOS:000377934800020 PM 27066860 ER PT J AU Murphy, RA Nisenbaum, L Labar, AS Sheridan, RL Ronat, JB Dilworth, K Pena, J Kilborn, E Teicher, C AF Murphy, Richard A. Nisenbaum, Luba Labar, Amy S. Sheridan, Robert L. Ronat, Jean-Baptiste Dilworth, Kelly Pena, Jade Kilborn, Erin Teicher, Carrie TI Invasive Infection and Outcomes in a Humanitarian Surgical Burn Program in Haiti SO WORLD JOURNAL OF SURGERY LA English DT Article ID EPIDEMIOLOGY; PREVENTION; CARE AB Compare to high-income settings, survival in burn units in low-income settings is lower with invasive infections one leading cause of death. M,decins Sans FrontiSres is involved in the treatment of large burns in adults and children in Haiti. In 2014, we performed a review of 228 patients admitted consecutively with burn injury during a 6-month period to determine patient outcomes and infectious complications. Microbiology was available through a linkage with a Haitian organization. Regression analysis was performed to determine covariates associated with bloodstream infection and mortality. 102 (45 %) patients were male, the median age was 8 years (IQR, 2-28), and the majority of patients (60 %) were admitted to the unit within 6 h of injury. There were 20 patients (9 %) with culture-proven bacteremia. Among organisms in blood, common isolates were Staphylococcus aureus (42 %), Pseudomonas aeruginosa (23 %), and Acinetobacter baumannii (15 %). Among patients with burns involving < 40 % total body area, 4 (2 %) of 192 died and 20 (65 %) of 31 with a parts per thousand yen40 % body surface area involvement died. Factors associated with mortality included involvement of a parts per thousand yen40 % of body surface, depth, and flame as the mechanism. Multidrug-resistant infections were common; 18 % of S. aureus isolates were methicillin resistant, and 83 % of P. aeruginosa isolates were imipenem resistant. A low mortality rate was observed in a humanitarian burn surgery project in patients with burns involving < 40 % of total body surface. Invasive infection was common and alarming rates of antibiotic resistance were observed, including infections not treatable with antibiotics available locally. C1 [Murphy, Richard A.] Harbor UCLA Med Ctr, Div Infect Dis, Los Angeles Biomed Res Inst, 1000 W Carson St,Box 466, Torrance, CA 90509 USA. [Nisenbaum, Luba; Ronat, Jean-Baptiste; Dilworth, Kelly; Pena, Jade; Kilborn, Erin] Med Sans Frontieres Doctors Borders, 8 Rue St Sabin, F-75011 Paris, France. [Nisenbaum, Luba] Rowan Univ, Sch Osteopath Med, One Med Ctr Dr, Stratford, NJ 08084 USA. [Labar, Amy S.; Teicher, Carrie] Epicentre, 55 Rue Crozatier, Paris, France. [Sheridan, Robert L.] Massachusetts Gen Hosp, Div Burns, 55 Blossom St, Boston, MA 02114 USA. RP Murphy, RA (reprint author), Harbor UCLA Med Ctr, Div Infect Dis, Los Angeles Biomed Res Inst, 1000 W Carson St,Box 466, Torrance, CA 90509 USA. EM ramurphy@gmail.com OI Murphy, Richard/0000-0003-2249-7452 NR 14 TC 0 Z9 0 U1 2 U2 3 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 2016 VL 40 IS 7 BP 1550 EP 1557 DI 10.1007/s00268-016-3458-5 PG 8 WC Surgery SC Surgery GA DO4SY UT WOS:000377775100003 PM 26913733 ER PT J AU Shimada, YJ Bansilal, S Wiviott, SD Becker, RC Harrington, RA Himmelmann, A Neely, B Husted, S James, SK Katus, HA Lopes, RD Steg, PG Storey, RF Wallentin, L Cannon, CP AF Shimada, Yuichi J. Bansilal, Sameer Wiviott, Stephen D. Becker, Richard C. Harrington, Robert A. Himmelmann, Anders Neely, Benjamin Husted, Steen James, Stefan K. Katus, Hugo A. Lopes, Renato D. Steg, Ph. Gabriel Storey, Robert F. Wallentin, Lars Cannon, Christopher P. CA PLATO Investigators TI Impact of glycoprotein IIb/IIIa inhibitors on the efficacy and safety of ticagrelor compared with clopidogrel in patients with acute coronary syndromes: Analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial SO AMERICAN HEART JOURNAL LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; RECEPTOR ANTAGONIST; INTERVENTION; PRETREATMENT AB Background Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel. Methods PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours. Results A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P<.05), whereas there was no such difference with GPI (P interaction <.05). Conclusions In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment. C1 [Shimada, Yuichi J.; Cannon, Christopher P.] Harvard Clin Res Inst, 930 Commonwealth Ave W, Boston, MA 02215 USA. [Shimada, Yuichi J.; Wiviott, Stephen D.; Cannon, Christopher P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Shimada, Yuichi J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Bansilal, Sameer] Icahn Sch Med Mt Sinai, Cardiovasc Inst, New York, NY 10029 USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Heart Lung & Vasc Inst, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA. [Harrington, Robert A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Himmelmann, Anders] AstraZeneca Res & Dev, Molndal, Sweden. [Neely, Benjamin; Lopes, Renato D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Husted, Steen] Hosp Unit West, Med Dept, Herning Holstebro, Denmark. [James, Stefan K.] Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden. [James, Stefan K.; Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Katus, Hugo A.] Univ Klinikum Heidelberg, Med Klin, Heidelberg, Germany. [Steg, Ph. Gabriel] INSERM, U1148, Paris, France. [Steg, Ph. Gabriel] Hop Bichat Claude Bernard, Dept Hosp Univ FIRE, AP HP, F-75877 Paris, France. [Steg, Ph. Gabriel] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Steg, Ph. Gabriel] NHLI Imperial Coll, Royal Brompton Hosp, ICMS, London, England. [Storey, Robert F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. RP Cannon, CP (reprint author), Harvard Clin Res Inst, 930 Commonwealth Ave W, Boston, MA 02215 USA. EM christopher.cannon@hcri.harvard.edu RI Katus, Hugo/P-1712-2016; OI Shimada, Yuichi/0000-0002-3494-307X NR 13 TC 0 Z9 0 U1 3 U2 4 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 2016 VL 177 BP 1 EP 8 DI 10.1016/j.ahj.2016.03.015 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO0MN UT WOS:000377473100002 PM 27297843 ER PT J AU Kim, EJ Yin, XY Fontes, JD Magnani, JW Lubitz, SA McManus, DD Seshadri, S Vasan, RS Ellinor, PT Larson, MG Benjamin, EJ Rienstra, M AF Kim, Eun-Jeong Yin, Xiaoyan Fontes, Joao D. Magnani, Jared W. Lubitz, Steve A. McManus, David D. Seshadri, Sudha Vasan, Ramachandran S. Ellinor, Patrick T. Larson, Martin G. Benjamin, Emelia J. Rienstra, Michiel TI Atrial fibrillation without comorbidities: Prevalence, incidence and prognosis (from the Framingham Heart Study) SO AMERICAN HEART JOURNAL LA English DT Article ID 30-YEAR FOLLOW-UP; RISK-FACTOR; PROGRESSION; SURVIVAL; DISEASE; CURVES AB Background The epidemiology of atrial fibrillation (AF) without comorbidities, known as 'lone AF', is uncertain. Although it has been considered a benign condition, we hypothesized that it confers a worse prognosis compared with a matched sample without AF. Methods We described the proportion of AF without comorbidities (clinical, subclinical cardiovascular disease and triggers) among the entire AF sample in Framingham Heart Study (FHS). We compared AF without comorbidities with typical AF, and age-, sex-and cohort-matched individuals without AF, using Cox proportional hazards analysis in relation to combined cardiovascular events (stroke, heart failure, myocardial infarction), and mortality. Results Of 10,311 FHS participants, 1,961 were diagnosed with incident AF, among which 173 individuals had AF without comorbidities (47% women, mean age 71 +/- 12 years). AF without comorbidities had a prevalence of 1.7% of the entire cohort, and an annual incidence of 0.5 per 1000 person-years. During a median follow-up of 9.7 years after initial AF, 137 individuals with AF without comorbidities (79.2%) died and 141 individuals developed cardiovascular events (81.5%). AF without comorbidities had significantly lower mortality (HR 0.67, 95% CI 0.55-0.81, P < .001) and total cardiovascular events (HR 0.66, 95% CI 0.55-0.80, P < .001) compared with typical AF. However, mortality (HR1.43, 95% CI 1.18-1.75, P < .001) and risk of total cardiovascular events (HR 1.73, 95% CI 1.39-2.16, P < .001) were higher than age-, sex-, and cohort-matched individuals without AF. Conclusions The risk of cardiovascular outcomes and mortality among individuals with AF without comorbidities is lower than typical AF, but is significantly elevated compared with matched individuals without AF. C1 [Kim, Eun-Jeong] Massachusetts Gen Hosp, Dept Med, Gen Internal Med Sect, Boston, MA 02114 USA. [Yin, Xiaoyan; Fontes, Joao D.; Magnani, Jared W.; Seshadri, Sudha; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Yin, Xiaoyan; Fontes, Joao D.; Magnani, Jared W.; Seshadri, Sudha; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Magnani, Jared W.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02215 USA. [Lubitz, Steve A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steve A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steve A.; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. RP Rienstra, M (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. EM m.rienstra@umcg.nl OI Ramachandran, Vasan/0000-0001-7357-5970; Rienstra, Michiel/0000-0002-2581-070X FU Doris Duke Charitable Foundation [2014105]; NCATS NIH HHS [UL1 TR001453]; NCRR NIH HHS [KL2 RR031981]; NHLBI NIH HHS [N01 HC025195, HHSN268201500001C, HHSN268201500001I, K23 HL114724, N01HC25195, R01 HL092577, R01 HL102214, R15 HL121761, RC1 HL101056]; NINDS NIH HHS [R01 NS017950] NR 24 TC 1 Z9 1 U1 5 U2 10 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 2016 VL 177 BP 138 EP 144 DI 10.1016/j.ahj.2016.03.023 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO0MN UT WOS:000377473100018 PM 27297859 ER PT J AU Mitra, M Long-Bellil, LM Iezzoni, LI Smeltzer, SC Smith, LD AF Mitra, Monika Long-Bellil, Linda M. Iezzoni, Lisa I. Smeltzer, Suzanne C. Smith, Lauren D. TI Pregnancy among women with physical disabilities: Unmet needs and recommendations on navigating pregnancy SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Pregnancy; Perinatal health; Women with physical disabilities; Qualitative ID REPRODUCTIVE HEALTH; EXPERIENCES; CARE; MOTHERS AB Background: Despite concerns raised in the literature on the adverse pregnancy outcomes of women with physical disabilities, there is little information about unmet needs of women with physical disabilities during pregnancy and childbirth. Objective: This article provides an in-depth examination of unmet health care needs during and around the time of pregnancy among a sample of women with physical disabilities. It also offers recommendations to other women with physical disabilities who are considering pregnancy. Methods: Twenty-five phone interviews were conducted with women with physical disabilities from across the United States who had a baby in the past ten years. Individual semi-structured qualitative interviews lasting about 2 h were conducted. Interviews were audio-recorded, transcribed, and analyzed using an iterative, interpretive process. Results: Women reported a wide range of disabling conditions. Analysis revealed three broad themes related to unmet needs during pregnancy among women with physical disabilities. They included (1) clinician knowledge and attitudes, (2) physical accessibility of health care facilities and equipment, (3) need for information related to pregnancy and postpartum supports. The women also provided recommendations to other women with disabilities who are currently pregnant or thinking of becoming pregnant. Recommendations related to finding a clinician one trusts, seeking peer support, self-advocating, and preparing oneself for the baby. Conclusions: This study sheds light on the unmet needs and barriers to care of women with mobility disabilities during pregnancy and childbirth. The study findings highlight the need for policy and practice recommendations for perinatal care of women with mobility disabilities. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mitra, Monika; Smith, Lauren D.] Brandeis Univ, Heller Sch Social Policy & Management, Lurie Inst Disabil Policy, 415 South St, Waltham, MA 01453 USA. [Long-Bellil, Linda M.] Univ Massachusetts, Sch Med, Ctr Hlth Policy & Res, 333 South St, Shrewsbury, MA 01545 USA. [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. [Smeltzer, Suzanne C.] Villanova Univ, Ctr Nursing Res, 800 Lancaster Ave, Villanova, PA 19085 USA. RP Mitra, M (reprint author), Brandeis Univ, Heller Sch Social Policy & Management, Lurie Inst Disabil Policy, 415 South St, Waltham, MA 01453 USA. EM mmitra@brandeis.edu FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development [R01HD074581] FX This research is funded by a grant from the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development. Award Number: R01HD074581. NR 27 TC 2 Z9 2 U1 3 U2 7 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 2016 VL 9 IS 3 BP 457 EP 463 DI 10.1016/j.dhjo.2015.12.007 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA DN9RP UT WOS:000377418100013 PM 26847669 ER PT J AU Iezzoni, LI Kurtz, SG Rao, SR AF Iezzoni, Lisa I. Kurtz, Stephen G. Rao, Sowmya R. TI Trends in colorectal cancer screening over time for persons with and without chronic disability SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Functional impairments; Colorectal cancer screening; Disparities; National Health Interview Survey ID PREVENTIVE SERVICES; PHYSICAL-DISABILITIES; MOBILITY IMPAIRMENTS; BREAST-CANCER; UNITED-STATES; HEALTH-CARE; BARRIERS; WOMEN; DISPARITIES; RECEIPT AB Background: Persons with disabilities have often experienced disparities in routine cancer screening. However, with civil rights protections from the 1990 Americans with Disabilities Act, such disparities may diminish over time. Objective: To examine whether disability disparities exist for colorectal cancer screening and whether these screening patterns have changed over time. Methods: We analyzed National Health Interview Survey responses from civilian, non-institutionalized U.S. residents 50-75 years old from selected years between 1998 and 2010. We specified 7 chronic disability indicators using self-reported functional impairments, activity/participation limitations, and expected duration. Separately for women and men, we conducted bivariable and multivariable logistic regression analyses examining associations of self-reported colorectal cancer screening services with sociodemographic factors and disability type. Results: Patterns of chronic disability differed somewhat between women and men; disability rates generally rose over time. For both women and men, colorectal cancer screening rates increased substantially from 1998 through 2010. Over time, relatively few statistically significant differences were reported in colorectal cancer screening rates between nondisabled persons and individuals with various disabilities. In 2010, reported screening rates were generally comparable between nondisabled and disabled persons. In the few statistically significant differences, persons with disabilities almost always reported higher colorectal cancer screening rates than nondisabled individuals. Conclusions: According to national survey data, reported use of colorectal cancer screening is similar between nondisabled persons and individuals with a variety of different disability types. Despite physical demands of some colorectal cancer screening tests, disparities do not appear between populations with and without disability. (C) 2016 Elsevier Inc. All rights reserved. C1 [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Kurtz, Stephen G.] Commonwealth Med, Ctr Hlth Policy & Res, Worcester, MA USA. [Rao, Sowmya R.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02215 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.edu FU National Cancer Institute [5 R01 CA160286-02] FX This work was funded by the National Cancer Institute, 5 R01 CA160286-02. NR 35 TC 1 Z9 1 U1 1 U2 1 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 2016 VL 9 IS 3 BP 498 EP 509 DI 10.1016/j.dhjo.2016.02.003 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA DN9RP UT WOS:000377418100018 PM 27130194 ER PT J AU Frappaz, D Federico, SM Pearson, ADJ Gore, L Macy, ME DuBois, SG Aerts, I Iannone, R Geschwindt, R Van Schanke, A Wang, R Geoerger, B AF Frappaz, Didier Federico, Sara M. Pearson, Andrew D. J. Gore, Lia Macy, Margaret E. DuBois, Steven G. Aerts, Isabelle Iannone, Robert Geschwindt, Ryan Van Schanke, Arne Wang, Rui Geoerger, Birgit TI Phase 1 study of dalotuzumab monotherapy and ridaforolimus-dalotuzumab combination therapy in paediatric patients with advanced solid tumours SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Dalotuzumab; Ridaforolimus; mTOR; IGF1-R; Paediatrics; Phase 1; Pharmacokinetics ID FACTOR-I RECEPTOR; RAPAMYCIN INHIBITOR RIDAFOROLIMUS; IGF-1R ANTIBODY CIXUTUMUMAB; HUMANIZED MONOCLONAL-ANTIBODY; PRECLINICAL TESTING PROGRAM; RESISTANT PROSTATE-CANCER; REFRACTORY EWING SARCOMA; SOFT-TISSUE SARCOMAS; MTOR INHIBITOR; ANTITUMOR-ACTIVITY AB Aim: Dalotuzumab is a highly specific, humanised immunoglobulin G1 monoclonal antibody against insulin-like growth factor receptor 1. This multicenter phase 1 study (NCT01431547) explored the safety and pharmacokinetics of dalotuzumab monotherapy (part 1) and the combination of dalotuzumab with the mammalian target of rapamycin inhibitor ridaforolimus (part 2) in paediatric patients with advanced solid tumours. Methods: Dalotuzumab was administered intravenously every 3 weeks starting at 900 mg/m(2) and escalating to 1200 and 1500 mg/m(2). Combination therapy included intravenous dalotuzumab at the defined single-agent recommended phase 2 dose (RP2D) and oral ridaforolimus 28 mg/m(2) daily (days 1-5), repeated weekly. Pharmacokinetic studies were performed to evaluate the mean serum trough dalotuzumab concentration, which guided the RP2D. Results: Twenty-four patients were enrolled (part 1, n = 20; part 2, n = 4). No dose-limiting toxicities were observed in patients receiving dalotuzumab alone. One patient experienced dose-limiting stomatitis in the combination arm. Pharmacokinetic data showed dose-dependent increases in exposure (area under the curve from zero to infinity [AUC(0-infinity)]) (87,900, 164,000, and 186,000 h*mg/ml for the 900, 1200, and 1500 mg/m(2) dose levels, respectively), maximum serum concentration (C-max) (392, 643, and 870 mg/ml), and serum trough concentration (C-trough) (67.1, 71.6, and 101 mg/ml). The mean half-life was 265, 394, and 310 h, respectively. Dalotuzumab pharmacokinetics were not affected by coadministration with ridaforolimus. One of six patients with Ewing sarcoma had confirmed partial response to dalotuzumab monotherapy at 900 mg/m(2). Time to response was 41 d, and progression occurred at 126 d. Conclusion: Dalotuzumab was well tolerated in paediatric patients with advanced solid malignancies. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Frappaz, Didier] Inst Hematol & Oncol Pediat, Pl Prof Joseph Renaut, F-69008 Lyon, France. [Federico, Sara M.] St Jude Childrens Res Hosp, Dept Oncol, MS 260,Room C6067,262 Danny Thomas Pl, Memphis, TN 38105 USA. [Pearson, Andrew D. J.] Royal Marsden Hosp, Inst Canc Res, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. [Gore, Lia; Macy, Margaret E.] Univ Colorado, Sch Med, Dept Pediat, 13001 East 17th Pl, Aurora, CO 80045 USA. [Gore, Lia; Macy, Margaret E.] Childress Hosp Colorado, 13123 East 16th Ave,B115, Aurora, CO 80045 USA. [DuBois, Steven G.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Aerts, Isabelle] Inst Curie, Dept Pediat Oncol, 26 Rue Ulm, F-75248 Paris 05, France. [Iannone, Robert; Geschwindt, Ryan] Merck & Co Inc, Clin Res, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA. [Van Schanke, Arne] Quantitat Solut BV, Pivot Pk Molenweg 79, NL-5349 AC Oss, Netherlands. [Wang, Rui] MSD R&D China Co Ltd, BARDS, Univ Business Pk,10 Jiu Xianqiao Rd, Beijing 100015, Peoples R China. [Geoerger, Birgit] Univ Paris 11, Gustave Roussy, Dept Pediat & Adolescent Oncol, 114 Rue Edouard Valliant, F-94805 Villejuif, France. RP Geoerger, B (reprint author), Univ Paris 11, Gustave Roussy, Dept Pediat & Adolescent Oncol, 114 Rue Edouard Valliant, F-94805 Villejuif, France. EM birgit.geoerger@gustaveroussy.fr FU Merck Sharp Dohme Corp [MK-8669_062-00] FX The study (MK-8669_062-00) was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. NR 40 TC 2 Z9 2 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 2016 VL 62 BP 9 EP 17 DI 10.1016/j.ejca.2016.03.084 PG 9 WC Oncology SC Oncology GA DN9FO UT WOS:000377385100002 PM 27185573 ER PT J AU DeLaney, TF Haas, RLM AF DeLaney, Thomas F. Haas, Rick L. M. TI Innovative radiotherapy of sarcoma: Proton beam radiation SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Proton beam radiation; Sarcoma ID SOFT-TISSUE SARCOMA; DOSE PHOTON/PROTON RADIOTHERAPY; INTENSITY-MODULATED PHOTON; COST-EFFECTIVENESS; PHASE-II; PROGNOSTIC-FACTORS; PARTICLE THERAPY; SPINE CHORDOMAS; BREAST-CANCER; SKULL BASE AB This review on proton beam radiotherapy (PBT) focusses on an historical overview, cost-effectiveness, techniques, acute and late toxicities and clinical results of PBT for sarcoma patients. PBT has gained its place among the armamentarium of modern radiotherapy techniques. For selected patients, it can be cost-effective. (C) 2016 Elsevier Ltd. All rights reserved. C1 [DeLaney, Thomas F.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, 55 Fruit St, Boston, MA 02114 USA. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, 55 Fruit St, Boston, MA 02114 USA. [Haas, Rick L. M.] Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Radiat Oncol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. RP Haas, RLM (reprint author), Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Radiat Oncol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM tdelaney@mgh.harvard.edu; r.haas@nki.nl OI Haas, Rick LM/0000-0003-4834-4331 FU GSK/Novartis; Nanobiotix Company FX TFD: None. RLMH: GSK/Novartis and Nanobiotix Company research grants to the institution. NR 76 TC 3 Z9 3 U1 3 U2 4 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 2016 VL 62 BP 112 EP 123 DI 10.1016/j.ejca.2016.04.015 PG 12 WC Oncology SC Oncology GA DN9FO UT WOS:000377385100013 PM 27258968 ER PT J AU Schwartz, LH Litiere, S de Vries, E Ford, R Gwyther, S Mandrekar, S Shankar, L Bogaerts, J Chen, A Dancey, J Hayes, W Hodi, FS Hoekstra, OS Huang, EP Lin, N Liu, Y Therasse, P Wolchok, JD Seymour, L AF Schwartz, Lawrence H. Litiere, Saskia de Vries, Elisabeth Ford, Robert Gwyther, Stephen Mandrekar, Sumithra Shankar, Lalitha Bogaerts, Jan Chen, Alice Dancey, Janet Hayes, Wendy Hodi, F. Stephen Hoekstra, Otto S. Huang, Erich P. Lin, Nancy Liu, Yan Therasse, Patrick Wolchok, Jedd D. Seymour, Lesley TI RECIST 1.1-Update and clarification: From the RECIST committee SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE RECIST; Clarifications; Tumour response ID SOLID TUMORS AB The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication. (C) 2016 Published by Elsevier Ltd. C1 [Schwartz, Lawrence H.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Schwartz, Lawrence H.] New York Presbyterian Hosp, New York, NY USA. [Litiere, Saskia; Bogaerts, Jan; Liu, Yan] EORTC HQ, Brussels, Belgium. [de Vries, Elisabeth] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9713 AV Groningen, Netherlands. [Ford, Robert] Clin Trials Imaging Consulting, Belle Mead, NJ USA. [Gwyther, Stephen] East Surrey Hosp, Dept Med Imaging, Redhill, Surrey, England. [Mandrekar, Sumithra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Shankar, Lalitha] NCI, Clin Trials Branch, Canc Imaging Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hayes, Wendy] Bristol Myers Squibb Co, Exploratory Clin & Translat Res, Princeton, NJ USA. [Hodi, F. Stephen; Lin, Nancy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Hoekstra, Otto S.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Huang, Erich P.] NCI, NIH, Rockville, MD USA. [Therasse, Patrick] Labs Servier, Paris, France. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Wolchok, Jedd D.] Grad Coll, New York, NY USA. [Wolchok, Jedd D.] Ludwig Inst Canc Res, New York, NY USA. [Dancey, Janet; Seymour, Lesley] Queens Univ, Canadian Canc Trials Grp, Kingston, ON, Canada. RP Schwartz, LH (reprint author), CUMC, 180 Ft Washington Ave, New York, NY 10032 USA. EM LSchwartz@columbia.edu FU Canadian Cancer Society Research Institute [021039]; EORTC Cancer Research Fund; National Cancer Institute (NCI) [5U10-CA11488-45] FX Canadian Cancer Trials Group participation was supported by the Canadian Cancer Society Research Institute (grant #021039). This publication was supported by the EORTC Cancer Research Fund and by the National Cancer Institute (NCI) grant number 5U10-CA11488-45. NR 6 TC 2 Z9 2 U1 2 U2 4 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 2016 VL 62 BP 132 EP 137 DI 10.1016/j.ejca.2016.03.081 PG 6 WC Oncology SC Oncology GA DN9FO UT WOS:000377385100015 PM 27189322 ER PT J AU Schwartz, LH Seymour, L Litiere, S Ford, R Gwyther, S Mandrekar, S Shankar, L Bogaerts, J Chen, A Dancey, J Hayes, W Hodi, FS Hoekstra, OS Huang, EP Lin, N Liu, Y Therasse, P Wolchok, JD de Vries, E AF Schwartz, Lawrence H. Seymour, Lesley Litiere, Saskia Ford, Robert Gwyther, Stephen Mandrekar, Sumithra Shankar, Lalitha Bogaerts, Jan Chen, Alice Dancey, Janet Hayes, Wendy Hodi, F. Stephen Hoekstra, Otto S. Huang, Erich P. Lin, Nancy Liu, Yan Therasse, Patrick Wolchok, Jedd D. de Vries, Elisabeth TI RECIST 1.1-Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE RECIST; Modifications; Tumour response ID METASTATIC PROSTATE-CANCER; RESPONSE ASSESSMENT CRITERIA; INTERNATIONAL WORKSHOP; END-POINTS; LYMPHOMA; CHEMOTHERAPY; MANAGEMENT; CARCINOMA; SURVIVAL; TRIALS AB Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta -analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation. (C) 2016 Published by Elsevier Ltd. C1 [Schwartz, Lawrence H.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Schwartz, Lawrence H.] New York Presbyterian Hosp, New York, NY USA. [Seymour, Lesley; Dancey, Janet] Queens Univ, Canadian Canc Trials Grp, Kingston, ON, Canada. [Litiere, Saskia; Bogaerts, Jan; Liu, Yan] EORTC HQ, Brussels, Belgium. [Ford, Robert] Clin Trials Imaging Consulting, Belle Mead, NJ USA. [Gwyther, Stephen] East Surrey Hosp, Dept Med Imaging, Redhill, Surrey, England. [Mandrekar, Sumithra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Shankar, Lalitha] NCI, Clin Trials Branch, Canc Imaging Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hayes, Wendy] Bristol Myers Squibb Co, Exploratory Clin & Translat Res, Princeton, NJ USA. [Hodi, F. Stephen; Lin, Nancy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Hoekstra, Otto S.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Huang, Erich P.] NCI, NIH, Rockville, MD USA. [Therasse, Patrick] Labs Servier, Paris, France. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Wolchok, Jedd D.] Grad Coll, New York, NY USA. [Wolchok, Jedd D.] Ludwig Inst Canc Res, New York, NY USA. [de Vries, Elisabeth] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9713 AV Groningen, Netherlands. RP Schwartz, LH (reprint author), Columbia Univ, Coll Phys & Surg, New York Presbyterian Hosp, Dept Radiol, 180 Ft Washington Ave, New York, NY 10032 USA. EM LSchwartz@columbia.edu FU Canadian Cancer Society Research Institute [021039]; EORTC Cancer Research Fund; National Cancer Institute [5U10-CA11488-45] FX Canadian Cancer Trials Group participation was supported by the Canadian Cancer Society Research Institute (grant #021039). This publication was supported by the EORTC Cancer Research Fund and by the National Cancer Institute grant number 5U10-CA11488-45. NR 22 TC 3 Z9 4 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 2016 VL 62 BP 138 EP 145 DI 10.1016/j.ejca.2016.03.082 PG 8 WC Oncology SC Oncology GA DN9FO UT WOS:000377385100016 PM 27237360 ER PT J AU Wagner, AJ Agulnik, M Heinrich, MC Mahadevan, D Riedel, RF von Mehren, M Trent, J Demetri, GD Corless, CL Yule, M Lyons, JF Oganesian, A Keer, H AF Wagner, Andrew J. Agulnik, Mark Heinrich, Michael C. Mahadevan, Daruka Riedel, Richard F. von Mehren, Margaret Trent, Jonathan Demetri, George D. Corless, Christopher L. Yule, Murray Lyons, John F. Oganesian, Aram Keer, Harold TI Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Onalespib (AT13387); Non-ansamycin HSP90 inhibitor; TKI-resistant GIST ID TYROSINE KINASE INHIBITORS; PROTEIN 90 INHIBITOR; SOLID TUMORS; PHASE-I; RESISTANCE; IPI-504; MUTATIONS; THERAPY; MODELS; CANCER AB Background: Gastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST. Patients and methods: In this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150-220 mg/m(2)) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored. Results: Common onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43-165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d. Conclusion: The combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population. Trial registration ID: clinicaltrials.gov: NCT01294202 (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Wagner, Andrew J.; Demetri, George D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Wagner, Andrew J.; Demetri, George D.] Harvard Univ, Sch Med, Ludwig Ctr, Boston, MA USA. [Wagner, Andrew J.; Demetri, George D.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Agulnik, Mark] Northwestern Univ, Sch Med, Div Hematol Oncol, 676 N St Claire St,Suite 850, Chicago, IL 60611 USA. [Heinrich, Michael C.; Corless, Christopher L.] VA Portland Hlth Care Syst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Heinrich, Michael C.; Corless, Christopher L.] Oregon Hlth & Sci Univ, Knight Canc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Mahadevan, Daruka] West Canc Ctr UTHSC, Memphis, TN USA. [Mahadevan, Daruka] West Clin, 7495 Wolf River Blvd, Germantown, TN 38138 USA. [Riedel, Richard F.] Duke Canc Inst, Box 3198, Durham, NC 27710 USA. [von Mehren, Margaret] Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. [Trent, Jonathan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Trent, Jonathan] Univ Miami, Miller Sch Med, 1120 NW 14th St, Miami, FL 33136 USA. [Yule, Murray; Lyons, John F.] Astex Pharmaceut, 436 Cambridge Sci Pk, Cambridge CB4 0QA, England. [Oganesian, Aram; Keer, Harold] Astex Pharmaceut Inc, 4420 Rosewood Dr,Suite 200, Pleasanton, CA 94588 USA. RP Wagner, AJ (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Andrew_Wagner@dfci.harvard.edu; m-agulnik@northwestern.edu; Heinrich@ohsu.edu; dmahadevan@westclinic.com; Richard.riedel@duke.edu; Margaret.vonmehren@fccc.edu; jtrent@med.miami.edu; george_demetri@dfci.harvard.edu; corlessc@ohsu.edu; Yule@astx.com; John.lyons@astx.com; Aram.oganesian@astx.com; Harold.keer@astx.com OI Heinrich, Michael/0000-0003-3790-0478 FU Astex Pharmaceuticals, Inc.; Ludwig Center at Harvard; Pan Mass Challenge via Paul's Posse; Russo Family Fund for GIST research; SPORE Grant for Gastrointestinal Cancers at Dana-Farber Cancer Institute from the US National Cancer Institute [1P50CA127003-05] FX This study was sponsored, monitored, and funded by Astex Pharmaceuticals, Inc. ( formerly SuperGen, Inc.). The sponsor was involved in study design and in the collection, analysis, and interpretation of data. Support for this work has also been provided to GDD from the following sources: Ludwig Center at Harvard, the Pan Mass Challenge via Paul's Posse, the Russo Family Fund for GIST research, and SPORE Grant 1P50CA127003-05 for Gastrointestinal Cancers at Dana-Farber Cancer Institute from the US National Cancer Institute. NR 20 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2016 VL 61 BP 94 EP 101 DI 10.1016/j.ejca.2016.03.076 PG 8 WC Oncology SC Oncology GA DN9FK UT WOS:000377384700012 PM 27156227 ER PT J AU El Ayadi, A Zigmond, MJ Smith, AD AF El Ayadi, Amina Zigmond, Michael J. Smith, Amanda D. TI IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE 6-OHDA; Akt; CREB; Parkinson's disease; Striatum; ERK1/2; GSK-3Beta ID GROWTH-FACTOR-I; SUBSTANTIA-NIGRA NEURONS; N-TERMINAL TRIPEPTIDE; NEUROTROPHIC FACTOR; CELL-LINE; PARKINSONS-DISEASE; NIGROSTRIATAL DOPAMINE; TYROSINE-HYDROXYLASE; DIFFERENTIAL EXPRESSION; HUMAN BRAIN AB Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson's disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 A mu g) 6 h prior to infusion of 4 A mu g 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 A mu g IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3 beta, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades. C1 [El Ayadi, Amina; Zigmond, Michael J.; Smith, Amanda D.] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, 3501 Fifth Ave,7026 Biomed Sci Tower 3, Pittsburgh, PA 15261 USA. [Smith, Amanda D.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [El Ayadi, Amina] Univ Texas Med Branch, Dept Surg, Galveston, TX 77550 USA. RP Smith, AD (reprint author), Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, 3501 Fifth Ave,7026 Biomed Sci Tower 3, Pittsburgh, PA 15261 USA.; Smith, AD (reprint author), Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM smithad@pitt.edu FU Rita Levi-Montalcini Fellowship; Udall Center of Excellence in Parkinson's Disease Research [NS19608]; [NS45698]; [NS070825] FX The study was funded by Career Development Award (NS45698) to ADS, Rita Levi-Montalcini Fellowship to AE and both a Udall Center of Excellence in Parkinson's Disease Research (NS19608) and a Research Project Grant Award (NS070825) to MJZ. NR 57 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUL PY 2016 VL 234 IS 7 BP 1863 EP 1873 DI 10.1007/s00221-016-4572-1 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DN9ZW UT WOS:000377440200008 ER PT J AU Kang, JJ Liu, IY Wang, MB Srivatsan, ES AF Kang, James J. Liu, Isabelle Y. Wang, Marilene B. Srivatsan, Eri S. TI A review of gigaxonin mutations in giant axonal neuropathy (GAN) and cancer SO HUMAN GENETICS LA English DT Review ID NF-KAPPA-B; CELL-LINES; GENE; PROTEIN; PATHWAY; DEGRADATION; UBIQUITINATION; CYTOSKELETON; POLYMORPHISM; RESTORATION AB Gigaxonin, the product of GAN gene localized to chromosome 16, is associated with the early onset neuronal degeneration disease giant axonal neuropathy (GAN). Gigaxonin is an E3 ubiquitin ligase adaptor protein involved in intermediate filament processing in neural cells, and vimentin filaments in fibroblasts. Mutations of the gene cause pre-neural filaments to accumulate and form giant axons resulting in the inhibition of neural cell signaling. Analysis of the catalog of somatic mutations in cancer, driver DB and IDGC data portal databases containing 21,000 tumor genomic sequences has identified GAN patient mutations in cancer cell lines and primary tumors. The database search has also shown the presence of identical missense and nonsense gigaxonin mutations in GAN and colon cancer. These mutations frequently occur in the domains associated with protein homodimerization and substrate interaction such as Broad-Complex, Tramtrack and Bric a brac (BTB), BTB associated C-terminal KELCH (BACK), and KELCH repeats. Analysis of the International HapMap Project database containing 1200 normal genomic sequences has identified a single nucleotide polymorphism (SNP), rs2608555, in exon 8 of the gigaxonin sequence. While this SNP is present in > 40 % of Caucasian population, it is present in less than 10 % of Japanese and Chinese populations. Although the role of gigaxonin polymorphism is not yet known, CFTR and MDR1 gene studies have shown that silent mutations play a role in the instability and aberrant splicing and folding of mRNAs. We believe that molecular and functional investigation of gigaxonin mutations including the exon 8 polymorphism could lead to an improved understanding of the relationship between GAN and cancer. C1 [Kang, James J.; Wang, Marilene B.; Srivatsan, Eri S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. [Liu, Isabelle Y.; Wang, Marilene B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Head & Neck Surg, Los Angeles, CA 90073 USA. [Wang, Marilene B.; Srivatsan, Eri S.] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90073 USA. RP Srivatsan, ES (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA.; Srivatsan, ES (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90073 USA. EM esrivats@g.ucla.edu FU VAGLAHS; West Los Angeles Surgical Education Research Center; UCLA Academic Senate Grants; Veterans Administration, Washington, D.C. FX The study was supported by funds from VAGLAHS, West Los Angeles Surgical Education Research Center, UCLA Academic Senate Grants (M. B. Wang), and Merit grant from the Veterans Administration, Washington, D.C. (E. S. Srivatsan). NR 41 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JUL PY 2016 VL 135 IS 7 BP 675 EP 684 DI 10.1007/s00439-016-1659-5 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DN8XX UT WOS:000377364300001 PM 27023907 ER PT J AU Zietman, AL AF Zietman, Anthony L. TI The Red Journal's Top Downloads of 2015 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID MODERN RADIATION-THERAPY; ONCOLOGY GROUP; DOSE GUIDELINES; NORMAL TISSUE; CONSENSUS GUIDELINES; BRAIN METASTASES; LYMPHOMAS FIELD; CANCER; ARTICLES; DELINEATION C1 [Zietman, Anthony L.] Massachusetts Gen Hosp, 100 Blossom St, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, 100 Blossom St, Boston, MA 02114 USA. EM azietman@partners.org NR 25 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2016 VL 95 IS 3 BP 861 EP 863 DI 10.1016/j.ijrobp.2016.02.047 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600001 PM 27302501 ER PT J AU Benedict, SH Hoffman, K Martel, MK Abernethy, AP Asher, AL Capala, J Chen, RC Chera, B Couch, J Deye, J Efstathiou, JA Ford, E Fraass, BA Gabriel, PE Huser, V Kavanagh, BD Khuntia, D Marks, LB Mayo, C McNutt, T Miller, RS Moore, KL Prior, F Roelofs, E Rosenstein, BS Sloan, J Theriault, A Vikram, B AF Benedict, Stanley H. Hoffman, Karen Martel, Mary K. Abernethy, Amy P. Asher, Anthony L. Capala, Jacek Chen, Ronald C. Chera, Bhisham Couch, Jennifer Deye, James Efstathiou, Jason A. Ford, Eric Fraass, Benedick A. Gabriel, Peter E. Huser, Vojtech Kavanagh, Brian D. Khuntia, Deepak Marks, Lawrence B. Mayo, Charles McNutt, Todd Miller, Robert S. Moore, Kevin L. Prior, Fred Roelofs, Erik Rosenstein, Barry S. Sloan, Jeff Theriault, Anna Vikram, Bhadrasain TI Overview of the American Society for Radiation Oncology-National Institutes of Health-American Association of Physicists in Medicine Workshop 2015: Exploring Opportunities for Radiation Oncology in the Era of Big Data SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID SECONDARY USE; RADIOTHERAPY; FRAMEWORK; CARE C1 [Benedict, Stanley H.] Univ Calif Davis, Sacramento, CA 95817 USA. [Hoffman, Karen; Martel, Mary K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Benedict, Stanley H.] Univ Calif Davis, Sacramento, CA 95817 USA. [Hoffman, Karen; Martel, Mary K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Abernethy, Amy P.] Duke Univ, Durham, NC USA. [Asher, Anthony L.] Amer Assoc Neurol Surg, Rolling Meadows, IL USA. [Capala, Jacek] NCI, Clin Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Ronald C.; Chera, Bhisham; Marks, Lawrence B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Couch, Jennifer; Deye, James; Vikram, Bhadrasain] NCI, NIH, Bethesda, MD 20892 USA. [Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Ford, Eric] Univ Washington, Seattle, WA 98195 USA. [Fraass, Benedick A.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Gabriel, Peter E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Huser, Vojtech] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD USA. [Kavanagh, Brian D.] Univ Colorado, Denver, CO 80202 USA. [Khuntia, Deepak] Varian Med Syst, Palo Alto, CA USA. [Mayo, Charles] Univ Michigan, Ann Arbor, MI 48109 USA. [McNutt, Todd] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Miller, Robert S.] Amer Soc Clin Oncol, Alexandria, VA USA. [Moore, Kevin L.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Prior, Fred] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Roelofs, Erik] Maastricht Univ, Med Ctr, Dept Radiat Oncol MAASTRO, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands. [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Sloan, Jeff] Mayo Clin, Rochester, MN USA. [Theriault, Anna] Elekta, Sunnyvale, CA USA. RP Benedict, SH (reprint author), Univ Calif Davis, Sacramento, CA 95817 USA. EM shbenedict@ucdavis.edu FU NCI NIH HHS [U01 CA187013] NR 18 TC 1 Z9 1 U1 2 U2 5 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 2016 VL 95 IS 3 BP 873 EP 879 DI 10.1016/j.ijrobp.2016.03.006 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600003 PM 27302503 ER PT J AU Rosenstein, BS Capala, J Efstathiou, JA Hammerbacher, J Kerns, SL Kong, FM Ostrer, H Prior, FW Vikram, B Wong, J Xiao, Y AF Rosenstein, Barry S. Capala, Jacek Efstathiou, Jason A. Hammerbacher, Jeff Kerns, Sarah L. Kong, Feng-Ming (Spring) Ostrer, Harry Prior, Fred W. Vikram, Bhadrasain Wong, John Xiao, Ying TI How Will Big Data Improve Clinical and Basic Research in Radiation Therapy? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; CANCER IMAGING ARCHIVE; SINGLE-NUCLEOTIDE POLYMORPHISMS; RADIOTHERAPY TOXICITY; PROSTATE-CANCER; RADIOGENOMICS; MEDICINE; NETWORK; HEALTH; ONCOLOGY C1 [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, Dept Radiat Oncol, One Gustave L Levy Pl,Box 1236, New York, NY 10029 USA. [Rosenstein, Barry S.; Hammerbacher, Jeff] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA. [Rosenstein, Barry S.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Rosenstein, Barry S.] NYU, Sch Med, Dept Radiat Oncol, New York, NY USA. [Capala, Jacek; Vikram, Bhadrasain] NCI, Clin Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Kerns, Sarah L.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Kong, Feng-Ming (Spring)] Georgia Regents Univ, GRU Canc Ctr, Dept Radiat Oncol, Augusta, GA USA. [Kong, Feng-Ming (Spring)] Georgia Regents Univ, Med Coll Georgia, Augusta, GA USA. [Ostrer, Harry] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. [Ostrer, Harry] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Prior, Fred W.] Univ Arkansas Med Sci, Dept Biomed Informat, Little Rock, AR 72205 USA. [Wong, John] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA. [Xiao, Ying] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Rosenstein, BS (reprint author), Icahn Sch Med Mt Sinai, Dept Radiat Oncol, One Gustave L Levy Pl,Box 1236, New York, NY 10029 USA. EM barry.rosenstein@mssm.edu OI Hammerbacher, Jeffrey/0000-0001-6596-8563 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E, K07 CA187546, R01 CA134444, R01 CA142840, U01 CA187013, U10 CA180822, U10 CA180868, U24 CA180803, UG1 CA189867] NR 34 TC 3 Z9 3 U1 1 U2 5 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 2016 VL 95 IS 3 BP 895 EP 904 DI 10.1016/j.ijrobp.2015.11.009 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600007 PM 26797542 ER PT J AU Unkelbach, J Bussiere, MR Chapman, PH Loeffler, JS Shih, HA AF Unkelbach, Jan Bussiere, Marc R. Chapman, Paul H. Loeffler, Jay S. Shih, Helen A. TI Spatiotemporal Fractionation Schemes for Irradiating Large Cerebral Arteriovenous Malformations SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID BEAM STEREOTACTIC RADIOSURGERY; STAGED RADIOSURGERY; CLINICAL ARTICLE; RADIOTHERAPY; MANAGEMENT AB Purpose: To optimally exploit fractionation effects in the context of radiosurgery treatments of large cerebral arteriovenous malformations (AVMs). In current practice, fractionated treatments divide the dose evenly into several fractions, which generally leads to low obliteration rates. In this work, we investigate the potential benefit of delivering distinct dose distributions in different fractions. Methods and Materials: Five patients with large cerebral AVMs were reviewed and replanned for intensity modulated arc therapy delivered with conventional photon beams. Treatment plans allowing for different dose distributions in all fractions were obtained by performing treatment plan optimization based on the cumulative biologically effective dose delivered at the end of treatment. Results: We show that distinct treatment plans can be designed for different fractions, such that high single-fraction doses are delivered to complementary parts of the AVM. All plans create a similar dose bath in the surrounding normal brain and thereby exploit the fractionation effect. This partial hypofractionation in the AVM along with fractionation in normal brain achieves a net improvement of the therapeutic ratio. We show that a biological dose reduction of approximately 10% in the healthy brain can be achieved compared with reference treatment schedules that deliver the same dose distribution in all fractions. Conclusions: Boosting complementary parts of the target volume in different fractions may provide a therapeutic advantage in fractionated radiosurgery treatments of large cerebral AVMs. The strategy allows for a mean dose reduction in normal brain that may be valuable for a patient population with an otherwise normal life expectancy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Unkelbach, Jan; Bussiere, Marc R.; Loeffler, Jay S.; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [Chapman, Paul H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Unkelbach, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM junkelbach@mgh.harvard.edu FU NCI NIH HHS [C06 CA059267, U19 CA021239] NR 14 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2016 VL 95 IS 3 BP 1067 EP 1074 DI 10.1016/j.ijrobp.2016.02.001 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DN9AE UT WOS:000377370600029 PM 27113566 ER PT J AU Hoganson, DM Owens, GE Meppelink, AM Bassett, EK Bowley, CM Hinkel, CJ Finkelstein, EB Goldman, SM Vacanti, JP AF Hoganson, David M. Owens, Gwen E. Meppelink, Amanda M. Bassett, Erik K. Bowley, Chris M. Hinkel, Cameron J. Finkelstein, Eric B. Goldman, Scott M. Vacanti, Joseph P. TI Decellularized extracellular matrix microparticles as a vehicle for cellular delivery in a model of anastomosis healing SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE cell adhesion; 3-D cell culture; cell migration; extracellular matrix; microparticles ID MESENCHYMAL STEM-CELLS; ENDOTHELIAL-CELLS; REGENERATION; APLIGRAF(R); SUBSTRATE; DERMIS; GROWTH AB Extracellular matrix (ECM) materials from animal and human sources have become important materials for soft tissue repair. Microparticles of ECM materials have increased surface area and exposed binding sites compared to sheet materials. Decellularized porcine peritoneum was mechanically dissociated into 200 mu m microparticles, seeded with fibroblasts and cultured in a low gravity rotating bioreactor. The cells avidly attached and maintained excellent viability on the microparticles. When the seeded microparticles were placed in a collagen gel, the cells quickly migrated off the microparticles and through the gel. Cells from seeded microparticles migrated to and across an in vitro anastomosis model, increasing the tensile strength of the model. Cell seeded microparticles of ECM material have potential for paracrine and cellular delivery therapies when delivered in a gel carrier. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1728-1735, 2016. C1 [Hoganson, David M.] Boston Childrens Hosp, Dept Cardiac Surg, Boston, MA USA. [Owens, Gwen E.] CALTECH, Grad Opt Biochem & Mol Biophys, Pasadena, CA 91125 USA. [Meppelink, Amanda M.] Massachusetts Gen Hosp, Dept Surg, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Bassett, Erik K.; Vacanti, Joseph P.] Massachusetts Gen Hosp, Dept Surg, Ctr Regenerat Med, Boston, MA 02114 USA. [Bowley, Chris M.; Goldman, Scott M.] DSM Biomed, Exton, PA USA. [Hinkel, Cameron J.] Washington Univ St Louis, Dept Biomed Engn, St Louis, MO USA. [Finkelstein, Eric B.] Syracuse Univ, Dept Biomed & Chem Engn, Syracuse Biomat Inst, Syracuse, NY USA. RP Hoganson, DM (reprint author), Boston Childrens Hosp, Dept Cardiac Surg, Boston, MA USA. EM david.hoganson@cardio.chboston.org FU DSM Biomedical; NIH [F32 DK076349-01] FX Contract grant sponsor: Kensey Nash Corporation (now DSM Biomedical); Contract grant sponsor: NIH; contract grant number: F32 DK076349-01 NR 34 TC 0 Z9 0 U1 5 U2 5 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 2016 VL 104 IS 7 BP 1728 EP 1735 DI 10.1002/jbm.a.35703 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DO1FW UT WOS:000377524900017 PM 26946064 ER PT J AU Livne, T Bar, M AF Livne, Tomer Bar, Moshe TI Cortical Integration of Contextual Information across Objects SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID EPISODIC MEMORY RETRIEVAL; SCENE CONTEXT; DEFAULT MODE; CORTEX; PARAHIPPOCAMPAL; IDENTIFICATION; PERCEPTION; PRECUNEUS; IMAGERY; AREA AB Recognizing objects in the environment and understanding our surroundings often depends on context: the presence of other objects and knowledge about their relations with each other. Such contextual information activates a set of medial lobe brain regions, the parahippocampal cortex and the retrosplenial complex. Both regions are more activated by single objects with a unique contextual association than by objects not associated with any specific context. Similarly they are more activated by spatially coherent arrangements of objects when those are consistent with their known spatial relations. The current study tested how context in multiple-object displays is represented in these regions in the absence of relevant spatial information. Using an fMRI slow-event-related design, we show that the precuneus (a subpart of the retrosplenial complex) is more activated by simultaneously presented contextually related objects than by unrelated objects. This suggests that the representation of context in this region is cumulative, representing integrated information across objects in the display. We discuss these findings in relation to processing of visual information and relate them to previous findings of contextual effects in perception. C1 [Livne, Tomer; Bar, Moshe] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Livne, Tomer; Bar, Moshe] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Livne, Tomer] Washington Univ, St Louis, MO 63110 USA. [Bar, Moshe] Bar Ilan Univ, IL-52100 Ramat Gan, Israel. RP Livne, T (reprint author), Washington Univ, Sch Med, Dept Radiol, 4525 Scott Ave, St Louis, MO 63110 USA. EM tlivne@hotmail.com FU NSF [BCS-0842947]; Israeli Center of Research Excellence in Cognitive Sciences (ICORE) [51/11] FX We thank Olivia Cheung for helpful discussions and for commenting on an early draft and Matthew Panichello for assistance in data acquisition. We thank the Harvard decision science laboratory for providing us with lab space and equipment to run the behavioral pilot part of the study. This work was supported by NSF grant BCS-0842947 and by the Israeli Center of Research Excellence in Cognitive Sciences (ICORE grant no. 51/11). NR 46 TC 2 Z9 2 U1 8 U2 10 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0898-929X EI 1530-8898 J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUL PY 2016 VL 28 IS 7 BP 948 EP 958 DI 10.1162/jocn_a_00944 PG 11 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA DO0AT UT WOS:000377442500004 PM 26942322 ER PT J AU van Leeuwen, WF Janssen, SJ Ring, D Chen, N AF van Leeuwen, Wouter F. Janssen, Stein J. Ring, David Chen, Neal TI Incidental magnetic resonance imaging signal changes in the extensor carpi radialis brevis origin are more common with age SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Extensor carpi radialis brevis; enthesopathy; tennis elbow; lateral epicondylitis; MRI; prevalence ID LATERAL EPICONDYLITIS; TENNIS ELBOW; PREVALENCE; ABNORMALITIES; ENTHESOPATHY AB Background: Patients with enthesopathy of the extensor carpi radialis brevis (ECRB) demonstrate signal changes on magnetic resonance imaging (MRI). It is likely that these MRI changes persist for many years or may be permanent, regardless of symptoms, and represent an estimation of disease prevalence. We tested the hypothesis that the prevalence of incidental signal changes in the ECRB origin increases with age. Methods: We searched MRI reports of 3374 patients who underwent an MRI scan, including the elbow, for signal changes in the ECRB origin. Medical records were reviewed for symptoms consistent with ECRB enthesopathy. Prevalences of incidental and symptomatic signal changes were calculated and stratified by age. We used multivariate logistic regression analysis to test whether age, sex, and race were independently associated with ECRB enthesopathy and calculated odds ratios. Results: Signal changes in ECRB origin were identified on MRI scans of 369 of 3374 patients (11%) without a clinical suspicion of tennis elbow. The prevalence increased from 5.7% in patients aged between 18 and 30 years up to 16% in patients aged 71 years and older. Older age (odds ratio, 1.04; P <.001) was independently associated with the incidental finding of ECRB enthesopathy on elbow MRI scans. Conclusions: Increased MRI signal in the ECRB origin is common in symptomatic and in asymptomatic elbows. Our findings support the concept that ECRB enthesopathy is a highly prevalent, self-limited process that seems to affect a minimum of 1 in approximately every 7 people. (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [van Leeuwen, Wouter F.; Janssen, Stein J.; Chen, Neal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand & Upper Extrem Serv,Dept Orthopaed Surg, Boston, MA USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Ste 1-114AC MC R1800, Austin, TX 78712 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Ste 1-114AC MC R1800, Austin, TX 78712 USA. EM david.ring@austin.utexas.edu OI Ring, David/0000-0002-6506-4879 NR 23 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD JUL PY 2016 VL 25 IS 7 BP 1175 EP 1181 DI 10.1016/j.jse.2016.01.033 PG 7 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DO1DV UT WOS:000377519600024 PM 27068386 ER PT J AU Fotiadis, P van Rooden, S van der Grond, J Schultz, A Martinez-Ramirez, S Auriel, E Reijmer, Y van Opstal, AM Ayres, A Schwab, KM Hedden, T Rosand, J Viswanathan, A Wermer, M Terwindt, GM Sperling, RA Polimeni, JR Johnson, KA van Buchem, MA Greenberg, SM Gurol, ME AF Fotiadis, Panagiotis van Rooden, Sanneke van der Grond, Jeroen Schultz, Aaron Martinez-Ramirez, Sergi Auriel, Eitan Reijmer, Yael van Opstal, Anna M. Ayres, Alison Schwab, Kristin M. Hedden, Trey Rosand, Jonathan Viswanathan, Anand Wermer, Marieke Terwindt, Gisela M. Sperling, Reisa A. Polimeni, Jonathan R. Johnson, Keith A. van Buchem, Mark A. Greenberg, Steven M. Gurol, M. Edip CA Alzheimer's Dis Neuroimaging Initi TI Cortical atrophy in patients with cerebral amyloid angiopathy: a case-control study SO LANCET NEUROLOGY LA English DT Article ID SURFACE-BASED ANALYSIS; SMALL VESSEL DISEASE; ALZHEIMERS-DISEASE; CLINICAL-DIAGNOSIS; BOSTON CRITERIA; DUTCH-TYPE; MICROBLEEDS; HEREDITARY; BRAIN; SEGMENTATION AB Background Loss of cortical grey matter is a diagnostic marker of many neurodegenerative diseases, and is a key mediator of cognitive impairment. We postulated that cerebral amyloid angiopathy (CAA), characterised by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer's disease pathology. We tested this hypothesis in patients with hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease with minimal or no concomitant Alzheimer's disease pathology, as well as in patients with sporadic CAA and healthy and Alzheimer's disease controls. Methods In this observational case-control study, we included six groups of participants: patients diagnosed with HCHWA-D using genetic testing; healthy controls age-matched to the HCHWA-D group; patients with probable sporadic CAA without dementia; two independent cohorts of healthy controls age-matched to the CAA group; and patients with Alzheimer's disease age-matched to the CAA group. De-identified (but unmasked) demographic, clinical, radiological, and genetic data were collected at Massachusetts General Hospital (Boston, MA, USA), at Leiden University (Leiden, Netherlands), and at sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The primary outcome measure was cortical thickness. The correlations between cortical thickness and structural lesions, and blood-oxygen-level-dependent time-to-peak (BOLD-TTP; a physiological measure of vascular dysfunction) were analysed to understand the potential mechanistic link between vascular amyloid and cortical thickness. The radiological variables of interest were quantified using previously validated computer-assisted tools, and all results were visually reviewed to ensure their accuracy. Results Between March 15, 2006, and Dec 1, 2014, we recruited 369 individuals (26 patients with HCHWA-D and 28 age-matched, healthy controls; 63 patients with sporadic CAA without dementia; two healthy control cohorts with 63 and 126 individuals; and 63 patients with Alzheimer's disease). The 26 patients with HCHWA-D had thinner cortices (2.31 mm [SD 0.18]) than the 28 healthy controls (mean difference -0.112 mm, 95% CI -0.190 to -0.034, p=0.006). The 63 patients with sporadic CAA without dementia had thinner cortices (2.17 mm [SD 0.11]) than the two healthy control cohorts (n=63, mean diff erence -0.14 mm, 95% CI -0.17 to -0.10, p<0.0001; and n=126, -0.10, -0.13 to -0.06, p<0.0001). All differences remained independent in multivariable analyses. The 63 patients with Alzheimer's disease displayed more severe atrophy than the patients with sporadic CAA (2.1 mm [SD 0.14], diff erence 0.07 mm, 95% CI 0.11 to 0.02, p=0.005). We found strong associations between cortical thickness and vascular dysfunction in the patients with HCHWA-D (rho=-0.58, p=0.003) or sporadic CAA (r=-0.4, p=0.015), but not in controls. Vascular dysfunction was identified as a mediator of the effect of hereditary CAA on cortical atrophy, accounting for 63% of the total effect. Interpretation The appearance of cortical thinning in patients with HCHWA-D indicates that vascular amyloid is an independent contributor to cortical atrophy. These results were reproduced in patients with the more common sporadic CAA. Our findings also suggest that CAA-related cortical atrophy is at least partly mediated by vascular dysfunction. Our results also support the view that small vessel diseases such as CAA can cause cortical atrophy even in the absence of Alzheimer's disease, a conclusion that can help radiologists, neurologists, and other clinicians who diagnose these common geriatric conditions. Funding National Institutes of Health. C1 [Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Auriel, Eitan; Reijmer, Yael; Ayres, Alison; Schwab, Kristin M.; Rosand, Jonathan; Viswanathan, Anand; Greenberg, Steven M.; Gurol, M. Edip] Harvard Univ, Sch Med, Hemorrhag Stroke Res Grp, Boston, MA USA. [Sperling, Reisa A.; Polimeni, Jonathan R.; Johnson, Keith A.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Schultz, Aaron; Hedden, Trey; Rosand, Jonathan; Viswanathan, Anand; Sperling, Reisa A.; Polimeni, Jonathan R.; Johnson, Keith A.; Greenberg, Steven M.; Gurol, M. Edip] Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA USA. [van Rooden, Sanneke; van der Grond, Jeroen; van Opstal, Anna M.; van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Wermer, Marieke; Terwindt, Gisela M.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. Alzheimers Dis Neuroimaging Initiat, San Francisco, CA USA. RP Gurol, ME (reprint author), Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. EM edip@mail.harvard.edu FU National Institutes of Health FX National Institutes of Health. NR 39 TC 3 Z9 3 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD JUL PY 2016 VL 15 IS 8 BP 811 EP 819 DI 10.1016/S1474-4422(16)30030-8 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DO1NR UT WOS:000377545800018 PM 27180034 ER PT J AU Moulin, S Labreuche, J Bombois, S Rossi, C Boulouis, G Henon, H Duhamel, A Leys, D Cordonnier, C AF Moulin, Solene Labreuche, Julien Bombois, Stephanie Rossi, Costanza Boulouis, Gregoire Henon, Hilde Duhamel, Alain Leys, Didier Cordonnier, Charlotte TI Dementia risk after spontaneous intracerebral haemorrhage: a prospective cohort study SO LANCET NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; CORTICAL SUPERFICIAL SIDEROSIS; COGNITIVE IMPAIRMENT; POSTSTROKE DEMENTIA; NATIONAL INSTITUTE; ALZHEIMERS-DISEASE; STROKE; MICROBLEEDS; VALIDATION; DISORDERS AB Background Dementia occurs in at least 10% of patients within 1 year after stroke. However, the risk of dementia after spontaneous intracerebral haemorrhage that accounts for about 15% of all strokes has not been investigated in prospective studies. We aimed to determine the incidence of dementia and risk factors after an intracerebral haemorrhage. Methods We did a prospective observational cohort study in patients with spontaneous intracerebral haemorrhage from the Prognosis of Intracerebral Haemorrhage (PITCH) cohort who were admitted to Lille University Hospital, Lille, France. We included patients aged 18 years and older with parenchymal haemorrhage on the first CT scan. Exclusion criteria were pure intraventricular haemorrhage; intracerebral haemorrhage resulting from intracranial vascular malformation, intracranial venous thrombosis, head trauma, or tumour; haemorrhagic transformation within an infarct; and referral from other hospitals. Median follow-up was 6 years. We studied risk factors (clinical and neuroradiological [MRI] biomarkers) of new-onset dementia as per a prespecified subgroup analysis, according to intracerebral haemorrhage location. Dementia diagnosis was based on the National Institute on Aging-Alzheimer's Association criteria for all-cause dementia. We did multivariable analyses using competing risk analyses, with death during follow-up as a competing event. Findings From the 560 patients with spontaneous intracerebral haemorrhage enrolled in the PITCH cohort between Nov 3, 2004 and March 29, 2009, we included 218 patients (median age 67.5 years) without pre-existing dementia who were alive at 6 months follow-up. 63 patients developed new-onset dementia leading to an incidence rate of 14.2% (95% CI 10.0-19.3) at 1 year after intracerebral haemorrhage, and incidence reached 28.3% (22.4-34.5) at 4 years. The incidence of new-onset dementia was more than two times higher in patients with lobar intracerebral haemorrhage (incidence at 1 year 23.4%, 14.6-33.3) than for patients with non-lobar intracerebral haemorrhage (incidence at 1 year 9.2%, 5.1-14.7). Disseminated superficial siderosis (subhazard ratio [SHR] 7.45, 95% CI 4.27-12.99), cortical atrophy score (SHR per 1-point increase 2.61, 1.70-4.01), a higher number of cerebral microbleeds (SHR for >5 cerebral microbleeds 2.33, 1.38-3.94), and older age (SHR per 10-year increase 1.34, 1.00-1.79) were risk factors of new-onset dementia. Interpretation There is a substantial risk of incident dementia in dementia-free survivors of spontaneous intracerebral haemorrhage; our results suggest that underlying cerebral amyloid angiopathy is a contributing factor to the occurrence of new-onset dementia. Future clinical trials including patients with intracerebral haemorrhage should assess cognitive endpoints. Funding French Ministry of Education, Research, and Technology, Adrinord, Inserm U1171. C1 [Moulin, Solene; Bombois, Stephanie; Rossi, Costanza; Henon, Hilde; Leys, Didier; Cordonnier, Charlotte] Univ Lille, CHU Lille, Inserm Degenerat & Vasc Cognit Disorders U1171, Dept Neurol, Lille, France. [Labreuche, Julien; Duhamel, Alain] Univ Lille, CHU Lille, EA 2694, Dept Biostat & Publ Hlth, Lille, France. [Boulouis, Gregoire] Massachusetts Gen Hosp, Ctr Stroke Res, Boston, MA 02114 USA. RP Cordonnier, C (reprint author), Univ Lille, CHU Lille, Inserm Degenerat & Vasc Cognit Disorders U1171, F-59000 Lille, France. EM charlotte.cordonnier@univ-lille2.fr RI LEYS, Didier/G-2955-2016; OI LEYS, Didier/0000-0003-4408-4392; Boulouis, Gregoire/0000-0001-8422-9205 FU French Ministry of Education, Research, and Technology; Adrinord; Inserm [U1171] FX French Ministry of Education, Research, and Technology, Adrinord, Inserm U1171. NR 37 TC 9 Z9 9 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD JUL PY 2016 VL 15 IS 8 BP 820 EP 829 DI 10.1016/S1474-4422(16)00130-7 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DO1NR UT WOS:000377545800019 PM 27133238 ER PT J AU Fernandez-Godino, R Garland, DL Pierce, EA AF Fernandez-Godino, Rosario Garland, Donita L. Pierce, Eric A. TI Isolation, culture and characterization of primary mouse RPE cells SO NATURE PROTOCOLS LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; TIGHT JUNCTION; EXTRACELLULAR-MATRIX; COMPLEMENT; SECRETION; BARRIER; PROTEIN; MICE; DIFFERENTIATION AB Mouse models are powerful tools for the study of ocular diseases. Alterations in the morphology and function of the retinal pigment epithelium (RPE) are common features shared by many ocular disorders. We report a detailed protocol to collect, seed, culture and characterize RPE cells from mice. We describe a reproducible method that we previously developed to collect and culture murine RPE cells on Transwells as functional polarized monolayers. The collection of RPE cells takes similar to 3 h, and the cultures mimic in vivo RPE cell features within 1 week. This protocol also describes methods to characterize the cells on Transwells within 1-2 weeks by transmission and scanning electron microscopy (TEM and SEM, respectively), immunostaining of vibratome sections and flat mounts, and measurement of transepithelial electrical resistance. The RPE cell cultures are suitable to study the biology of the RPE from wild-type and genetically modified strains of mice between the ages of 10 d and 12 months. The RPE cells can also be manipulated to investigate molecular mechanisms underlying the RPE pathology in the numerous mouse models of ocular disorders. Furthermore, modeling the RPE pathology in vitro represents a new approach to testing drugs that will help accelerate the development of therapies for vision-threatening disorders such as macular degeneration (MD). C1 [Fernandez-Godino, Rosario; Garland, Donita L.; Pierce, Eric A.] Massachusetts Eye & Ear Infirm, Ocular Genom Inst, Boston, MA 02114 USA. RP Fernandez-Godino, R (reprint author), Massachusetts Eye & Ear Infirm, Ocular Genom Inst, Boston, MA 02114 USA. EM rosario_godino@meei.harvard.edu OI Pierce, Eric/0000-0002-2354-4102 FU Ocular Genomics Institute; National Eye Institute Core [P30EY003790] FX This work was supported by the Ocular Genomics Institute. The TEM work was supported in part by the National Eye Institute Core (grant P30EY003790). We would like to thank Schepens Eye Research Institute Morphology Core Facility for performing the TEM, A. Tisdale for helpful technical assistance with SEM and A. Langsdorf for helpful comments that improved the manuscript. NR 51 TC 1 Z9 1 U1 5 U2 7 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 2016 VL 11 IS 7 BP 1206 EP 1218 DI 10.1038/nprot.2016.065 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DO0SS UT WOS:000377489200005 PM 27281648 ER PT J AU Zhao, F Ohgaki, H Xu, L Giangaspero, F Li, CD Li, P Yang, ZJ Wang, B Wang, XC Wang, ZM Ai, L Zhang, J Luo, L Liu, PA AF Zhao, Fu Ohgaki, Hiroko Xu, Lei Giangaspero, Felice Li, Chunde Li, Peng Yang, Zhijun Wang, Bo Wang, Xingchao Wang, Zhenmin Ai, Lin Zhang, Jing Luo, Lin Liu, Pinan TI Molecular subgroups of adult medulloblastoma: a long-term single-institution study SO NEURO-ONCOLOGY LA English DT Article DE adult medulloblastoma; histology; molecular subgroup; prognosis; survival ID PEDIATRIC-ONCOLOGY-GROUP; STEM-CELL RESCUE; RISK STRATIFICATION; CHEMOTHERAPY; DISTINCT; RADIOTHERAPY; SURVIVAL AB Background. Recent transcriptomic approaches have demonstrated that there are at least 4 distinct subgroups in medulloblastoma (MB); however, survival studies of molecular subgroups in adult MB have been inconclusive because of small sample sizes. The aim of this study is to investigate the molecular subgroups in adult MB and identify their clinical and prognostic implications in a large, single-institution cohort. Methods. We determined gene expression profiles for 13 primary adult MBs. Bioinformatics tools were used to establish distinct molecular subgroups based on the most informative genes in the dataset. Immunohistochemistry with subgroup-specific antibodies was then used for validation within an independent cohort of 201 formalin-fixed MB tumors, in conjunction with a systematic analysis of clinical and histological characteristics. Results. Three distinct molecular variants of adult MB were identified: the SHH, WNT, and group 4 subgroups. Validation of these subgroups in the 201-tumor cohort by immunohistochemistry identified significant differences in subgroup-specific demographics, histology, and metastatic status. The SHH subgroup accounted for the majority of the tumors (62%), followed by the group 4 subgroup (28%) and the WNT subgroup (10%). Group 4 tumors had significantly worse progression-free and overall survival compared with tumors of the other molecular subtypes. Conclusions. We have identified 3 subgroups of adult MB, characterized by distinct expression profiles, clinical features, pathological features, and prognosis. Clinical variables incorporated with molecular subgroup are more significantly informative for predicting adult patient outcome. C1 [Zhao, Fu; Zhang, Jing; Liu, Pinan] Capital Med Univ, Beijing Neurosurg Inst, Neural Reconstruct Dept, 6 Tiantan Xili, Beijing, Peoples R China. [Luo, Lin] Capital Med Univ, Beijing Neurosurg Inst, Dept Pathol, 6 Tiantan Xili, Beijing, Peoples R China. [Zhao, Fu; Li, Chunde; Li, Peng; Yang, Zhijun; Wang, Bo; Wang, Xingchao; Wang, Zhenmin; Liu, Pinan] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg, 6 Tiantan Xili, Beijing, Peoples R China. [Ai, Lin] Capital Med Univ, Beijing Tiantan Hosp, Dept Imaging & Nucl Med, 6 Tiantan Xili, Beijing, Peoples R China. [Ohgaki, Hiroko] WHO, Int Agcy Res Canc, Sect Mol Pathol, Lyon, France. [Xu, Lei] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Boston, MA 02114 USA. [Xu, Lei] Harvard Univ, Sch Med, Boston, MA USA. [Giangaspero, Felice] Univ Roma La Sapienza, Dept Radiol Sci Oncol & Anat Pathol, Piazzale Aldo Moro 5, I-00185 Rome, Italy. RP Liu, PA (reprint author), Capital Med Univ, Beijing Tiantan Hosp, Beijing Neurosurg Inst, Dept Neurosurg,Neural Reconstruct Dept, 6 Tiantan Xili, Beijing, Peoples R China. EM liupinan@bjctf.org FU National Science and Technology [2012BAI12B03]; National Science Foundation of China [7112049]; Capital Health Development and Research Special Projects of Beijing [2011-1015-01]; American Cancer Society; NIH/National Cancer Institute [R35CA197743]; Department of Defense; Children's Tumor Foundation; Drug Discovery Initiative FX This work was supported by the National Science and Technology Support Program of the 12th Five-Year Plan of China (grant number: 2012BAI12B03), the National Science Foundation of China (grant number: 7112049), and the Capital Health Development and Research Special Projects of Beijing (grant number: 2011-1015-01). Additional support came from an American Cancer Society Research Scholar award, an NIH/National Cancer Institute Outstanding Investigator grant (R35CA197743), a Department of Defense New Investigator award, a Children's Tumor Foundation Clinical Research award, and the Drug Discovery Initiative (L.X.). NR 29 TC 2 Z9 3 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2016 VL 18 IS 7 BP 982 EP 990 DI 10.1093/neuonc/now050 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DN7QZ UT WOS:000377273700011 PM 27106407 ER PT J AU Merluzzi, AP Dean, DC Adluru, N Suryawanshi, GS Okonkwo, OC Oh, JM Hermann, BP Sager, MA Asthana, S Zhang, H Johnson, SC Alexander, AL Bendlin, BB AF Merluzzi, Andrew P. Dean, Douglas C., III Adluru, Nagesh Suryawanshi, Gaurav S. Okonkwo, Ozioma C. Oh, Jennifer M. Hermann, Bruce P. Sager, Mark A. Asthana, Sanjay Zhang, Hui Johnson, Sterling C. Alexander, Andrew L. Bendlin, Barbara B. TI Age-dependent differences in brain tissue microstructure assessed with neurite orientation dispersion and density imaging SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; Diffusion-weighted imaging; MRI; Neurites; Cognition; Microstructure ID WHITE-MATTER MICROSTRUCTURE; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; DIFFUSION MRI; IN-VIVO; EXECUTIVE FUNCTIONS; CEREBRAL-CORTEX; OLDER-ADULTS; NERVE-FIBERS; DEMENTIA AB Human aging is accompanied by progressive changes in executive function and memory, but the biological mechanisms underlying these phenomena are not fully understood. Using neurite orientation dispersion and density imaging, we sought to examine the relationship between age, cellular microstructure, and neuropsychological scores in 116 late middle-aged, cognitively asymptomatic participants. Results revealed widespread increases in the volume fraction of isotropic diffusion and localized decreases in neurite density in frontal white matter regions with increasing age. In addition, several of these microstructural alterations were associated with poorer performance on tests of memory and executive function. These results suggest that neurite orientation dispersion and density imaging is capable of measuring age-related brain changes and the neural correlates of poorer performance on tests of cognitive functioning, largely in accordance with published histological findings and brain-imaging studies of people of this age range. Ultimately, this study sheds light on the processes underlying normal brain development in adulthood, knowledge that is critical for differentiating healthy aging from changes associated with dementia. (C) 2016 Elsevier Inc. All rights reserved. C1 [Merluzzi, Andrew P.; Okonkwo, Ozioma C.; Oh, Jennifer M.; Asthana, Sanjay; Johnson, Sterling C.; Bendlin, Barbara B.] Univ Wisconsin, Dept Med, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53705 USA. [Merluzzi, Andrew P.] Univ Wisconsin, Neurosci & Publ Policy Program, Madison, WI USA. [Dean, Douglas C., III; Adluru, Nagesh; Suryawanshi, Gaurav S.; Alexander, Andrew L.] Waisman Lab Brain Imaging & Behav, Madison, WI USA. [Okonkwo, Ozioma C.; Hermann, Bruce P.; Sager, Mark A.; Johnson, Sterling C.; Bendlin, Barbara B.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI USA. [Asthana, Sanjay; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Zhang, Hui] UCL, Dept Comp Sci, London WC1E 6BT, England. [Zhang, Hui] UCL, Ctr Med Image Comp, London, England. [Alexander, Andrew L.] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, 1530 Med Sci Ctr, Madison, WI 53706 USA. [Alexander, Andrew L.] Univ Wisconsin, Dept Psychiat, Sch Med & Publ Hlth, Madison, WI 53706 USA. RP Bendlin, BB (reprint author), Univ Wisconsin, Dept Med, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53705 USA. EM bbb@medicine.wisc.edu FU NIH [R01AG037639, AG027161, P50 AG033514]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32 HD007489]; UW Institute for Clinical and Translation Research grant [1UL1RR025011]; Waisman Core Grant [P30 HD003352-45]; National Science Foundation Graduate Research Fellowship [DGE-1256259] FX This project was supported by NIH grants R01AG037639 (BBB), AG027161 (SCJ), P50 AG033514 (SA), the Eunice Kennedy Shriver National Institute of Child Health and Human Development T32 HD007489 (DCD), the UW Institute for Clinical and Translation Research grant 1UL1RR025011, the Waisman Core Grant P30 HD003352-45, resources from the Geriatric Research, Education, and Clinical Center (GRECC) of the William S. Middleton Memorial Veterans Hospital, and the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1256259 (APM). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation. The authors acknowledge the support of researchers and staff at the Waisman Center and the Wisconsin Institute for Medical Research at the University of Wisconsin-Madison, where imaging data were collected. Finally, the authors thank their dedicated participants for their valuable time. NR 77 TC 3 Z9 3 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2016 VL 43 BP 79 EP 88 DI 10.1016/j.neurobiolaging.2016.03.026 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DN7XI UT WOS:000377293100008 PM 27255817 ER PT J AU Zoccali, C Torino, C Curatola, G Panuccio, V Tripepi, R Pizzini, P Versace, M Bolignano, D Cutrupi, S Ghiadoni, L Thadhani, R Tripepi, G Mallamaci, F AF Zoccali, C. Torino, C. Curatola, G. Panuccio, V. Tripepi, R. Pizzini, P. Versace, M. Bolignano, D. Cutrupi, S. Ghiadoni, L. Thadhani, R. Tripepi, G. Mallamaci, F. TI Serum phosphate modifies the vascular response to vitamin D receptor activation in chronic kidney disease (CKD) patients SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE CKD; Effect modification; Flow mediated vasodilation; Paricalcitol; Phosphate ID SMOOTH-MUSCLE-CELLS; FIBROBLAST GROWTH FACTOR-23; GLOMERULAR-FILTRATION-RATE; GENE-EXPRESSION; ENDOTHELIAL FUNCTION; CONTROLLED-TRIAL; D ANALOGS; PARICALCITOL; DYSFUNCTION; REDUCTION AB Background and aims: Vitamin D receptor activation (VDRA) ameliorates endothelial dysfunction in CKD patients but also increases phosphate and FGF-23, which may attenuate the beneficial effect of VDRA on endothelial function. Methods and Results: This is a pre-specified secondary analysis of the PENNY trial (NCT01680198) testing the effect of phosphate and FGF-23 on the flow mediated vasodilatory (FMD) response to paricalcitol (PCT, 2 mu g/day) and placebo over a 12-weeks treatment period. Eighty-eight stage G3-4 CKD patients were randomized to PCT (n = 44) and Placebo (n = 44). Endothelial function was assessed by measuring endothelium dependent forearm blood flow (FBF) response to ischemia. The FMD response was by the 61% higher in PCT treated patients than in those on placebo (P = 0.01). Phosphate (+11%, P = 0.039), calcium (+3%, P = 0.01) and, particularly so, FGF23 (+164%, P < 0.001) increased in PCT treated patients. Changes in FMD by PCT associated inversely with phosphate (r = -0.37, P = 0.01) but were independent of FGF-23, calcium and PTH changes. The response to PCT was maximal in patients with no changes in phosphate (1st tertile), attenuated in those with mild-to-moderate rise in phosphate (2nd tertile) and abolished in those with the most pronounced phosphate increase (3rd tertile) (effect modification P = 0.009). No effect modification by FGF-23 and other variables was observed. Conclusions: The beneficial effect of PCT on endothelial function in CKD is maximal in patients with no or minimal changes in phosphate and it is abolished in patients with a pronounced phosphate rise. These findings generate the hypothesis that the endothelium protective effect by VDRA may be potentiated by phosphate lowering interventions. (C) 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. C1 [Zoccali, C.; Torino, C.; Curatola, G.; Tripepi, R.; Pizzini, P.; Versace, M.; Bolignano, D.; Cutrupi, S.; Tripepi, G.; Mallamaci, F.] Osped Riuniti Reggio Calabria, CNR IBIM IFC Clin Epidemiol & Pathophysiol Renal, I-89124 Reggio Di Calabria, Italy. [Panuccio, V.; Mallamaci, F.] Osped Riuniti Reggio Calabria, Nephrol Hypertens & Renal Transplantat Unit, I-89124 Reggio Di Calabria, Italy. [Ghiadoni, L.] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy. [Thadhani, R.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Zoccali, C (reprint author), Osped Riuniti Reggio Calabria, CNR IFC, I-89124 Reggio Di Calabria, Italy. EM carmine.zoccali@tin.it OI Ghiadoni, Lorenzo/0000-0002-7399-2720 FU Abbott SRL FX This study was supported by a grant of Abbott SRL. The study was designed by the first author (C. Zoccali) and approved by the funding company (Abbott). The Company did not participate in data collection and in the statistical analysis and writing of the article. The first two authors made the final decision to submit for publication. The Company had an opportunity to review the article, but all decisions about the final manuscript were made by the study investigators. All authors vouch for the integrity of the data. NR 32 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 EI 1590-3729 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD JUL PY 2016 VL 26 IS 7 BP 581 EP 589 DI 10.1016/j.numecd.2016.03.008 PG 9 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA DN8XG UT WOS:000377362600004 PM 27113290 ER PT J AU Nikrahan, GR Suarez, L Asgari, K Beach, SR Celano, CM Kalantari, M Abedi, MR Etesampour, A Abbas, R Huffman, JC AF Nikrahan, Gholam Reza Suarez, Laura Asgari, Karim Beach, Scott R. Celano, Christopher M. Kalantari, Mehrdad Abedi, Mohammad Reza Etesampour, Ali Abbas, Rezaei Huffman, Jeff C. TI Positive Psychology Interventions for Patients With Heart Disease: A Preliminary Randomized Trial SO PSYCHOSOMATICS LA English DT Article DE positive psychology; optimism; depression; heart disease; coronary artery disease; coronary artery bypass graft ID QUALITY-OF-LIFE; MORTALITY; OPTIMISM; HEALTH; ASSOCIATIONS; METAANALYSIS; VALIDATION; HAPPINESS; FAILURE; DESIGN AB Background: Positive psychologic characteristics have been linked to superior cardiac outcomes. Objective: Accordingly, in this exploratory study, we assessed positive psychology interventions in patients who had recently undergone a procedure to treat cardiovascular disease. Method: Participants were randomly assigned to receive 1 of 3 different 6-week face-to-face interventions or a wait-list control condition. We assessed intervention feasibility and compared changes in psychologic outcome measures postintervention (7 wk) and at follow-up (15 wk) between intervention and control participants. Across the interventions, 74% of assigned sessions were completed. Results: When comparing outcomes between interventions and control participants (N = 55 total), there were no between-group differences post-intervention, but at follow-up intervention participants had greater improvements in happiness (beta = 14.43, 95% CI: 8.66-20.2, p < 0.001), depression (beta = 3.87, 95% CI: 7.72 to 0.02, p = 0.049), and hope (beta = 7.12, 95% CI: 1.25-13.00, p =0.017), with moderate-large effect sizes. Efficacy of the 3 interventions was similar. Conclusions: Future studies are needed to identify an optimal positive psychology intervention for cardiac patients. C1 [Nikrahan, Gholam Reza; Asgari, Karim; Kalantari, Mehrdad] Univ Isfahan, Dept Psychol, Esfahan, Iran. [Abedi, Mohammad Reza] Univ Isfahan, Dept Consulting, Esfahan, Iran. [Nikrahan, Gholam Reza] Islamic Azad Univ Borujen, Dept Psychol, Borujen, Iran. [Suarez, Laura; Beach, Scott R.; Celano, Christopher M.; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Beach, Scott R.; Celano, Christopher M.; Huffman, Jeff C.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Etesampour, Ali] Najafabad Islamic Azad Univ, Dept Internal Med, Najafabad, Iran. [Abbas, Rezaei] Isfahan Univ Med Sci, Dept Immunol, Esfahan, Iran. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,Blake 11, Boston, MA 02114 USA. EM jhuffman@mgh.harvard.edu FU Center of Excellence for Psychology of Spirituality and Happiness, The University of Isfahan, Isfahan, Iran; National Institutes of Health National Heart, Lung, and Blood Institute, United States [R01HL113272] FX This study was supported by Center of Excellence for Psychology of Spirituality and Happiness, The University of Isfahan, Isfahan, Iran. Investigator time for data analysis and article preparation for C. C., S. B., and J. H. was supported by the National Institutes of Health National Heart, Lung, and Blood Institute, United States, Grant no. R01HL113272. NR 45 TC 0 Z9 0 U1 5 U2 10 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 2016 VL 57 IS 4 BP 348 EP 358 PG 11 WC Psychiatry; Psychology SC Psychiatry; Psychology GA DN7XX UT WOS:000377294600002 PM 27137709 ER PT J AU Nikrahan, GR Laferton, JAC Asgari, K Kalantari, M Abedi, MR Etesampour, A Rezaei, A Suarez, L Huffman, JC AF Nikrahan, Gholam Reza Laferton, Johannes A. C. Asgari, Karim Kalantari, Mehrdad Abedi, Mohammad Reza Etesampour, Ali Rezaei, Abbas Suarez, Laura Huffman, Jeff C. TI Effects of Positive Psychology Interventions on Risk Biomarkers in Coronary Patients: A Randomized, Wait-List Controlled Pilot Trial SO PSYCHOSOMATICS LA English DT Article DE positive psychology; intervention; coronary artery disease; inflammation; HPA-axis functioning; randomized controlled trial ID HEART-DISEASE; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; DEPRESSIVE SYMPTOMS; MORTALITY; HEALTH; METAANALYSIS; ASSOCIATIONS; MECHANISMS; OPTIMISM AB Background: Among cardiac patients, positive psycho logic factors are consistently linked with superior clinical outcomes and improvement in key markers of inflammation and hypothalamic-pituitary-adrenal axis functioning. Further, positive psychology interventions (PPI) have effectively increased psychologic well-being in a wide variety of populations. However, there has been minimal study of PPIs in cardiac patients, and no prior study has evaluated their effect on key prognostic biomarkers of cardiac outcome. Accordingly, we investigated the effect of 3 distinct PPIs on risk biomarkers in cardiac patients. Methods: In an exploratory trial, 69 patients with recent coronary artery bypass graft surgery or percutaneous intervention were randomized to (1) one of three 6-week in person PPIs (based on the work of Seligman, Lyubomirsky, or Fordyce) or (2) a wait-list control group. Risk biomarkers were assessed at baseline, postintervention (7 weeks), and at 15-week follow-up. Between-group differences in change from baseline biomarker levels were examined via random effects models. Results: Compared with the control group, participants randomized to the Seligman (B = 2.06; p = 0.02) and Fordyce PPI (B = 1.54; p = 0.04) had signcantly lower high-sensitivity C-reactive protein levels at 7 weeks. Further, the Lyubomirsky PPI (B = 245.86; p = 0.04) was associated with a signcantly lower cortisol awakening response at 7 weeks when compared with control participants. There were no other signcant between-group differences. Conclusion: Despite being an exploratory pilot study with multiple between-group comparisons, this initial trial offers the first suggestion that PPIs might be effective in reducing risk biomarkers in high-risk cardiac patients. C1 [Nikrahan, Gholam Reza; Asgari, Karim; Kalantari, Mehrdad] Univ Isfahan, Dept Psychol, Hezarjarib St, Esfahan, Iran. [Nikrahan, Gholam Reza] Islamic Azad Univ Borujen, Dept Psychol, Borujen, Iran. [Laferton, Johannes A. C.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Laferton, Johannes A. C.; Suarez, Laura; Huffman, Jeff C.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Abedi, Mohammad Reza] Univ Isfahan, Dept Consulting, Esfahan, Iran. [Etesampour, Ali] Najafabad Islamic Azad Univ, Dept Internal Med, Najafabad, Iran. [Rezaei, Abbas] Isfahan Univ Med Sci, Dept Immunol, Esfahan, Iran. [Suarez, Laura; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Nikrahan, GR (reprint author), Univ Isfahan, Dept Psychol, Hezarjarib St, Esfahan, Iran. EM rezanikrahan@yahoo.com FU Center of Excellence for Psychology of Spirituality and Happiness, The University of Isfahan, Isfahan, Iran; NIH, USA [R01HL113272]; German Academic Exchange Service (DAAD) FX This study was supported by Center of Excellence for Psychology of Spirituality and Happiness, The University of Isfahan, Isfahan, Iran. Editing/analysis time for Jeff Huffman was supported by NIH, USA Grant R01HL113272. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Johannes A.C. Laferton was supported by a fellowship within the Postdoc Program of the German Academic Exchange Service (DAAD). NR 47 TC 2 Z9 2 U1 5 U2 6 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 2016 VL 57 IS 4 BP 359 EP 368 PG 10 WC Psychiatry; Psychology SC Psychiatry; Psychology GA DN7XX UT WOS:000377294600003 PM 27129358 ER PT J AU Briet, JP Hageman, MGJS Overbeek, CL Mudgal, C Ring, DC Vranceanu, AM AF Briet, Jan Paul Hageman, Michiel G. J. S. Overbeek, Celeste L. Mudgal, Chaitanya Ring, David C. Vranceanu, Ana-Maria TI Factors Associated With Met Expectations in Patients With Hand and Upper Extremity Disorders: A Pilot Study SO PSYCHOSOMATICS LA English DT Article DE satisfaction; disability; pain; expectations ID TOTAL HIP-ARTHROPLASTY; VISUAL ANALOG SCALES; PRIMARY-CARE; PSYCHOLOGICAL DISTRESS; SELF-EFFICACY; HEALTH-CARE; SATISFACTION; DEPRESSION; PAIN; QUESTIONNAIRE AB Purpose: The degree to which patients' expectations are met during an office visit consistently correlates with patients' satisfaction, whereas the relationship between previsit expectations and satisfaction varies. Objective: The aim of this pilot study was to preliminarily assess the relationship of psychosocial factors, pain intensity, and magnitude of disability to previsit expectations, met expectations, and satisfaction with medical care in patients with hand and upper extremity conditions in a surgical outpatient clinic. Methods: A cohort of 85 outpatients with upper extremity illnesses indicated their previsit expectations (Patients Intention Questionnaire), degree to which these expectations were met (Expectations Met Questionnaire), level of depressive symptoms (Patient Health Questionnaire-2), confidence about the ability to achieve one's goals in spite of pain (Pain Self-Efficacy Questionnaire), pain intensity (Numerical Rating Scale for pain), disability (Disabilities of the Arm Shoulder and Hand, short version; QuickDASH), and satisfaction with the medical visit (Medical Interview Satisfaction Scale). Results: Higher previsit expectations were associated with more depressive symptoms, lower pain self-efficacy, higher pain intensity, and fewer years of education. Patients in the low and moderate met expectations categories had signcantly more symptoms of depression, fewer years of education, and more pain compared to those in the high-met expectations category. Fewer years of education and higher pain intensity predicted higher previsit expectations and explained 19% of variance. Conclusion: Psychosocial factors affect both previsit expectations and met expectations during an outpatient visit to a hand surgeon. Met expectations, but not previsit expectations, affect satisfaction. C1 [Briet, Jan Paul; Hageman, Michiel G. J. S.; Overbeek, Celeste L.; Mudgal, Chaitanya; Ring, David C.; Vranceanu, Ana-Maria] Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM AVRANCEANU@PARTNERS.ORG FU Anna Foundation\NOREF; Marti-Keunig Eckhart Stichting; Anna Foundation FX Anna Foundation vertical bar NOREF provided C.L. Overbeek financial support for this research project. M.G. Hageman is supported by Dutch research grants from Marti-Keunig Eckhart Stichting and Anna Foundation. No benefits in any form have been received or would be received related directly or indirectly to the subject of this article. NR 34 TC 0 Z9 0 U1 4 U2 5 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 2016 VL 57 IS 4 BP 401 EP 408 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA DN7XX UT WOS:000377294600007 PM 27080458 ER PT J AU Jimenez, X Shukla, SK Ortega, I Illana, FJ Castro-Gonzalez, C Marti-Fuster, B Butterworth, I Arroyo, M Anthony, B Elvira, L AF Jimenez, Xavier Shukla, Shiva K. Ortega, Isabel Illana, Francisco J. Castro-Gonzalez, Carlos Marti-Fuster, Berta Butterworth, Ian Arroyo, Manuel Anthony, Brian Elvira, Luis TI QUANTIFICATION OF VERY LOW CONCENTRATIONS OF LEUKOCYTE SUSPENSIONS IN VITRO BY HIGH-FREQUENCY ULTRASOUND SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE Cerebrospinal fluid; White blood cell; Cell count; High frequency ultrasound; Meningitis; Cytometry ID QUANTITATIVE ULTRASOUND; BACKSCATTER; AGREEMENT; TISSUES; CELLS AB Accurate measurement of very low cerebrospinal fluid (CSF) white blood cell (WBC) concentration is key to the diagnosis of bacterial meningitis, lethal if not promptly treated. Here we show that high frequency ultrasound (HFUS) can detect CSF WBC in vitro in concentrations relevant to meningitis diagnosis with a much finer precision than gold standard manual counting in a Fuchs-Rosenthal chamber. WBC concentrations in a mock CSF model, in the range 0-50 WBC/mu L, have been tested and compared to gold standard ground truth. In this range, excellent agreement (Cohen's kappa [kappa] 5 0.78-90) (Cohen 1960) was observed between HFUS and the gold standard method. The presented experimental set-up allowed us to detect WBC concentrations as low as 2 cells/mu L. HFUS shows promise as a low-cost, reliable and automated technology to measure very low CSF WBC concentrations for the diagnosis of early meningitis. (E-mail: javijimenezg@gmail.com) (C) 2016 World Federation for Ultrasound in Medicine & Biology. C1 [Jimenez, Xavier; Castro-Gonzalez, Carlos; Marti-Fuster, Berta; Butterworth, Ian] MIT, Madrid MIT Vis Consortium Res Lab Elect, 50 Vassar St B36, Cambridge, MA 02139 USA. [Shukla, Shiva K.; Elvira, Luis] CSIC, Inst Tecnol Fis & Informac, Madrid, Spain. [Ortega, Isabel; Illana, Francisco J.; Arroyo, Manuel] Hosp Clin San Carlos, Prote & Metabol Unit, Clin Lab Dept, Inst Invest Sanitaria, Madrid, Spain. [Marti-Fuster, Berta] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Anthony, Brian] MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Jimenez, X (reprint author), MIT, Madrid MIT Vis Consortium Res Lab Elect, 50 Vassar St B36, Cambridge, MA 02139 USA. EM javijimenezg@gmail.com OI Elvira, Luis/0000-0001-8748-966X FU Consejeria de Educacion, Juventud y Deporte de la Comunidad de Madrid through the Madrid-MIT M+Vision Consortium; CSIC PIE [201450 E084]; DOE [DE-SC0008430] FX This work was supported in part by the Consejeria de Educacion, Juventud y Deporte de la Comunidad de Madrid through the Madrid-MIT M+Vision Consortium, CSIC PIE 201450 E084 and DOE training grant DE-SC0008430. NR 26 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 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD JUL PY 2016 VL 42 IS 7 BP 1568 EP 1573 DI 10.1016/j.ultrasmedbio.2016.01.027 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DN8BZ UT WOS:000377305500016 PM 27067281 ER PT J AU Kwak, PE Tritter, AG Donovan, DT Ongkasuwan, J AF Kwak, Paul E. Tritter, Andrew G. Donovan, Donald T. Ongkasuwan, Julina TI Long-term Voice Outcomes of Early Thyroplasty for Unilateral Vocal Fold Paralysis Following Aortic Arch Surgery SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE reconstructive techniques; vocal cord movement; vocal fold paralysis; voice disorders; voice outcomes ID MEDIALIZATION LARYNGOPLASTY; CORD PARALYSIS; INJECTION MEDIALIZATION; FRAMEWORK SURGERY AB Objective: To describe this institution's experience with and the long-term outcomes of early type 1 thyroplasty for unilateral vocal fold paralysis (UVFP) following surgery on the aortic arch. Study Design: Retrospective chart review with telephone questionnaire. Setting: Academic tertiary care center. Subjects and Methods: Three hundred forty-eight patients with UVFP following surgery on the aortic arch since 1999 were identified; 40 were available for follow-up. The number of revision procedures following initial thyroplasty was ascertained, and the Voice Handicap Index (VHI) was administered by telephone. The hypothesis that early thyroplasty produced voice outcomes and revision rates comparable to injection laryngoplasty was established prior to the initiation of data collection. Results: Six out of the 40 patients (15%) required revision thyroplasty following their initial procedure. Mean VHI of all patients was 36.0 (SD, 27.2). Mean VHI was significantly different in the 18 to 39 age group (13.1) when compared to the 40 to 59 (51.8) and 60+ (37.7) age groups (P = .013). Mean follow-up since initial thyroplasty was 46.5 months (SD, 42.2). Conclusions: In the setting of aortic arch surgery with injury to the recurrent laryngeal nerve, early thyroplasty produces voice outcomes comparable to those achieved in the literature with repeated injection and delayed thyroplasty and can be considered in select populations. C1 [Kwak, Paul E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Laryngeal Surg, Boston, MA 02114 USA. [Tritter, Andrew G.] Louisiana State Univ Shreveport, Dept Otolaryngol Head & Neck Surg, Shreveport, LA USA. [Donovan, Donald T.; Ongkasuwan, Julina] Baylor Coll Med, Bobby R Alford Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. RP Ongkasuwan, J (reprint author), Louisiana State Univ Shreveport, Dept Otolaryngol Head & Neck Surg, One Baylor Plaza,NA-102, Houston, TX 77030 USA. EM paulekwak@gmail.com OI Kwak, Paul/0000-0002-3864-9935 NR 21 TC 1 Z9 1 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JUL PY 2016 VL 125 IS 7 BP 559 EP 563 DI 10.1177/0003489416636127 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA DN7GN UT WOS:000377243400005 PM 26969453 ER PT J AU Marcum, ZA Perera, S Thorpe, JM Switzer, GE Castle, NG Strotmeyer, ES Simonsick, EM Ayonayon, HN Phillips, CL Rubin, S Zucker-Levin, AR Bauer, DC Shorr, RI Kang, YH Gray, SL Hanlon, JT AF Marcum, Zachary A. Perera, Subashan Thorpe, Joshua M. Switzer, Galen E. Castle, Nicholas G. Strotmeyer, Elsa S. Simonsick, Eleanor M. Ayonayon, Hilsa N. Phillips, Caroline L. Rubin, Susan Zucker-Levin, Audrey R. Bauer, Douglas C. Shorr, Ronald I. Kang, Yihuang Gray, Shelly L. Hanlon, Joseph T. CA Hlth ABC Study TI Antidepressant Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE antidepressants; aging; drug-related problems; epidemiology; geriatrics; outcomes research/analysis; pharmacoepidemiology ID BODY-COMPOSITION; RISK-FACTOR; PEOPLE; MEDICATION; ASSOCIATIONS; PERFORMANCE; DEPRESSION; ELDERS; WOMEN AB Background: Few studies have compared the risk of recurrent falls across various antidepressant agents-using detailed dosage and duration data-among community-dwelling older adults, including those who have a history of a fall/fracture. Objective: To examine the association of antidepressant use with recurrent falls, including among those with a history of falls/fractures, in community-dwelling elders. Methods: This was a longitudinal analysis of 2948 participants with data collected via interview at year 1 from the Health, Aging and Body Composition study and followed through year 7 (19972004). Any antidepressant medication use was self-reported at years 1, 2, 3, 5, and 6 and further categorized as (1) selective serotonin reuptake inhibitors (SSRIs), (2) tricyclic antidepressants, and (3) others. Dosage and duration were examined. The outcome was recurrent falls (>= 2) in the ensuing 12-month period following each medication data collection. Results: Using multivariable generalized estimating equations models, we observed a 48% greater likelihood of recurrent falls in antidepressant users compared with nonusers (adjusted odds ratio [AOR] = 1.48; 95% CI = 1.12-1.96). Increased likelihood was also found among those taking SSRIs (AOR = 1.62; 95% CI = 1.15-2.28), with short duration of use (AOR = 1.47; 95% CI = 1.04-2.00), and taking moderate dosages (AOR = 1.59; 95% CI = 1.15-2.18), all compared with no antidepressant use. Stratified analysis revealed an increased likelihood among users with a baseline history of falls/fractures compared with nonusers (AOR = 1.83; 95% CI = 1.28-2.63). Conclusion: Antidepressant use overall, SSRI use, short duration of use, and moderate dosage were associated with recurrent falls. Those with a history of falls/fractures also had an increased likelihood of recurrent falls. C1 [Marcum, Zachary A.; Gray, Shelly L.] Univ Washington, Seattle, WA 98102 USA. [Perera, Subashan; Thorpe, Joshua M.; Switzer, Galen E.; Castle, Nicholas G.; Strotmeyer, Elsa S.; Kang, Yihuang; Hanlon, Joseph T.] Univ Pittsburgh, Pittsburgh, PA USA. [Thorpe, Joshua M.; Switzer, Galen E.; Hanlon, Joseph T.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Simonsick, Eleanor M.; Phillips, Caroline L.] NIA, Baltimore, MD 21224 USA. [Ayonayon, Hilsa N.; Rubin, Susan; Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Zucker-Levin, Audrey R.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Shorr, Ronald I.] Vet Affairs Med Ctr, Gainesville, FL 32608 USA. RP Marcum, ZA (reprint author), Univ Washington, Sch Pharm, Dept Pharm, 1959 NE Pacific St,H375G,Box 357630, Seattle, WA 98102 USA. EM zmarcum@uw.edu FU National Institute on Aging (NIA) [P30AG024827, T32 AG021885, K07AG033174, R01AG028050]; National Institutes of Health; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research [R01NR012459] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was primarily supported by National Institute on Aging (NIA) grants and contracts (P30AG024827, T32 AG021885, K07AG033174, R01AG028050). This research was also supported in part by the Intramural Research program of the National Institutes of Health and NIA (N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106) and a National Institute of Nursing Research grant (R01NR012459). NR 27 TC 2 Z9 2 U1 5 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL PY 2016 VL 50 IS 7 BP 525 EP 533 DI 10.1177/1060028016644466 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DN5JO UT WOS:000377102900001 PM 27066988 ER PT J AU Patel, CH Zimmerman, KM Fonda, JR Linsky, A AF Patel, Chirag H. Zimmerman, Kristin M. Fonda, Jennifer R. Linsky, Amy TI Medication Complexity, Medication Number, and Their Relationships to Medication Discrepancies SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE drug safety; medication safety; medication reconciliation; medication complexity; medication discrepancy ID ADVERSE DRUG EVENTS; REGIMEN COMPLEXITY; RECORDS; NONADHERENCE; PREDICTORS; CARE AB Background: Medication reconciliation to identify discrepancies is a National Patient Safety Goal. Increasing medication number and complex medication regimens are associated with discrepancies, nonadherence, and adverse events. The Medication Regimen Complexity Index (MRCI) integrates information about dosage form, dosing frequency, and additional directions. Objective: This study evaluates the association of MRCI scores and medication number with medication discrepancies and commissions, a discrepancy subtype. Methods: This was a retrospective cohort study of a convenience sample of 104 ambulatory care patients seen from April 2010 to July 2011 within the Department of Veterans Affairs. Primary outcomes included any medication discrepancy and commissions. Primary exposures included MRCI scores and medication number. Multivariable logistic regression models associated MRCI scores and medication number with discrepancies. Receiver operating characteristic (ROC) curves provided discrepancy thresholds. Results: For the 104 patients analyzed, the median MRCI score was 25 (interquartile range [IQR] = 14-43), and the median medication number was 8 (IQR = 5-13); 60% of patients had any discrepancy, whereas 36% had a commission. In adjusted analyses, patients with MRCI scores >= 25 or medication number >= 8 were more likely to have commissions (odds ratio [OR] = 3.64, 95% CI = 1.41-9.41; OR = 4.51, 95% CI = 1.73-11.73, respectively). The unadjusted ROC threshold for commissions was 36 for MRCI (sensitivity, 59%; specificity, 82%) and 9 for medication number (sensitivity 68%; specificity 67%). Conclusion: Patients with either MRCI scores >= 25 or >= 8 medications were more likely to have commissions. Given equal performance in predicting discrepancies, the efficiency and simplicity of medication number supports its use in identifying patients for intensive medication review beyond medication reconciliation. C1 [Patel, Chirag H.; Zimmerman, Kristin M.] MCPHS Univ, Boston, MA USA. [Patel, Chirag H.; Zimmerman, Kristin M.; Fonda, Jennifer R.; Linsky, Amy] VA Boston Healthcare Syst, Boston, MA USA. [Zimmerman, Kristin M.] Virginia Commonwealth Univ, Sch Pharm, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Linsky, Amy] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Zimmerman, KM (reprint author), Virginia Commonwealth Univ, Dept Pharmacotherapy & Outcomes Sci, 410 N 12th St,POB 980533, Richmond, VA 23298 USA. EM kzimmerman@vcu.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Career Development Award [CDA12-166]; MCPHS University Honors PharmD Program FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Amy Linsky was supported by a Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Career Development Award (CDA12-166). The study was conducted using resources of the VA Boston Healthcare System. Additional support was provided by the MCPHS University Honors PharmD Program. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. NR 22 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL PY 2016 VL 50 IS 7 BP 534 EP 540 DI 10.1177/1060028016647067 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DN5JO UT WOS:000377102900002 PM 27147704 ER PT J AU Jeganathan, AN Shanmugan, S Bleier, JIS Hall, GM Paulson, EC AF Jeganathan, Arjun N. Shanmugan, Skandan Bleier, Joshua I. S. Hall, Glenn M. Paulson, Emily C. TI Colorectal Specialization Increases Lymph Node Yield: Evidence from a National Database SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID TOTAL MESORECTAL EXCISION; COLON-CANCER; RECTAL-CANCER; SURVIVAL; SURGERY; ASSOCIATION; POPULATION; FELLOWSHIP; RECURRENCE; RETRIEVAL AB Current guidelines recommend the evaluation of at least 12 lymph nodes (LNs) in the pathologic specimen following surgery for colorectal cancer (CRC). We sought to examine the role of colorectal specialization on nodal identification. We conducted a retrospective cohort study using SEER-Medicare data to examine the association between colorectal specialization and LN identification following surgery for colon and rectal adenocarcinoma between 2001 and 2009. Our dataset included patients > 65 years who underwent surgical resection for CRC. We excluded patients with rectal cancer who had received neoadjuvant therapy. The primary outcome measure was the number of LNs identified in the pathologic specimen following surgery for CRC. Multivariate analysis was used to identify the association between surgical specialization and LN identification in the pathologic specimen. In multivariate analysis, odds of an adequate lymphadenectomy following surgery with a colorectal specialist were 1.32 and 1.41 times greater for colon and rectal cancer, respectively, than following surgery by a general surgeon (p < 0.001). These odds increased to 1.36 and 1.58, respectively, when analysis was limited to board-certified colorectal surgeons. Hospital factors associated with a parts per thousand yen12 LNs identified included high-volume CRC surgery (colon OR 1.84, p < 0.001; rectal OR 1.78, p < 0.001) and NCI-designated Cancer Centers (colon OR 1.75, p < 0.001; rectal OR 1.64; p = 0.007). Colorectal specialization and, in particular, board-certification in colorectal surgery, is significantly associated with increased LN identification following surgery for colon and rectal adenocarcinoma since the adoption of the 12-LN guideline in 2001. C1 [Jeganathan, Arjun N.] Univ Penn, Dept Gen Surg, Philadelphia, PA 19104 USA. [Shanmugan, Skandan; Bleier, Joshua I. S.; Hall, Glenn M.; Paulson, Emily C.] Univ Penn, Dept Gen Surg, Div Colon & Rectal Surg, Philadelphia, PA 19104 USA. [Paulson, Emily C.] Philadelphia VA Med Ctr, Dept Gen Surg, Philadelphia, PA USA. RP Jeganathan, AN (reprint author), Univ Penn, Dept Gen Surg, Philadelphia, PA 19104 USA. EM arjun.jeganathan@uphs.upenn.edu OI Jeganathan, Arjun/0000-0003-1520-1473 NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JUL PY 2016 VL 23 IS 7 BP 2258 EP 2265 DI 10.1245/s10434-016-5122-6 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA DN6LL UT WOS:000377186000021 PM 26856723 ER PT J AU Gnanasekaran, S Choueiri, R Neumeyer, A Ajari, O Shui, A Kuhlthau, K AF Gnanasekaran, Sangeeth Choueiri, Roula Neumeyer, Ann Ajari, Ogheneochuko Shui, Amy Kuhlthau, Karen TI Impact of employee benefits on families with children with autism spectrum disorders SO AUTISM LA English DT Article DE autism spectrum disorders; family functioning and support; policy ID HEALTH-CARE NEEDS; PARENTAL EMPLOYMENT; PSYCHOLOGICAL DISTRESS; DISABLED-CHILDREN; CHILDHOOD AUTISM; CHRONIC ILLNESS; MENTAL-HEALTH; AGED CHILDREN; UNITED-STATES; STRESS AB The objectives of this study are to evaluate the employee benefits parents of children with autism spectrum disorders have, how benefits are used, work change, and job satisfaction. We conducted a cross-sectional mailed survey study of 435 families with children with autism spectrum disorders residing in the United States. We received 161 surveys for a response rate of 37%. Families reported using the following benefits: 39% paid family leave, 19% unpaid family leave, 91% flexible work arrangements, and 86% telecommuting. Of respondents, 43% reported stopping work, cutting down on hours worked, or changing jobs because of their child's condition. Having paid family leave was a positive predictor for job satisfaction. Parents of children with autism spectrum disorders have an interest and need for alternative work arrangements. C1 [Gnanasekaran, Sangeeth] Cambridge Hlth Alliance, Cambridge, MA USA. [Choueiri, Roula] Univ Massachusetts, Mem Childrens Med Ctr, Amherst, MA 01003 USA. [Neumeyer, Ann; Kuhlthau, Karen] MassGen Hosp Children, Boston, MA USA. [Neumeyer, Ann; Shui, Amy; Kuhlthau, Karen] Massachusetts Gen Hosp, 125 Nashua St 860, Boston, MA 02114 USA. [Ajari, Ogheneochuko] Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Kuhlthau, K (reprint author), Massachusetts Gen Hosp, 125 Nashua St 860, Boston, MA 02114 USA. EM kkuhlthau@partners.org FU Deborah Munroe Noonan fund; Nancy Lurie Marks Foundation FX This work was supported by grants from the Deborah Munroe Noonan fund and the Nancy Lurie Marks Foundation. NR 47 TC 0 Z9 0 U1 5 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1362-3613 EI 1461-7005 J9 AUTISM JI Autism PD JUL PY 2016 VL 20 IS 5 BP 616 EP 622 DI 10.1177/1362361315598891 PG 7 WC Psychology, Developmental SC Psychology GA DN3OE UT WOS:000376971000011 PM 26341992 ER PT J AU Bankoff, SM Richards, LK Bartlett, B Wolf, EJ Mitchell, KS AF Bankoff, Sarah M. Richards, Lauren K. Bartlett, Brooke Wolf, Erika J. Mitchell, Karen S. TI Examining weight and eating behavior by sexual orientation in a sample of male veterans SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; FOOD ADDICTION SCALE; WOMEN VETERANS; BODY DISSATISFACTION; PREVALENCE; HEALTH; SYMPTOMS; TRAUMA; VALIDATION AB Objective: Eating disorders are understudied in men and in sexual minority populations; however, extant evidence suggests that gay men have higher rates of disordered eating than heterosexual men. The present study examined the associations between sexual orientation, body mass index (BMI), disordered eating behaviors, and food addiction in a sample of male veterans. Method: Participants included 642 male veterans from the Knowledge Networks-GfK Research Panel. They were randomly selected from a larger study based on previously reported trauma exposure; 96% identified as heterosexual. Measures included the Eating Disorder Diagnostic Scale, the Yale Food Addiction Scale, and self-reported height and weight. Results: Heterosexual and sexual minority men did not differ significantly in terms of BMI. However, gay and bisexual men (n = 24) endorsed significantly greater eating disorder symptoms and food addiction compared to heterosexual men. Conclusions: Our findings that sexual minority male veterans may be more likely to experience eating disorder and food addiction symptoms compared to heterosexual male veterans highlight the importance of prevention, assessment, and treatment efforts targeted to this population. Published by Elsevier Inc. C1 [Bankoff, Sarah M.; Bartlett, Brooke; Wolf, Erika J.; Mitchell, Karen S.] VA Boston Healthcare Syst, 150 S Huntington Ave 11PC, Boston, MA 02130 USA. [Richards, Lauren K.] Red Sox Fdn, Boston, MA USA. [Richards, Lauren K.] MGH Home Base Program, Dept Psychiat, Boston, MA USA. [Richards, Lauren K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bartlett, Brooke; Mitchell, Karen S.] Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Wolf, Erika J.] Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Wolf, Erika J.; Mitchell, Karen S.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Bankoff, SM (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave 11PC, Boston, MA 02130 USA. EM Sarah.Bankoff@va.gov; lrichards3@mgh.harvard.edu; Brooke.Bartlett@va.gov; Erika.Wolf@va.gov; Karen.Mitchell5@va.gov FU NIMH NIH HHS [K01 MH093750] NR 35 TC 0 Z9 0 U1 8 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JUL PY 2016 VL 68 BP 134 EP 139 DI 10.1016/j.comppsych.2016.03.007 PG 6 WC Psychiatry SC Psychiatry GA DN4SX UT WOS:000377058600019 PM 27234194 ER PT J AU Chiu, YHM Garshick, E Hart, JE Spiegelman, D Dockery, DW Smith, TJ Laden, F AF Chiu, Yueh-Hsiu Mathilda Garshick, Eric Hart, Jaime E. Spiegelman, Donna Dockery, Douglas W. Smith, Thomas J. Laden, Francine TI Occupational vehicle-related particulate exposure and inflammatory markers in trucking industry workers SO ENVIRONMENTAL RESEARCH LA English DT Article DE Cardiovascular disease; Inflammatory marker; Occupational exposure; Traffic air pollution; Trucking industry ID HEART-RATE-VARIABILITY; AMBIENT AIR-POLLUTION; C-REACTIVE PROTEIN; S-TRANSFERASE M1; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; BLOOD MARKERS; SYSTEMIC INFLAMMATION; PROFESSIONAL DRIVERS; UNITED-STATES AB Background: Previous studies have suggested an association between particulate air pollution and cardiovascular disease, but the mechanism is still unclear. Objective: We examined the association between workplace exposure to vehicle-related particles and cardiovascular disease related systemic inflammatory markers, C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and interleukin-6 (IL-6) in 137 trucking terminal workers (non-drivers) in the U.S. trucking industry. Methods: We visited two large trucking terminals in 2009 and measured vehicle-related elemental carbon (EC), organic carbon (OC), and particulate matter with aerodynamic diameter <= 2.5 mu m (PM2.5), for 5 days consecutively at the main work areas. Each participant provided a blood sample and completed a health questionnaire during the sampling period. Individual workplace exposure level was calculated by 12-h time weighted moving averages based on work shift. The association between each blood marker and exposure to each pollutant during 0-12, 12-24, 24-36, and 36-48 h before the blood draw was examined by multivariable regression analyses. Results: In general, OC and EC had a positive association with sICAM-1, especially for exposure periods 12-24 (lag(12-24)) and 24-36 (lag(24-36)) h prior to blood draw [beta=54.9 (95%CI: 12.3-97.5) for lag(12-24) and beta=46.5 (95%CI: 21.2-71.8) for lag(12-24); change in sICAM-1 (in ng/mL) corresponding to an IQR increase in OC]. A similar pattern was found for EC and PM2.5. We did not find an association between measured pollutants up to 48 h before blood draw and hs-CRP or IL-6. Conclusion: In this group of healthy workers, short-term exposure to vehicle-related air pollutants may be associated with sICAM-1. Our findings may be dependent on the exposure period studied. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chiu, Yueh-Hsiu Mathilda; Hart, Jaime E.; Dockery, Douglas W.; Smith, Thomas J.; Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Chiu, Yueh-Hsiu Mathilda] Icahn Sch Med Mt Sinai, Dept Prevent Med, 17 102nd St,CAM Bldg 3F West D3-133, New York, NY 10029 USA. [Chiu, Yueh-Hsiu Mathilda] Icahn Sch Med Mt Sinai, Dept Pediat, 17 102nd St,CAM Bldg 3F West D3-133, New York, NY 10029 USA. [Garshick, Eric] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Boston, MA USA. [Garshick, Eric; Hart, Jaime E.; Laden, Francine] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Garshick, Eric; Hart, Jaime E.; Laden, Francine] Harvard Univ, Sch Med, Boston, MA USA. [Spiegelman, Donna; Dockery, Douglas W.; Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Spiegelman, Donna] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Chiu, YHM (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, 17 102nd St,CAM Bldg 3F West D3-133, New York, NY 10029 USA. EM mathilda.chiu@mssm.edu FU NIH/NIEHS [R21 ES013726, P30 ES000002]; American Heart Association (AHA) Award [0815689D] FX This study is supported by the NIH/NIEHS R21 ES013726 (Garshick E, PI; Laden F; Hart JE), P30 ES000002 (Dockery D) and American Heart Association (AHA) Award 0815689D (Chiu YHM). The authors have no actual or potential competing financial interests to declare. NR 58 TC 0 Z9 0 U1 7 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JUL PY 2016 VL 148 BP 310 EP 317 DI 10.1016/j.envres.2016.04.008 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DM9VC UT WOS:000376712800033 PM 27104805 ER PT J AU Agarwal, N Sonpavde, G Choueiri, TK Pal, SK AF Agarwal, Neeraj Sonpavde, Guru Choueiri, Toni K. Pal, Sumanta K. TI Ruffling the Immunotherapy Response Paradigm with a Novel Personalized Peptide Vaccine SO EUROPEAN UROLOGY LA English DT Editorial Material ID RESISTANT PROSTATE-CANCER; ENZALUTAMIDE; DOCETAXEL; TRIAL C1 [Agarwal, Neeraj] Univ Utah, Dept Internal Med, Huntsman Canc Inst, 2000 Circle Hope,Ste 2123, Salt Lake City, UT 84112 USA. [Sonpavde, Guru] UAB Med Ctr, Sect Med Oncol, Dept Internal Med, Birmingham, AL USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Dept Med Oncol & Expt Therapeut, Duarte, CA USA. RP Agarwal, N (reprint author), Univ Utah, Dept Internal Med, Huntsman Canc Inst, 2000 Circle Hope,Ste 2123, Salt Lake City, UT 84112 USA. EM neeraj.agarwal@hci.utah.edu NR 10 TC 1 Z9 1 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 2016 VL 70 IS 1 BP 42 EP 44 DI 10.1016/j.eururo.2016.01.045 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DN7WE UT WOS:000377290100022 PM 26873842 ER PT J AU Chung, DY Claassen, J Agarwal, S Schmidt, JM Mayer, SA AF Chung, David Y. Claassen, Jan Agarwal, Sachin Schmidt, J. Michael Mayer, Stephan A. TI Assessment of Noninvasive Regional Brain Oximetry in Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome SO JOURNAL OF INTENSIVE CARE MEDICINE LA English DT Article DE brain injury; brain ischemia; hemodynamic monitoring; neurocritical care ID NEAR-INFRARED SPECTROSCOPY; LEUKOENCEPHALOPATHY SYNDROME; SUBARACHNOID HEMORRHAGE; OXYGEN-SATURATION; CARDIAC-ARREST; SURGERY; HYPOXIA; INJURY; ADULTS AB Background: Posterior reversible encephalopathy syndrome (PRES) leads to small-and large-vessel circulatory dysfunction. While aggressive lowering of elevated blood pressure is the usual treatment for PRES, excessive blood pressure reduction may lead to ischemia or infarction, particularly when PRES is accompanied by reversible cerebral vasoconstriction syndrome (RCVS). Regional cerebral oximetry using near-infrared spectroscopy is a noninvasive modality that is commonly used intraoperatively and in intensive care settings to monitor regional cerebral oxygenation (rSO(2)) and may be useful in guiding treatment in select cases of PRES and RCVS. Results: We report a case of a patient with PRES complicated by infarction and RCVS where the optimal blood pressure management was unclear. A decision was made to decrease blood pressure which resulted in an improved neurological examination and increase in rSO(2) from 40% to 55% in at-risk brain. Infarcted brain as determined by diffusion-weighted magnetic resonance imaging and computed tomography perfusion imaging showed no change in rSO(2) during the same time period. Furthermore, there was a qualitative change in the rSO(2)-mean arterial pressure (MAP) relationship, suggesting an alteration in cerebrovascular autoregulation as a result of lowering blood pressure. Conclusions: Regional cerebral oximetry can provide valuable diagnostic feedback in complicated cases of PRES and RCVS. C1 [Chung, David Y.] Brigham & Womens Hosp, Dept Neurol, Massachusetts Gen Hosp, 75 Francis St, Boston, MA 02115 USA. [Claassen, Jan; Agarwal, Sachin; Schmidt, J. Michael] Columbia Univ, Dept Neurol & Neurosurg, New York, NY USA. [Mayer, Stephan A.] Mt Sinai Hosp, Dept Crit Care, New York, NY 10029 USA. RP Chung, DY (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. EM dychung@mgh.harvard.edu OI Schmidt, J. Michael/0000-0001-8141-2944 FU NINDS NIH HHS [R25 NS070697] NR 20 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0885-0666 EI 1525-1489 J9 J INTENSIVE CARE MED JI J. Intensive Care Med. PD JUL PY 2016 VL 31 IS 6 BP 415 EP 419 DI 10.1177/0885066615623465 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA DN6TQ UT WOS:000377209600008 PM 26732768 ER PT J AU Rutter, CM Knudsen, AB Marsh, TL Doria-Rose, VP Johnson, E Pabiniak, C Kuntz, KM van Ballegooijen, M Zauber, AG Lansdorp-Vogelaar, I AF Rutter, Carolyn M. Knudsen, Amy B. Marsh, Tracey L. Doria-Rose, V. Paul Johnson, Eric Pabiniak, Chester Kuntz, Karen M. van Ballegooijen, Marjolein Zauber, Ann G. Lansdorp-Vogelaar, Iris TI Validation of Models Used to Inform Colorectal Cancer Screening Guidelines: Accuracy and Implications SO MEDICAL DECISION MAKING LA English DT Article DE colorectal cancer; preventive medicine; gastroenterology; discrete event simulation; simulation methods ID SERVICES TASK-FORCE; COST-EFFECTIVENESS; FLEXIBLE SIGMOIDOSCOPY; MEDICARE POPULATION; BOWEL PREPARATION; COLONOSCOPY; COLON; PREVALENCE; CALIBRATION; STRATEGIES AB Background. Microsimulation models synthesize evidence about disease processes and interventions, providing a method for predicting long-term benefits and harms of prevention, screening, and treatment strategies. Because models often require assumptions about unobservable processes, assessing a model's predictive accuracy is important. Methods. We validated 3 colorectal cancer (CRC) microsimulation models against outcomes from the United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial, a randomized controlled trial that examined the effectiveness of one-time flexible sigmoidoscopy screening to reduce CRC mortality. The models incorporate different assumptions about the time from adenoma initiation to development of preclinical and symptomatic CRC. Analyses compare model predictions to study estimates across a range of outcomes to provide insight into the accuracy of model assumptions. Results. All 3 models accurately predicted the relative reduction in CRC mortality 10 years after screening (predicted hazard ratios, with 95% percentile intervals: 0.56 [0.44, 0.71], 0.63 [0.51, 0.75], 0.68 [0.53, 0.83]; estimated with 95% confidence interval: 0.56 [0.45, 0.69]). Two models with longer average preclinical duration accurately predicted the relative reduction in 10-year CRC incidence. Two models with longer mean sojourn time accurately predicted the number of screen-detected cancers. All 3 models predicted too many proximal adenomas among patients referred to colonoscopy. Conclusion. Model accuracy can only be established through external validation. Analyses such as these are therefore essential for any decision model. Results supported the assumptions that the average time from adenoma initiation to development of preclinical cancer is long (up to 25 years), and mean sojourn time is close to 4 years, suggesting the window for early detection and intervention by screening is relatively long. Variation in dwell time remains uncertain and could have important clinical and policy implications. C1 [Rutter, Carolyn M.] RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Marsh, Tracey L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Doria-Rose, V. Paul] NCI, Hlth Syst & Intervent Res Branch, Bethesda, MD 20892 USA. [Johnson, Eric; Pabiniak, Chester] Grp Hlth Res Inst, Seattle, WA USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Dept Hlth Policy & Management, Minneapolis, MN USA. [van Ballegooijen, Marjolein; Lansdorp-Vogelaar, Iris] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Rutter, CM (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM crutter@rand.org OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute as part of the Cancer Intervention and Surveillance Modeling Network (CISNET) [U01-CA-52959]; Center Core Grant [P30-CA-008748] FX This publication was made possible by financial support for this study by a grant from the National Cancer Institute (U01-CA-52959) as part of the Cancer Intervention and Surveillance Modeling Network (CISNET). The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. For all authors other than Zauber, the entirety of this work was supported by U01-CA-52959. Zauber was also supported by a Center Core Grant (P30-CA-008748). Revision accepted for publication 20 October 2015. NR 46 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL PY 2016 VL 36 IS 5 BP 604 EP 614 DI 10.1177/0272989X15622642 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DN5XL UT WOS:000377144900005 PM 26746432 ER PT J AU John-Baptiste, A Schapira, MM Cravens, C Chambers, JD Neumann, PJ Siegel, J Lawrence, W AF John-Baptiste, Ava Schapira, Marilyn M. Cravens, Catherine Chambers, James D. Neumann, Peter J. Siegel, Joanna Lawrence, William TI The Role of Decision Models in Health Care Policy: A Case Study SO MEDICAL DECISION MAKING LA English DT Article DE health care policy; decision models; policy discussion; colorectal cancer ID COST-EFFECTIVENESS ANALYSIS; MAKERS; IMPACT; TRANSPARENCY; NEED AB Background. In 2009, the Centers for Medicare and Medicaid Services (CMS) underwent a National Coverage Determination on computed tomography colonography (CTC) to screen for colorectal cancer. The Cancer Intervention & Surveillance Network developed decision models to inform this decision. The purpose of our study was to investigate the role of models in this decision. Methods. We performed a descriptive case study. We conducted semistructured telephone interviews with members of the CMS coverage and analysis group (CAG) and Medicare Coverage and Analysis Advisory Committee (MEDCAC) panelists. Informed by previously published literature, we developed a coding scheme to analyze interview transcripts, MEDCAC meeting transcripts, and the final CMS decision memo. Results. Four members of the CAG and 8 MEDCAC panelists were interviewed. The total number of codes across all study documents was 772. We found evidence that decision makers believed in the adequacy of models to inform decision making. In interview transcripts, the code Models Are Adequate to Inform was more frequent than the code Models Are Inadequate to Inform (47 times v. 5). Discussion of model conceptualization dominated the MEDCAC meeting (Model Conceptualization assigned 113 times) and was frequently discussed during interviews (Model Conceptualization assigned 84 times). We also found evidence that the models helped to focus the policy discussion. Across study documents, the codes Focus on Cost, Focus on ClinicalHealth Impact, and Focus on Inadequacy of Evidence Base were assigned 99, 98, and 97 times, respectively. Conclusions. Decision makers involved in the CTC decision believed in the adequacy of models to inform coverage decisions. The model played a role in focusing the CTC coverage policy discussion. C1 [John-Baptiste, Ava; Cravens, Catherine; Siegel, Joanna; Lawrence, William] Agcy Healthcare Res & Qual, Ctr Outcomes & Evidence, Dept Hlth & Human Serv, Rockville, MD USA. [John-Baptiste, Ava] Univ Western Ontario, Dept Anesthesia & Perioperat Med, Schulich Sch Med & Dent, Interfac Program Publ Hlth, London, ON, Canada. [John-Baptiste, Ava] Univ Western Ontario, Dept Epidemiol & Biostat, Schulich Sch Med & Dent, Interfac Program Publ Hlth, London, ON, Canada. [John-Baptiste, Ava] Ctr Med Evidence Decis Integr Clin MEDICI, London, ON, Canada. [John-Baptiste, Ava] Lawson Hlth Res Inst, London, ON, Canada. [John-Baptiste, Ava; Chambers, James D.; Neumann, Peter J.] Tufts Med Ctr, Ctr Evaluat Value & Risk Hlth, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Schapira, Marilyn M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Ctr Hlth Equ & Res Program, Philadelphia, PA USA. RP John-Baptiste, A (reprint author), Western Ctr Publ Hlth & Family Med, Rm 4111,1465 Richmond St, London, ON N6G 2M1, Canada. EM ajohnbap@uwo.ca FU Society for Medical Decision Making (SMDM); Agency for Healthcare Research and Policy Health Policy Fellowship in Comparative Effectiveness; Canadian Institutes of Health Research (CIHR) Institute of Nutrition, Metabolism and Diabetes [OTG-88591]; Cancer Care Ontario; Ontario Institute for Cancer Research through Ministry of Health and Long-Term Care; Ontario Institute for Cancer Research through Ministry of Economic Development and Innovation of the Government of Ontario; Canadian Institutes of Health Research through Ministry of Health and Long-Term Care FX This article was presented at the 32nd Annual Meeting of the Society for Medical Decision Making (Toronto, Ontario, Canada, 2010) and the annual symposium of the Canadian Agency for Drugs and Technologies in Health (Vancouver, British Columbia, Canada, 2011). During the conduct of the study, Ava John-Baptiste was funded by the Society for Medical Decision Making (SMDM), Agency for Healthcare Research and Policy Health Policy Fellowship in Comparative Effectiveness, and hosted in the Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center. The funding agreement ensured the author's independence in designing the study, interpreting the data, writing, and publishing the report. The following authors were employed by the Agency for Healthcare Research and Policy: Catherine Cravens, Joanna Siegel, and William Lawrence. Ava John-Baptiste was subsequently supported by a Team Grant (grant OTG-88591) from the Canadian Institutes of Health Research (CIHR) Institute of Nutrition, Metabolism and Diabetes, Cancer Care Ontario and the Ontario Institute for Cancer Research (through funding provided by the Ministry of Health and Long-Term Care and the Ministry of Economic Development and Innovation of the Government of Ontario). Ava John-Baptiste was also supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (through funding provided by the Ministry of Health and Long-Term Care). Revision accepted for publication 26 March 2016. NR 30 TC 0 Z9 0 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL PY 2016 VL 36 IS 5 BP 666 EP 679 DI 10.1177/0272989X16646732 PG 14 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DN5XL UT WOS:000377144900010 PM 27225487 ER PT J AU Ahn, KY Lee, MK Kim, DI Park, J Min, J Yang, HI Lee, J Oh, M An, J Lee, JW Chu, SH Meyerhardt, JA Kim, NK Jeon, JY AF Ahn, Ki-Yong Lee, Mi Kyung Kim, Dong-Il Park, Jihye Min, Jihee Yang, Hyuk In Lee, Junga Oh, Minsuk An, Joongbae Lee, Ji-Won Chu, Sang Hui Meyerhardt, Jeffrey A. Kim, Nam-Kyu Jeon, Justin Y. TI Cardiopulmonary fitness, adiponectin, chemerin associated fasting insulin level in colorectal cancer patients SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Adiponectin; Chemerin; Fitness; Insulin; Colorectal cancer ID BIOELECTRICAL-IMPEDANCE ANALYSIS; PHYSICAL-ACTIVITY; METABOLIC SYNDROME; BREAST-CANCER; CARDIOVASCULAR FITNESS; PROSPECTIVE COHORT; OBESE ADULTS; RESISTANCE; SENSITIVITY; SURVIVORS AB Purpose Since circulating level of insulin is associated with colorectal cancer prognosis, it is important to identify factors contributing to fasting insulin level in colorectal cancer patients. The purpose of the current study is to investigate the association of physical fitness, adiponectin, and chemerin levels with circulating level of insulin in colorectal cancer patients. Methods A total of 123 stage II-III colorectal cancer patients who completed standard cancer treatment were recruited. Anthropometric characteristics, fitness measurements, fasting insulin level, homeostasis model assessment of insulin resistance, lipid profiles, and adiponectin and chemerin levels were analyzed. Result Cardiopulmonary fitness level inversely associated with fasting insulin levels (the least fit (1st tertile): 8.11 +/- 0.64, moderately fit (2nd tertile): 6.02 +/- 0.63, and highly fit (3rd tertile): 5.58 +/- 0.66 mu U/ml, unfit vs. moderately fit, p < 0.01; unfit vs. highly fit, p < 0.05) after adjustment for gender, age, stage, and BMI. In addition, fasting adiponectin and chemerin levels were associated with fasting insulin levels after adjustment for gender, age, stage, and BMI. In our combined analyses, participants with high adiponectin and low chemerin levels showed significantly lower fasting insulin levels (4.92 +/- 0.75 vs. 8.07 +/- 0.80 mu U/ml, p < 0.01) compared with participants with low adiponectin and high chemerin levels. Multiple linear regression analysis confirmed that cardiopulmonary fitness and adiponectin levels (beta = -0.299, p = 0.002; beta = -0.201, p = 0.033) were independently associated with fasting insulin level. Conclusion Our results suggest that physical fitness and adiponectin and chemerin levels may contribute to circulating levels of insulin. These results suggest that exercise may influence the prognosis of colorectal cancer patients by influencing physical fitness level, circulating levels of adiponectin and chemerin. C1 [Ahn, Ki-Yong; Lee, Mi Kyung; Kim, Dong-Il; Park, Jihye; Min, Jihee; Yang, Hyuk In; Lee, Junga; Oh, Minsuk; Jeon, Justin Y.] Yonsei Univ, Coll Med, Dept Med, Canc Prevent Ctr,Yonsei Canc Canter, Seoul 120749, South Korea. [An, Joongbae] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 120749, South Korea. [Lee, Ji-Won] Yonsei Univ, Coll Med, Dept Family Med, Seoul 120749, South Korea. [Chu, Sang Hui] Yonsei Univ, Coll Nursing, Nursing Policy Res Inst, Dept Clin Nursing Sci,Biobehav Res Ctr, Seoul 120749, South Korea. [Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Kim, Nam-Kyu] Yonsei Univ, Coll Med, Dept Surg, 250 Seongsan Ro, Seoul 120752, South Korea. [Kim, Nam-Kyu; Jeon, Justin Y.] Yonsei Univ, Exercise Med Ctr Diabet & Canc Patients, Dept Sport & Leisure Studies, Seoul 120749, South Korea. RP Jeon, JY (reprint author), Yonsei Univ, Coll Med, Dept Med, Canc Prevent Ctr,Yonsei Canc Canter, Seoul 120749, South Korea.; Kim, NK (reprint author), Yonsei Univ, Coll Med, Dept Surg, 250 Seongsan Ro, Seoul 120752, South Korea.; Kim, NK; Jeon, JY (reprint author), Yonsei Univ, Exercise Med Ctr Diabet & Canc Patients, Dept Sport & Leisure Studies, Seoul 120749, South Korea. EM namkyuk@yuhs.ac; jjeon@yonsei.ac.kr OI Kim, Nam-Kyu/0000-0003-0639-5632 FU National Research Foundation of Korea [NRF-2010-0009048]; National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea [1120230] FX This research was supported by the National Research Foundation of Korea (NRF-2010-0009048) and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1120230). NR 50 TC 0 Z9 0 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 2016 VL 24 IS 7 BP 2927 EP 2935 DI 10.1007/s00520-016-3095-4 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DM9II UT WOS:000376678400015 PM 26847448 ER PT J AU Castleberry, SA Golberg, A Abu Sharkh, M Khan, S Almquist, BD Austen, WG Yarmush, ML Hammond, PT AF Castleberry, Steven A. Golberg, Alexander Abu Sharkh, Malak Khan, Saiqa Almquist, Benjamin D. Austen, William G., Jr. Yarmush, Martin L. Hammond, Paula T. TI Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns SO BIOMATERIALS LA English DT Article DE siRNA delivery; Controlled release; CTGF; Scar formation; Layer-by-layer; Wound healing ID TISSUE GROWTH-FACTOR; LAYER-BY-LAYER; SMOOTH-MUSCLE ACTIN; RABBIT EAR MODEL; FACTOR-BETA; TGF-BETA; EXTRACELLULAR-MATRIX; ANTISENSE OLIGONUCLEOTIDES; RENAL FIBROSIS; WOUND CONTRACTION AB Wound healing is an incredibly complex biological process that often results in thickened collagen enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGF beta pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of alpha SMA, TIMP1, and Col1a1 al, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Castleberry, Steven A.; Abu Sharkh, Malak; Almquist, Benjamin D.; Hammond, Paula T.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Castleberry, Steven A.; Almquist, Benjamin D.; Hammond, Paula T.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Castleberry, Steven A.; Almquist, Benjamin D.; Hammond, Paula T.] MIT, Inst Soldier Nanotechnol, Cambridge, MA 02139 USA. [Castleberry, Steven A.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Golberg, Alexander; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med,Dept Surg, Boston, MA 02114 USA. [Golberg, Alexander; Yarmush, Martin L.] Shriners Burns Hosp, Boston, MA 02114 USA. [Golberg, Alexander] Tel Aviv Univ, Porter Sch Environm Studies, IL-69978 Tel Aviv, Israel. [Khan, Saiqa; Austen, William G., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08901 USA. RP Hammond, PT (reprint author), MIT, Dept Chem Engn, Koch Inst Integrat Canc Res, Room 76-553, Cambridge, MA 02139 USA. EM hammond@mit.edu OI Almquist, Benjamin/0000-0001-9718-777X FU U.S. Army Research Office [W911NF-07-D-0004]; Shriners Grant [85120-BOS]; NCI [2P30CA014051-39] FX This research was supported in part by funding and core facilities provided by the U.S. Army Research Office under contract W911NF-07-D-0004 at the MIT Institute of Soldier Nanotechnology. We acknowledge Shriners Grant #85120-BOS for the support of this study. This work was also supported by use of core facilities at the Koch Institute for Integrative Cancer Research (supported by the NCI under grant 2P30CA014051-39). We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the microscopy, flow cytometry, and histology cores. The authors wish to dedicate this paper to the memory of Officer Sean Collier, for his caring service to the MIT community and for his sacrifice. NR 82 TC 1 Z9 1 U1 13 U2 27 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JUL PY 2016 VL 95 BP 22 EP 34 DI 10.1016/j.biomaterials.2016.04.007 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DM9PM UT WOS:000376698200003 PM 27108403 ER PT J AU Trivedi, MH McGrath, PJ Fava, M Parsey, RV Kurian, BT Phillips, ML Oquendo, MA Bruder, G Pizzagalli, D Toups, M Cooper, C Adams, P Weyandt, S Morris, DW Grannemann, BD Ogden, RT Buckner, R McInnis, M Kraemer, HC Petkova, E Carmody, TJ Weissman, MM AF Trivedi, Madhukar H. McGrath, Patrick J. Fava, Maurizio Parsey, Ramin V. Kurian, Benji T. Phillips, Mary L. Oquendo, Maria A. Bruder, Gerard Pizzagalli, Diego Toups, Marisa Cooper, Crystal Adams, Phil Weyandt, Sarah Morris, David W. Grannemann, Bruce D. Ogden, R. Todd Buckner, Randy McInnis, Melvin Kraemer, Helena C. Petkova, Eva Carmody, Thomas J. Weissman, Myrna M. TI Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Review DE Biosignatures; Antidepressant response; Moderators; Mediators; EMBARC; Sertraline ID MAJOR DEPRESSIVE DISORDER; FUNCTIONAL MAGNETIC-RESONANCE; STAR-ASTERISK-D; ANTERIOR CINGULATE ACTIVITY; DYNAMIC TREATMENT REGIMES; PHARMACOLOGICAL-TREATMENT; INDIVIDUAL-DIFFERENCES; INTENSITY DEPENDENCE; COGNITIVE PREDICTORS; ANXIETY DISORDERS AB Remission rates for Major Depressive Disorder (MDD) are low and unpredictable for any given antidepressant. No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment. Biosignatures developed from the systematic exploration of multiple biological markers, which optimize treatment selection for individuals (moderators) and provide early indication of ultimate treatment response (mediators) are needed. The rationale and design of a multi-site, placebo controlled randomized clinical trial of sertraline examining moderators and mediators of treatment response is described. The target sample is 300 participants with early onset (<= 30 years) recurrent MDD. Non-responders to an 8-week trial are switched double blind to either bupropion (for sertraline non responders) or sertraline (for placebo non-responders) for an additional 8 weeks. Clinical moderators include anxious depression, early trauma, gender, melancholic and atypical depression, anger attacks, Axis II disorder, hypersomnia/fatigue, and chronicity of depression. Biological moderator and mediators include cerebral cortical thickness, task-based fMRI (reward and emotion conflict), resting connectivity, diffusion tensor imaging (DTI), arterial spin labeling (ASL), electroencephalograpy (EEG), cortical evoked potentials, and behavioral/cognitive tasks evaluated at baseline and week 1, except DTI, assessed only at baseline. The study is designed to standardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods, and to use advanced data analytic methods to integrate these markers. A Differential Depression Treatment Response Index (DTRI) will be developed. The data, including biological samples (DNA, RNA, and plasma collected before and during treatment), will become available in a public scientific repository. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Trivedi, Madhukar H.; Kurian, Benji T.; Toups, Marisa; Cooper, Crystal; Weyandt, Sarah; Morris, David W.; Grannemann, Bruce D.; Carmody, Thomas J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [McGrath, Patrick J.; Oquendo, Maria A.; Bruder, Gerard; Adams, Phil; Weissman, Myrna M.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [McGrath, Patrick J.; Oquendo, Maria A.; Bruder, Gerard; Adams, Phil; Weissman, Myrna M.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Parsey, Ramin V.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Phillips, Mary L.] Univ Pittsburgh, Pittsburgh, PA USA. [Pizzagalli, Diego] Harvard Univ, Sch Med, McLean Hosp, Boston, MA USA. [Ogden, R. Todd] Columbia Univ, New York, NY USA. [Buckner, Randy] Harvard Univ, Cambridge, MA 02138 USA. [McInnis, Melvin] Univ Michigan, Ann Arbor, MI 48109 USA. [Kraemer, Helena C.] Stanford Univ, Stanford, CA 94305 USA. [Petkova, Eva] NYU, New York, NY USA. RP Trivedi, MH (reprint author), Univ Texas SW Med Ctr Dallas, Ctr Depress Res & Clin Care, Betty Jo Hay Distinguished Chair Mental Hlth, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM madhukar.trivedi@utsouthwestern.edu RI Parsey, Ramin/J-8254-2014 FU National Institute of Mental Health of the National Institutes of Health [U01MH092221, U01MH092250]; EMBARC National Coordinating Center at UT Southwestern Medical Center; Data Center at Columbia and Stony Brook Universities FX The EMBARC study was supported by the National Institute of Mental Health of the National Institutes of Health under award numbers U01MH092221 (Trivedi, M.H.) and U01MH092250 (McGrath, P.J., Parsey, R.V., Weissman, M.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Valeant Pharmaceuticals donated the Wellbutrin XL used in the study. This work was supported by the EMBARC National Coordinating Center at UT Southwestern Medical Center, Madhukar H. Trivedi, M.D., Coordinating PI, and the Data Center at Columbia and Stony Brook Universities. NR 101 TC 7 Z9 7 U1 8 U2 15 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 PY 2016 VL 78 BP 11 EP 23 DI 10.1016/j.jpsychires.2016.03.001 PG 13 WC Psychiatry SC Psychiatry GA DM9QN UT WOS:000376700900002 PM 27038550 ER PT J AU Hwang, JW Xin, SC Ou, YM Zhang, WY Liang, YL Chen, J Yang, XQ Chen, XY Guo, TW Yang, XJ Ma, WH Li, J Zhao, BC Tu, Y Kong, J AF Hwang, J. W. Xin, S. C. Ou, Y. M. Zhang, W. Y. Liang, Y. L. Chen, J. Yang, X. Q. Chen, X. Y. Guo, T. W. Yang, X. J. Ma, W. H. Li, J. Zhao, B. C. Tu, Y. Kong, J. TI Enhanced default mode network connectivity with ventral striatum in subthreshold depression individuals (vol 76, pg 112, 2016) SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Correction C1 [Hwang, J. W.; Xin, S. C.; Zhang, W. Y.; Liang, Y. L.; Yang, X. Q.; Guo, T. W.; Yang, X. J.; Ma, W. H.; Li, J.; Zhao, B. C.; Tu, Y.] Beijing Univ Tradit Chinese Med, Sch Acupuncture Moxibust & Tuina, Beijing 100029, Peoples R China. [Hwang, J. W.; Chen, X. Y.; Kong, J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02138 USA. [Ou, Y. M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02138 USA. [Zhang, W. Y.] Capital Med Univ, Beijing Rehabil Hosp, Beijing, Peoples R China. [Liang, Y. L.] Wellesley Coll, Neurosci Program, Wellesley, MA 02181 USA. [Chen, J.] Beijing Univ Chinese Med, Sch Management, Beijing, Peoples R China. [Yang, X. Q.] Beijing Univ Chinese Med, Inst Hlth Preserving Chinese Med, Beijing, Peoples R China. [Guo, T. W.] Beijing Univ Chinese Med, Dongzhimen Hosp, Dept Hematol & Oncol, Beijing, Peoples R China. RP Tu, Y (reprint author), Beijing Univ Tradit Chinese Med, Sch Acupuncture Moxibust & Tuina, Beijing 100029, Peoples R China. EM tuyab@263.net; kongj@nmr.mgh.harvard.edu NR 1 TC 0 Z9 0 U1 4 U2 4 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 PY 2016 VL 78 BP 56 EP 56 DI 10.1016/j.jpsychires.2016.03.007 PG 1 WC Psychiatry SC Psychiatry GA DM9QN UT WOS:000376700900007 ER PT J AU Kennelty, KA Witry, MJ Gehring, M Dattalo, M Rogus-Pulia, N AF Kennelty, Korey A. Witry, Matthew J. Gehring, Michael Dattalo, Melissa Rogus-Pulia, Nicole TI A four-phase approach for systematically collecting data and measuring medication discrepancies when patients transition between health care settings SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Community pharmacy; Medication discrepancies; Transitions of care; Adverse drug events ID HOSPITAL ADMISSION; INTERRATER RELIABILITY; RISK-FACTORS; RECONCILIATION; ERRORS; DISCHARGE; RECORDS; MATCH AB Background: No methodological standards are available for researchers and clinicians to examine medication discrepancies between health care settings. Systematic methods of examining medication discrepancies will allow researchers and clinicians to better understand factors driving medication discrepancies, to better measure effects of medication reconciliation interventions, and to compare findings across studies. Objective: This article proposes a four-phase approach for systematically collecting medication data and measuring medication discrepancies between a hospital and community pharmacies. Methodologic considerations related to studying medication discrepancies in health services research are also discussed. Methods: A multi-disciplinary study team developed a four-phase systematic approach to improve quality of data and study rigor: 1) operationalization of a medication discrepancy, 2) acquiring medication data, 3) abstraction of medication data and creation of dataset, and 4) measuring and reporting medication discrepancies. Results: Using this phase-based approach, the study team successfully identified and reported medication discrepancies between a hospital and community pharmacies at the patient, medication, and community pharmacy units of analyses. Conclusions: Systematically measuring medication discrepancies that occur in the care transitions process is a critical step as researchers, clinicians, and other stakeholders work to improve health care quality and patient outcomes. This article detailed how a phase-based approach can be used in research to examine medication discrepancies as well as address the complexity of collecting medication data and analyzing medication discrepancies. Such methods should be considered when developing, conducting, and reporting research on medication discrepancies. Published by Elsevier Inc. C1 [Kennelty, Korey A.; Gehring, Michael; Dattalo, Melissa; Rogus-Pulia, Nicole] William S Middleton Mem Vet Adm Med Ctr, GRECC, 2500 Overlook Terrace,11G, Madison, WI 53705 USA. [Kennelty, Korey A.] Univ Wisconsin, Sch Pharm, Social & Adm Sci Div, Madison, WI 53705 USA. [Kennelty, Korey A.; Gehring, Michael; Dattalo, Melissa; Rogus-Pulia, Nicole] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. [Witry, Matthew J.] Univ Iowa, Coll Pharm, Dept Pharm Practice & Sci, Iowa City, IA 52242 USA. RP Kennelty, KA (reprint author), 2500 Overlook Terrace,11-G, Madison, WI 53705 USA. EM kennelty@wisc.edu OI Witry, Matthew/0000-0001-8381-7224 FU Agency for Healthcare Research and Quality (AHRQ) Health Services Research Dissertation Grant of the National Institutes of Health [R36HS021984]; 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] FX 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 R36HS021984 [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 in this dissertation also was supported by the UW-Madison School of Pharmacy Sonderegger Research Center Dissertation Grant.; The project described also was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427. NR 35 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 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD JUL-AUG PY 2016 VL 12 IS 4 BP 548 EP 558 DI 10.1016/j.sapharm.2015.09.001 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DM6CN UT WOS:000376437600040 PM 26781670 ER PT J AU Blashill, AJ Tomassilli, J Biello, K O'Cleirigh, C Safren, SA Mayer, KH AF Blashill, Aaron J. Tomassilli, Julia Biello, Katie O'Cleirigh, Conall Safren, Steven A. Mayer, Kenneth H. TI Body Dissatisfaction Among Sexual Minority Men: Psychological and Sexual Health Outcomes SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Body dissatisfaction; Sexual minority men; Depression; Sexual health ID USE SELF-EFFICACY; DYSMORPHIC DISORDER; CONDOM USE; OBJECTIFICATION THEORY; METHAMPHETAMINE USE; RISK-FACTORS; IMAGE; MUSCULARITY; HIV; DRIVE AB Body dissatisfaction is common among sexual minority (i.e., gay and bisexual) men; however, few studies have investigated the relationship between body dissatisfaction and psychosexual health variables among this population. The data that do exist are exclusively cross-sectional, casting uncertainty regarding temporal associations. Thus, the aims of the current study were to assess the prospective relationship between body dissatisfaction and psychological and sexual health outcomes. Participants were 131 gay and bisexual men who completed a battery of self-report measures across two time points (baseline and 3-month follow-up), including assessment of body dissatisfaction, depressive symptoms, and sexual health variables (sexual self-efficacy and sexual anxiety). Generalized linear modeling was employed to assess the prospective relationship between body dissatisfaction and outcomes variables, accounting for non-normal distributions. Body dissatisfaction significantly predicted elevated depressive symptoms (B = .21, p = .01), lower sexual self-efficacy (B = -.22, p = .04), and elevated sexual anxiety (B = .05, p = .03). Elevated body dissatisfaction is prospectively associated with negative psychological and sexual health outcomes. Given the high prevalence of body image concerns in sexual minority men, depression and/or HIV/STI prevention programs may benefit from routinely assessing for body dissatisfaction among this population, and addressing those who report concerns. C1 [Blashill, Aaron J.] San Diego State Univ, Dept Psychol, 6363 Alvarado Court,Suite 103, San Diego, CA 92120 USA. [Blashill, Aaron J.] SDSU UCSD Joint Doctoral Program Clin Psychol, San Diego, CA USA. [Tomassilli, Julia] Calif State Univ Sacramento, Sacramento, CA 95819 USA. [Biello, Katie; O'Cleirigh, Conall; Mayer, Kenneth H.] Fenway Inst, Boston, MA USA. [Biello, Katie] Brown Univ, Dept Behav & Social Sci, Providence, RI 02912 USA. [O'Cleirigh, Conall] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [O'Cleirigh, Conall; Mayer, Kenneth H.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Safren, Steven A.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. RP Blashill, AJ (reprint author), San Diego State Univ, Dept Psychol, 6363 Alvarado Court,Suite 103, San Diego, CA 92120 USA.; Blashill, AJ (reprint author), SDSU UCSD Joint Doctoral Program Clin Psychol, San Diego, CA USA. EM aaron.blashill@sdsu.edu FU NIH [P01 AI074415]; Harvard University Center for AIDS Research; [K23MH096 647]; [K24MH094214] FX Author time was supported by Grant K23MH096 647 (Blashill), K24MH094214 (Safren). This study was supported by NIH grant P01 AI074415, an unrestricted research grant from the Harvard University Center for AIDS Research. NR 37 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD JUL PY 2016 VL 45 IS 5 BP 1241 EP 1247 DI 10.1007/s10508-015-0683-1 PG 7 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA DM1DW UT WOS:000376086500018 PM 26857379 ER PT J AU Moye, J AF Moye, Jennifer TI Assessing Older Adults, their Caregivers, and their Environments SO CLINICAL GERONTOLOGIST LA English DT Editorial Material ID DEMENTIA C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA USA. [Moye, Jennifer] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Boston, MA USA.; Moye, J (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM Jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 5 TC 0 Z9 0 U1 1 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PD JUL-SEP PY 2016 VL 39 IS 4 BP 261 EP 262 DI 10.1080/07317115.2016.1174498 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DL9IT UT WOS:000375956700001 ER PT J AU Murray, SS Murray, EJB Wang, JC Duarte, MEL AF Murray, Samuel S. Murray, Elsa J. Brochmann Wang, Jeffrey C. Leite Duarte, Maria Eugenia TI The history and histology of bone morphogenetic protein SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE Bone morphogenetic protein; Bone; Endochondral bone formation ID BOVINE OSTEOGENIC PROTEIN; PROCOLLAGEN C-PROTEINASE; TGF-BETA; DIFFUSION-CHAMBERS; DIFFERENTIATION; PURIFICATION; ANTAGONISTS; INDUCTION; CARTILAGE; REPAIR AB Bone morphogenetic proteins are a group of structurally related proteins within the TGF-beta superfamily of proteins with a diverse repertoire of functions in embryonic and adult organisms. As is apparent from the name, the members first characterized participate in bone growth, development, and remodeling. The "morphogenic" activity per se is defined as the induction of a recapitulation of endochondral bone formation by appropriate stem cells. The regenerative capacity of bone has been recognized since ancient times. The mechanism, applications, and conceptual basis of bone transplantation, bone implantation, ectopic bone formation, and exogenously induced bone formation have been studied by many investigators for more than a century. This review examines the efforts to characterize this activity in the European and American literature over approximately the last century. Because of the inherently complex nature of the process induced by these molecules (inflammation, stem cell proliferation, cartilage differentiation, replacement of cartilage with bone) it is important to evaluate previous investigations through a histological perspective. The cellular basis of the contemporary bioassay for BMP activity is illustrated and discussed from the histological point of view. C1 [Murray, Samuel S.; Murray, Elsa J. Brochmann] Univ Calif Los Angeles, Geriatr Res Educ & Clin Ctr, Sepulveda Ambulatory Care Ctr, VA Greater Los Angeles, Los Angeles, CA USA. [Murray, Samuel S.; Murray, Elsa J. Brochmann] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Wang, Jeffrey C.] Univ So Calif, Dept Orthopaed Surg, Los Angeles, CA USA. [Leite Duarte, Maria Eugenia] Natl Inst Traumatol & Orthopaed INTO, Rio De Janeiro, Brazil. RP Murray, SS (reprint author), VA Med Ctr, 16111 Plummer St, Sepulveda, CA 91343 USA. EM samuel.murray@va.gov FU Department of Veterans Affairs, USA; National Institute of Orthopaedics and Traumatology, Rio de Janeiro, Brazil FX This work was supported by the Department of Veterans Affairs, USA and the National Institute of Orthopaedics and Traumatology, Rio de Janeiro, Brazil. The authors would like to thank Nadia Vatamanu for her expert medical library assistance. NR 63 TC 1 Z9 1 U1 9 U2 13 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 2016 VL 31 IS 7 BP 721 EP 732 DI 10.14670/HH-11-774 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DM3YZ UT WOS:000376284000002 PM 26907674 ER PT J AU Danek, BA Karatasakis, A Karmpaliotis, D Alaswad, K Yeh, RW Jaffer, FA Patel, M Bahadorani, J Lombardi, WL Wyman, MR Grantham, JA Doing, A Moses, JW Kirtane, A Parikh, M Ali, ZA Kalra, S Kandzari, DE Lembo, N Garcia, S Rangan, BV Thompson, CA Banerjee, S Brilakis, ES AF Danek, Barbara Anna Karatasakis, Aris Karmpaliotis, Dimitri Alaswad, Khaldoon Yeh, Robert W. Jaffer, Farouc A. Patel, Mitul Bahadorani, John Lombardi, William L. Wyman, Michael R. Grantham, J. Aaron Doing, Anthony Moses, Jeffrey W. Kirtane, Ajay Parikh, Manish Ali, Ziad A. Kalra, Sanjog Kandzari, David E. Lembo, Nicholas Garcia, Santiago Rangan, Bavana V. Thompson, Craig A. Banerjee, Subhash Brilakis, Emmanouil S. TI Use of antegrade dissection re-entry in coronary chronic total occlusion percutaneous coronary intervention in a contemporary multicenter registry SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Chronic total occlusion; Techniques; Dissection and re-entry; Outcomes; Complications ID IN-STENT RESTENOSIS; HYBRID APPROACH; CROSSING CORONARY; STAR TECHNIQUE; TERM OUTCOMES; TRUE LUMEN; INSIGHTS; RECANALIZATION; SYSTEM; EXPERIENCE AB Background: We assessed efficacy and safety of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) using antegrade dissection re-entry (ADR). Methods: We examined outcomes of ADR among 1313 CTO PCIs performed at 11 US centers between 2012-2015. Results: 84.1% of patients were men. Prevalence of prior coronary artery bypass graft surgery was 34.3%. Overall technical and procedural success were 90.1% and 88.7%, respectively. In-hospital major adverse cardiovascular events (MACE) occurred in 31 patients (2.4%). ADR was used in 458 cases (34.9%), and was the first strategy in 169 cases (12.9%). ADR cases were angiographically more complex than non-ADR cases (mean J-CTO score: 2.8 +/- 1.2 vs. 2.4 +/- 1.2, p < 0.001). ADR was performed using the CrossBoss catheter in 246 of 458 (53.7%) and the Stingray system in 251 ADR cases (54.8%). Compared with non-ADR cases, ADR cases had lower technical (86.9% vs. 91.8%, p= 0.005) and procedural success (85.0% vs. 90.7%, p= 0.002), but similar risk for MACE (2.9% vs. 2.2%, p= 0.42). ADR was associated with longer procedure and fluoroscopy time, and higher patient air kerma dose and contrast volume (all p < 0.001). After excluding retrograde cases, ADR and antegrade wire escalation (AWE) had similar technical success (92.7% vs. 94.2%, p = 0.43), procedural success (91.8% vs. 94.1%, p= 0.23), and MACE (2.1% vs. 0.6%, p= 0.12). Conclusions: ADR is used relatively frequently in contemporary CTO PCI, especially for challenging lesions and after failure of other strategies. ADR is associated with similar success rates and risk for complications as compared with AWE, and is important for achieving high procedural success. Published by Elsevier Ireland Ltd. C1 [Danek, Barbara Anna; Karatasakis, Aris; Rangan, Bavana V.; Banerjee, Subhash; Brilakis, Emmanouil S.] VA North Texas Healthcare Syst, Dallas, TX USA. [Danek, Barbara Anna; Karatasakis, Aris; Rangan, Bavana V.; Banerjee, Subhash; Brilakis, Emmanouil S.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Karmpaliotis, Dimitri; Moses, Jeffrey W.; Kirtane, Ajay; Parikh, Manish; Ali, Ziad A.; Kalra, Sanjog] Columbia Univ, New York, NY USA. [Alaswad, Khaldoon] Henry Ford Hosp, Detroit, MI 48202 USA. [Yeh, Robert W.; Jaffer, Farouc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yeh, Robert W.; Jaffer, Farouc A.] Harvard Univ, Sch Med, Boston, MA USA. [Patel, Mitul; Bahadorani, John] VA San Diego Healthcare Syst, San Diego, CA USA. [Patel, Mitul; Bahadorani, John] Univ Calif San Diego, San Diego, CA 92103 USA. [Lombardi, William L.] Univ Washington, Seattle, WA 98195 USA. [Wyman, Michael R.] Torrance Mem Med Ctr, Torrance, CA USA. [Grantham, J. Aaron] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Doing, Anthony] Med Ctr Rockies, Loveland, CO USA. [Kandzari, David E.; Lembo, Nicholas] Piedmont Heart Inst, Atlanta, GA USA. [Garcia, Santiago] Minneapolis VA Healthcare Syst, Minneapolis, MN USA. [Garcia, Santiago] Univ Minnesota, Minneapolis, MN USA. [Thompson, Craig A.] Boston Sci, Natick, MA USA. RP Brilakis, ES (reprint author), Dallas VA Med Ctr 111A, 4500 South Lancaster Rd, Dallas, TX 75216 USA. EM esbrilakis@gmail.com OI Danek, Barbara/0000-0002-7607-4204; Parikh, Manish/0000-0002-8612-5407 FU Terumo; Boston Scientific; National Heart, Lung, and Blood Institute [1K23HL118138]; National Institutes of Health [HL-R01-108229]; Abbott Vascular; Asahi; Asahi Intecc; Medtronic; Abiomed; St. Jude Medical; Vascular Dynamics; Glaxo SmithKline; Eli Lilly; InfraRedX; Medtronic Cardiovascular; Abbott; Gilead; Medicines Company FX Dr. Alaswad: consulting fees from Terumo and Boston Scientific; consultant, no financial, Abbott Laboratories.; Dr. Yeh: Career Development Award (1K23HL118138) from the National Heart, Lung, and Blood Institute.; Dr. Jaffer: consultant to Boston Scientific, Siemens, and Merck, non-financial research support from Abbott Vascular, research grant from National Institutes of Health (HL-R01-108229).; Dr. Wyman: Honoraria/consulting/speaking fees from Boston Scientific, Abbott Vascular, and Asahi.; Dr. Grantham: Speaking fees, consulting, and honoraria from Boston Scientific, Asahi Intecc. Research grants from Boston Scientific, Asahi Intecc, Abbott Vascular, Medtronic.; Dr. Kirtane: Institutional research grants to Columbia University from Boston Scientific, Medtronic, Abbott Vascular, Abiomed, St. Jude Medical, Vascular Dynamics, Glaxo SmithKline, and Eli Lilly.; Dr. Ali: grant support and is a consultant for St. Jude Medical and InfraRedX.; Dr. Kandzari: research/grant support and consulting honoraria from Boston Scientific. and Medtronic Cardiovascular, and research/grant support from Abbott.; Dr. Garcia: consulting fees from Medtronic.; Dr. Banerjee: research grants from Gilead and the Medicines Company; consultant/speaker honoraria from Covidien and Medtronic; ownership in MDCARE Global (spouse); intellectual property in HygeiaTel.; Dr. Brilakis: consulting/speaker honoraria from Abbott Vascular, Asahi, Boston Scientific, Elsevier, GE Healthcare, St Jude Medical, and Terumo; research support from Boston Scientific and InfraRedx; spouse is employee of Medtronic. NR 34 TC 2 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 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 1 PY 2016 VL 214 BP 429 EP 438 DI 10.1016/j.ijcard.2016.03.215 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL9BG UT WOS:000375935700124 PM 27088405 ER PT J AU Langdon, KJ Farris, SG Hogan, JBD Grover, KW Zvolensky, MJ AF Langdon, Kirsten J. Farris, Samantha G. Hogan, Julianna B. D. Grover, Kristin W. Zvolensky, Michael J. TI Anxiety sensitivity in relation to quit day dropout among adult daily smokers recruited to participate in a self-guided cessation attempt SO ADDICTIVE BEHAVIORS LA English DT Article DE Smoking; Cessation; Quitting; Anxiety sensitivity ID MAJOR DEPRESSIVE DISORDER; SMOKING-CESSATION; DISTRESS TOLERANCE; CIGARETTE-SMOKING; VALIDATION; QUESTIONNAIRE; MOTIVATION; ATTRITION; ETHNICITY; RELAPSE AB Anxiety sensitivity (AS; fear of anxiety and internal sensations) has been implicated in a variety of aspects of smoking, including difficulties achieving and maintaining abstinence during tobacco cessation. However, research has yet to evaluate whether AS impacts premature termination of initiating a quit attempt. Therefore, the aim of the present investigation was to explore the extent to which AS was associated with tobacco cessation dropout, as indexed by attendance on the scheduled quit day visit. Participants included 84 adult daily cigarette smokers (61.7% male; M-age = 34.6 years, SD = 13.9), who were recruited to participate in a self-guided quit attempt (an attempt to quit smoking without professional or pharmacological aid). Results indicated that after controlling for the effects of participant sex, race, current (past month) psychological disorder, cigarettes smoked per day, number of years as a regular smoker, and pre-quit levels of motivation to quit AS significantly predicted increased odds of study dropout prior to attending the scheduled quit day. These findings suggest that AS may be a mechanism involved with challenges in the initiation of quitting. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Langdon, Kirsten J.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, 150 South Huntington Ave,116B-3, Boston, MA 02130 USA. [Langdon, Kirsten J.] Boston Univ, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Farris, Samantha G.; Zvolensky, Michael J.] Univ Houston, 3695 Cullen Blvd, Houston, TX 77204 USA. [Farris, Samantha G.] Brown Univ, Warren Alpert Med Sch, Box G-A1, Providence, RI 02912 USA. [Hogan, Julianna B. D.] Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd,MHCL116, Houston, TX 77030 USA. [Grover, Kristin W.] Univ Vermont, 2 Colchester Ave, Burlington, VT 05405 USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. RP Langdon, KJ (reprint author), VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, 150 South Huntington Ave,116B-3, Boston, MA 02130 USA. EM kirstenjlangdon@gmail.com FU National Institute on Drug Abuse [F31-DA026634, F31-DA035564-02]; National Institute of Mental Health [R01-MH076629-01A1] FX This work was supported by grant F31-DA026634 awarded to Dr. Langdon by the National Institute on Drug Abuse. This work was also supported by grant R01-MH076629-01A1 awarded to Dr. Zvolensky by the National Institute of Mental Health and F31-DA035564-02 awarded to Ms. Farris by the National Institute on Drug Abuse. Please note that the content presented does not necessarily represent the official views of the National Institutes of Health and that the funding sources had no other role other than financial support NR 31 TC 0 Z9 0 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2016 VL 58 BP 12 EP 15 DI 10.1016/j.addbeh.2016.02.017 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DJ6ZD UT WOS:000374360800003 PM 26896560 ER PT J AU Colombo, NH Pereira, JA da Silva, MER Ribas, LFF Parisotto, TM Mattos-Graner, RD Smith, DJ Duque, C AF Colombo, Natalia Helena Pereira, Jesse Augusto Rodrigues da Silva, Marjully Eduardo Fonseca Ribas, Lais Fernanda Parisotto, Thais Manzano Mattos-Graner, Renata de Oliveira Smith, Daniel J. Duque, Cristiane TI Relationship between the IgA antibody response against Streptococcus mutans GbpB and severity of dental caries in childhood SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Early childhood caries; Imunoglobulin A; S. mutans; Glucan binding proteins ID YOUNG-CHILDREN; SOCIAL-FACTORS; IMMUNIZATION; EXPERIENCE; INFECTION; GLUCOSYLTRANSFERASE; COLONIZATION; TRANSMISSION; PREVALENCE; IMMUNITY AB Objective: Explore the associations between the severity of dental caries in childhood, mutans streptococci (MS) levels and IgA antibody response against Streptococcus mutans GbpB. Moreover, other caries-related etiological factors were also investigated. Design: 36-60 month-old children were grouped into Caries-Free (CF, n = 19), Early Childhood Caries (ECC, n = 17) and Severe Early Childhood Caries (S-ECC, n = 21). Data from socio-economic-cultural status, oral hygiene habits and dietary patterns were obtained from a questionnaire and a food-frequency diary filled out by parents. Saliva was collected from children for microbiological analysis and detection of salivary IgA antibody reactive with S. mutans GbpB in western blot. Results: S-ECC children had reduced family income compared to those with ECC and CF. There was difference between CF and caries groups (ECC and S-ECC) in MS counts. Positive correlations between salivary IgA antibody response against GbpB and MS counts were found when the entire population was evaluated. When children with high MS counts were compared, S-ECC group showed significantly lower IgA antibody levels to GbpB compared to CF group. This finding was not observed for the ECC group. Conclusions: This study suggests that children with S-ECC have reduced salivary IgA immune responses to S. mutans GbpB, potentially compromising their ability to modify MS infection and its cariogenic potential. Furthermore, a reduced family income and high levels of MS were also associated with S-ECC. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Colombo, Natalia Helena; Pereira, Jesse Augusto; Rodrigues da Silva, Marjully Eduardo; Fonseca Ribas, Lais Fernanda; Duque, Cristiane] UNESP Univ Estadual Paulista, Aracatuba Dent Sch, Dept Pediat Dent & Publ Hlth, R Jose Bonifacio 1193, BR-16015050 Aracatuba, SP, Brazil. [Parisotto, Thais Manzano] Univ Sao Francisco, Sch Dent, Lab Microbiol & Mol Biol, BR-12900000 Braganca Paulista, SP, Brazil. [Mattos-Graner, Renata de Oliveira] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Oral Diag, Piracicaba, SP, Brazil. [Smith, Daniel J.] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Duque, C (reprint author), UNESP Univ Estadual Paulista, Aracatuba Dent Sch, Dept Pediat Dent & Publ Hlth, R Jose Bonifacio 1193, BR-16015050 Aracatuba, SP, Brazil. EM cristianeduque@yahoo.com.br RI Mattos-Graner, Renata/C-9410-2012 OI Mattos-Graner, Renata/0000-0001-8309-8135 FU Sao Paulo Research Foundation (FAPESP), Sao Paulo, SP, Brazil [2012/19235-5, 2013/12167-7]; Coordination for the Improvement of Higher Education Personnel (CAPES) FX This study was supported by grants (2012/19235-5; 2013/12167-7) from Sao Paulo Research Foundation (FAPESP), Sao Paulo, SP, Brazil and Coordination for the Improvement of Higher Education Personnel (CAPES). NR 32 TC 0 Z9 0 U1 4 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 EI 1879-1506 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD JUL PY 2016 VL 67 BP 22 EP 27 DI 10.1016/j.archoralbio.2016.03.006 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DL3BE UT WOS:000375508400004 PM 27019137 ER PT J AU Indolfi, L Ligorio, M Ting, DT Xega, K Tzafriri, AR Bersani, F Aceto, N Thapar, V Fuchs, BC Deshpande, V Baker, AB Ferrone, CR Haber, DA Langer, R Clark, JW Edelman, ER AF Indolfi, Laura Ligorio, Matteo Ting, David T. Xega, Kristina Tzafriri, Abraham R. Bersani, Francesca Aceto, Nicola Thapar, Vishal Fuchs, Bryan C. Deshpande, Vikram Baker, Aaron B. Ferrone, Cristina R. Haber, Daniel A. Langer, Robert Clark, Jeffrey W. Edelman, Elazer R. TI A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma SO BIOMATERIALS LA English DT Article DE Pancreatic cancer; Chemoresistance; Local delivery; Patient-derived xenograft; Paclitaxel; Poly(lactic-co-glycolic acid) ID PACLITAXEL-INCORPORATED MEMBRANE; MALIGNANT BILIARY OBSTRUCTION; NAB-PACLITAXEL; PLUS GEMCITABINE; TUMOR-CELLS; CANCER; THERAPY; STENT; FOLFIRINOX; DIAGNOSIS AB Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Indolfi, Laura; Langer, Robert; Edelman, Elazer R.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave,Bldg E25-449, Cambridge, MA 02139 USA. [Indolfi, Laura; Ligorio, Matteo; Ting, David T.; Xega, Kristina; Bersani, Francesca; Aceto, Nicola; Thapar, Vishal; Fuchs, Bryan C.; Deshpande, Vikram; Ferrone, Cristina R.; Haber, Daniel A.; Clark, Jeffrey W.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Indolfi, Laura; Ligorio, Matteo; Ting, David T.; Xega, Kristina; Bersani, Francesca; Aceto, Nicola; Thapar, Vishal; Fuchs, Bryan C.; Deshpande, Vikram; Ferrone, Cristina R.; Haber, Daniel A.; Clark, Jeffrey W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Indolfi, Laura; Ligorio, Matteo; Ting, David T.; Xega, Kristina; Bersani, Francesca; Aceto, Nicola; Thapar, Vishal; Fuchs, Bryan C.; Deshpande, Vikram; Ferrone, Cristina R.; Haber, Daniel A.; Clark, Jeffrey W.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ligorio, Matteo] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Tzafriri, Abraham R.] CBSET Inc, Dept Appl Sci, Lexington, MA USA. [Baker, Aaron B.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Langer, Robert] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave,Bldg E25-449, Cambridge, MA 02139 USA. [Edelman, Elazer R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. RP Indolfi, L (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave,Bldg E25-449, Cambridge, MA 02139 USA.; Ting, DT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, 149 13th St,CNY149 6-618B, Charlestown, MA 02129 USA. EM lindolfi@mit.edu; dting1@mgh.harvard.edu RI Haber, Shimon/H-2095-2016; Niren MD, Neil/H-2184-2016; OI Haber, Shimon/0000-0002-6221-6136; Niren MD, Neil/0000-0003-2841-5366; Ting, David/0000-0002-3261-2322 FU Koch Institute for Integrative Cancer Research at MIT; Dana-Farber Harvard Cancer Center (DF/HCC); Burroughs Wellcome Fund; NIH [K12CA087723-11A1, RO1GM49039]; Koch Institute from the National Cancer Institute [P30-CA14051]; Deshpande Center for Technological Innovation at MIT; American-Italian Cancer Foundation FX This work was supported by The Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and Dana-Farber Harvard Cancer Center (DF/HCC) (L.I., M.L., D.T.T., C.R.F., V.D., R.L., J.W.C., E.R.E.), the Burroughs Wellcome Fund (D.T.T.), NIH K12CA087723-11A1 (D.T.T.) and RO1GM49039 (E.R.E.). We thank the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute and the Grant from the Deshpande Center for Technological Innovation at MIT. We also thank the American-Italian Cancer Foundation Fellowship Program for its support. NR 32 TC 0 Z9 0 U1 8 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JUL PY 2016 VL 93 BP 71 EP 82 DI 10.1016/j.biomaterials.2016.03.044 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DL7MT UT WOS:000375825500008 PM 27082874 ER PT J AU Huang, SS Chen, CL Huang, FW Hou, WH Huang, JS AF Huang, Shuan Shian Chen, Chun-Lin Huang, Franklin W. Hou, Wei-Hsien Huang, Jung San TI DMSO Enhances TGF-beta Activity by Recruiting the Type II TGF-beta Receptor From Intracellular Vesicles to the Plasma Membrane SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE TGF-beta ENHANCER; T beta R-II; CYTOPLASMIC VESICLES; NON-LIPID RAFT MICRODOMAINS; CANONICAL SIGNALING ID GROWTH-FACTOR-BETA; DIMETHYL-SULFOXIDE; LIPID RAFTS; TRANSFORMING GROWTH-FACTOR-BETA-1; FUNCTIONAL-CHARACTERIZATION; CELL-DIFFERENTIATION; EPITHELIAL-CELLS; HL-60 CELLS; DIMETHYLSULFOXIDE; RESPONSIVENESS AB Dimethyl sulfoxide (DMSO) is used to treat many diseases/symptoms. The molecular basis of the pharmacological actions of DMSO has been unclear. We hypothesized that DMSO exerts some of these actions by enhancing TGF-beta activity. Here we show that DMSO enhances TGF-beta activity by similar to 3-4-fold in Mv1Lu and NMuMG cells expressing Smad-dependent luciferase reporters. In Mv1Lu cells, DMSO enhances TGF-beta-stimulated expression of P-Smad2 and PAI-1. It increases cell-surface expression of TGF-beta receptors (T beta R-I and/or T beta R-II) by similar to 3-4-fold without altering their cellular levels as determined by I-125-labeled TGF-beta-cross-linking/Western blot analysis, suggesting the presence of large intracellular pools in these cells. Sucrose density gradient ultracentrifugation/Western blot analysis reveals that DMSO induces recruitment of T beta R-II (but not T beta R-I) from its intracellular pool to plasma-membrane microdomains. It induces more recruitment of T beta R-II to non-lipid raft microdomains than to lipid rafts/caveolae. Mv1Lu cells transiently transfected with T beta R-II-HA plasmid were treated with DMSO and analyzed by indirect immunofluoresence staining using anti-HA antibody. In these cells, T beta R-II-HA is present as a vesicle-like network in the cytoplasm as well as in the plasma membrane. DMSO causes depletion of T beta R-II-HA-containing vesicles from the cytoplasm and co-localization of T beta R-II-HA and cveolin-1 at the plasma membrane. These results suggest that DMSO, a fusogenic substance, enhances TGF-beta activity presumably by inducing fusion of cytoplasmic vesicles (containing T beta R-II) and the plasma membrane, resulting in increased localization of T beta R-II to non-lipid raft microdomains where canonical signaling occurs. Fusogenic activity of DMSO may play a pivotal role in its pharmacological actions involving membrane proteins with large cytoplasmic pools. (C) 2015 Wiley Periodicals, Inc. C1 [Huang, Shuan Shian] Auxagen Inc, St Louis, MO 63132 USA. [Chen, Chun-Lin] Natl Sun Yat Sen Univ, Dept Biol Sci, Kaohsiung 804, Taiwan. [Chen, Chun-Lin] Natl Sun Yat Sen Univ, Doctoral Degree Program Marine Biotechnol, Kaohsiung 804, Taiwan. [Chen, Chun-Lin] Acad Sinica, Kaohsiung 804, Taiwan. [Huang, Franklin W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Huang, Franklin W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hou, Wei-Hsien; Huang, Jung San] St Louis Univ, Sch Med, Doisy Res Ctr, Dept Biochem & Mol Biol, Room 413,1100 S Grand Blvd, St Louis, MO 63104 USA. RP Huang, JS (reprint author), St Louis Univ, Sch Med, Doisy Res Ctr, Dept Biochem & Mol Biol, Room 413,1100 S Grand Blvd, St Louis, MO 63104 USA. EM huangjs@slu.edu FU NIH [HL 095261, AR 052578, AA019233]; NSYSU-KMU Joint Research Project [NSYSUKMU104I004]; National Sun Yatsen University FX Grant sponsor: NIH; Grant numbers: HL 095261, AR 052578, AA019233; Grant sponsor: President's Research Fund; Grant sponsor: NSYSU-KMU Joint Research Project; Grant number: NSYSUKMU104I004; Grant sponsor: National Sun Yatsen University (C.L.C). NR 58 TC 0 Z9 0 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUL PY 2016 VL 117 IS 7 BP 1568 EP 1579 DI 10.1002/jcb.25448 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL8UH UT WOS:000375916800009 PM 26587792 ER PT J AU Zhang, WT Zhang, H Mu, HF Zhu, W Jiang, XY Hu, XM Shi, YJ Leak, RK Dong, Q Chen, J Gao, YQ AF Zhang, Wenting Zhang, Hui Mu, Hongfeng Zhu, Wen Jiang, Xiaoyan Hu, Xiaoming Shi, Yejie Leak, Rehana K. Dong, Qiang Chen, Jun Gao, Yanqin TI Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Hypoxia/ischemia; Blood brain barrier; MMP-9; MMP-2; Tight junction ID FOCAL CEREBRAL-ISCHEMIA; RECEPTOR-RELATED PROTEIN-1; INFLAMMATORY RESPONSE; EXPERIMENTAL STROKE; MATRIX-METALLOPROTEINASE-9; CELLS; NEUROPROTECTION; SUPPLEMENTATION; INHIBITION; EXPRESSION AB Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to protect the neonatal brain against hypoxic/ischemic (H/I) injury. However, the mechanism of n-3 PUFA-afforded neuroprotection is not well understood. One major determinant of H/I vulnerability is the permeability of the blood brain barrier (BBB). Therefore, we examined the effects of n-3 PUFAs on BBB integrity after neonatal H/I. Female rats were fed a diet with or without n-3 PUFA enrichment from day 2 of pregnancy to 14 days after parturition. H/I was introduced in 7 day-old offspring. We observed relatively rapid BBB penetration of the small molecule cadaverine (640 Da) at 4 h post-H/I and a delayed penetration of larger dextrans (3 kD-40 kD) 24-48 h after injury. Surprisingly, the neonatal BBB was impermeable to Evans Blue or 70 kD dextran leakage for up to 48 h post-H/I, despite evidence of IgG extravasation at this time. As expected, n-3 PUFAs ameliorated H/I-induced BBB damage, as shown by reductions in tracer efflux and IgG extravasation, preservation of BBB ultrastructure, and enhanced tight junction protein expression. Furthermore, n-3 PUFAs prevented the elevation in matrix metalloproteinase (MMP) activity in the brain and blood after H/I. Thus, n-3 PUFAs may protect neonates against BBB damage by blunting MMPs activation after H/I. Published by Elsevier Inc. C1 [Zhang, Wenting; Zhang, Hui; Mu, Hongfeng; Jiang, Xiaoyan; Hu, Xiaoming; Dong, Qiang; Chen, Jun; Gao, Yanqin] Fudan Univ, Inst Brain Sci, Collaborat Innovat Ctr Brain Sci, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Zhang, Hui; Dong, Qiang] Fudan Univ, Dept Neurol, Huashan Hosp, Shanghai 200032, Peoples R China. [Zhang, Wenting; Zhu, Wen; Jiang, Xiaoyan; Hu, Xiaoming; Shi, Yejie; Chen, Jun; Gao, Yanqin] Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis, Pittsburgh, PA 15213 USA. [Zhang, Wenting; Zhu, Wen; Jiang, Xiaoyan; Hu, Xiaoming; Shi, Yejie; Chen, Jun; Gao, Yanqin] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Leak, Rehana K.] Duquesne Univ, Div Pharmaceut Sci, Mylan Sch Pharm, Pittsburgh, PA 15282 USA. [Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, S507 Biomed Sci Tower,3500 Terrace St, Pittsburgh, PA 15213 USA.; Gao, YQ (reprint author), Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. EM chenj2@upmc.edu; yqgao@shmu.edu.cn RI Gao, Yanqin/I-6790-2016; OI Gao, Yanqin/0000-0002-4915-9819; Shi, Yejie/0000-0001-7502-9201 FU Chinese Natural Science Foundation [81020108021, 81171149, 81371306, 81571285, 81529002, 81100978, 81471332]; Shanghai Committee of Science and Technology Support Program [14431907002]; Young Teacher Program of Fudan University [20520131150]; U.S. NIH [NS095671, NS36736, NS089534, NS45048]; U.S. Department of Veterans Affairs [I01RX000420]; American Heart Association [13SDG14570025, 15POST22260011] FX This project was supported by the Chinese Natural Science Foundation grants 81020108021, 81171149, 81371306, 81571285 (to Dr Gao), 81529002 (to Dr Chen), 81100978 and 81471332 (to Dr Zhang); the Shanghai Committee of Science and Technology Support Program 14431907002 (to Dr Gao); Young Teacher Program of Fudan University 20520131150 (to Dr Zhang); the U.S. NIH grants NS095671, NS36736, NS089534 and NS45048 (to Dr Chen); the U.S. Department of Veterans Affairs Research Career Scientist Award and RR & D Merit Review I01RX000420 (to Dr Chen); and the American Heart Association Scientist Development grant 13SDG14570025 (to Dr Hu) and 15POST22260011 (to Dr. Shi). NR 42 TC 6 Z9 7 U1 5 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUL PY 2016 VL 91 BP 37 EP 46 DI 10.1016/j.nbd.2016.02.020 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DL8IL UT WOS:000375885600004 PM 26921472 ER PT J AU Cao, B Bauer, IE Sharma, AN Mwangi, B Frazier, T Lavagnino, L Zunta-Soares, GB Walss-Bass, C Glahn, DC Kapczinski, F Nielsen, DA Soares, JC AF Cao, Bo Bauer, Isabelle E. Sharma, Ajaykumar N. Mwangi, Benson Frazier, Thomas Lavagnino, Luca Zunta-Soares, Giovana B. Walss-Bass, Consuelo Glahn, David C. Kapczinski, Flavio Nielsen, David A. Soares, Jair C. TI Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder type I; BDNF val66met; Polymorphism; Hippocampus; Volume; Memory; MRI; Bipolar; Major depressive disorder ID NEUROTROPHIC FACTOR GENE; MAGNETIC-RESONANCE IMAGES; FAMILY-BASED ASSOCIATION; TEMPORAL-LOBE STRUCTURES; TERM LITHIUM TREATMENT; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; I DISORDER; COGNITIVE IMPAIRMENT; CORTICAL THICKNESS AB Background: Previous studies investigated the impact of brain-derived neurotrophic factor (BDNF) val66met (rs6265) on hippocampus volumes and neurocognition in bipolar disorders (BD), but the results were not consistent. This study aimed to investigate the effect of BDNF polymorphism on hippo campus volumes and memory performance in well-characterized adult populations diagnosed with type I BD (BD-I) and major depressive disorder (MDD) compared with healthy controls (HC). Methods: 48 BD-I patients, 33 MDD patients and 60 HC were genotyped for BDNF rs6265 using DNA isolated from white blood cells. Individuals with val/met and met/met genotypes were grouped as met carriers and compared to those with the val/val. Brain segmentations were obtained from structural magnetic resonance imaging (MRI) using the Freesurfer. Memory performance was assessed with the California Verbal Learning Task (CVLT). Results: We found a significant diagnosis effect and marginal interaction between diagnosis and BDNF genotype group for both hippocampus volumes and memory performance. BDNF met allele carrier BD patients had smaller hippocampus volumes and reduced performance on multiple CVLT scores compared to MDD patients and HC. Conclusions: We provide strong evidence for the BDNF val66met polymorphism as a putative biological signature for the neuroanatomical and cognitive abnormalities commonly observed in BD patients. (C) 2016 Elsevier B.V. All rights reserved. C1 [Cao, Bo; Bauer, Isabelle E.; Sharma, Ajaykumar N.; Mwangi, Benson; Lavagnino, Luca; Zunta-Soares, Giovana B.; Walss-Bass, Consuelo; Soares, Jair C.] Univ Texas Hlth Sci Ctr Houston, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Frazier, Thomas] Cleveland Clin, Ctr Pediat Behav Hlth, Cleveland, OH 44106 USA. [Frazier, Thomas] Cleveland Clin, Ctr Autism, Cleveland, OH 44106 USA. [Glahn, David C.] Yale Univ, Sch Med, Inst Living, Olin Neuropsychiat Res Ctr, New Haven, CT 06520 USA. [Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Kapczinski, Flavio] Univ Fed Rio Grande do Sul, Dept Psychiat, Rua Ramiro Barcelos 2350, BR-90035903 Rio Grande do Sul, RS, Brazil. [Nielsen, David A.] Baylor Coll Med, Dept Psychiat & Behav Sci, DeBakey VA Med Ctr, Houston, TX 77030 USA. RP Cao, B (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. EM CloudBoCao@gmail.com RI Cao, Bo/D-1983-2017 OI Cao, Bo/0000-0003-3401-6900 FU NIH/NIDA through MD Anderson's Cancer Center Support Grant [5 P50 DA018197-05, NIH/NIDA DA026120]; Toomim Family Fund; NIMH Grant [R01 085667]; Dunn Research Foundation; Pat Rutherford, Jr. Endowed Chair in Psychiatry FX The current work was supported by: NIH/NIDA 5 P50 DA018197-05 (DN), through MD Anderson's Cancer Center Support Grant NIH/NIDA DA026120 (DN), and the Toomim Family Fund (David A. Nielsen), NIMH Grant R01 085667, the Dunn Research Foundation and the Pat Rutherford, Jr. Endowed Chair in Psychiatry (Jair C. Soares). The genetic findings are the result of work supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, TX (David Nielsen). NR 95 TC 2 Z9 2 U1 7 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL 1 PY 2016 VL 198 BP 198 EP 205 DI 10.1016/j.jad.2016.03.044 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DK6TK UT WOS:000375058100028 PM 27018938 ER PT J AU MacNaughton, P Adamkiewicz, G Arku, RE Vallarino, J Levy, DE AF MacNaughton, Piers Adamkiewicz, Gary Arku, Raphael E. Vallarino, Jose Levy, Douglas E. TI The impact of a smoke-free policy on environmental tobacco smoke exposure in public housing developments SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Tobacco smoke exposure; Smoking intervention; Multi-unit housing; Nicotine; Particulate matter ID STATE AB Background: Smoke-free housing policies have the potential to reduce secondhand smoke (SHS) exposures for residents of multi-unit housing. Since common areas represent a pathway of SHS movement between units, smoke-free policies would be expected to reduce SHS in these microenvironments. Methods: Week-long air nicotine and PM2.5 (particulate matter below 2.5 mu m in aerodynamic diameter) samples were collected in the common areas of 10 Boston Housing Authority (BHA) and 6 Cambridge Housing Authority (CHA) buildings from January 2012 to October 2013. We also measured one outdoor PM level at each study building. Samples from BHA included pre and post-smoke-free policy measurements. Each development was visited three times over the course of the study period. The effect of the smoking ban on indoor PM2.5 was examined using generalized mixed effect models to accommodate repeated measurement at each site. Changes in nicotine concentrations were modeled using quantile mixed regression to reduce the impact of outliers. Results: After controlling for season, site, and background PM2.5 concentrations, PM2.5 levels were 4.05 mu g/m(3) (p-value - 0.09) lower in BHA after the smoke-free policy was implemented in the summer of 2012, compared with CHA developments, which had no smoking policy in place. Similarly, nicotine levels decreased by 57% (p-value = 0.08) in Boston relative to Cambridge after the ban. Conclusions: Our findings support the use of smoke-free policies as an effective tool to reduce SHS exposure and protect non-smokers, especially residents of multi-unit housing. (C) 2016 Elsevier B.V. All rights reserved. C1 [MacNaughton, Piers; Adamkiewicz, Gary; Arku, Raphael E.; Vallarino, Jose] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Levy, Douglas E.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Levy, Douglas E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP MacNaughton, P (reprint author), Harvard Univ, Dept Environm Hlth, TH Chan Sch Publ Hlth, Landmark Ctr, Rm 409 West,401 Pk Dr, Boston, MA 02215 USA. EM pom422@mail.harvard.edu FU Flight Attendants Medical Research Institute [YCSA-072044]; National Institute of Health [R01-HL112212, P50-CA148596] FX This work was conducted with support from the Flight Attendants Medical Research Institute (YCSA-072044) and the National Institute of Health (R01-HL112212, P50-CA148596). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. We would like to acknowledge management and facilities at the CHA and BHA developments for their continued assistance over the course of this study. We thank Charles Perrino at the University of California, Berkeley, for preparing and analyzing all passive nicotine monitors. NR 24 TC 1 Z9 1 U1 6 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JUL 1 PY 2016 VL 557 BP 676 EP 680 DI 10.1016/j.scitotenv.2016.03.110 PG 5 WC Environmental Sciences SC Environmental Sciences & Ecology GA DK7VZ UT WOS:000375136200070 PM 27037889 ER PT J AU Briggs, KJ Koivunen, P Cao, SG Backus, KM Olenchock, BA Patel, H Zhang, Q Signoretti, S Gerfen, GJ Richardson, AL Witkiewicz, AK Cravatt, BF Clardy, J Kaelin, WG AF Briggs, Kimberly J. Koivunen, Peppi Cao, Shugeng Backus, Keriann M. Olenchock, Benjamin A. Patel, Hetalben Zhang, Qing Signoretti, Sabina Gerfen, Gary J. Richardson, Andrea L. Witkiewicz, Agnieszka K. Cravatt, Benjamin F. Clardy, Jon Kaelin, William G., Jr. TI Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine SO CELL LA English DT Article ID HYDROXYLASE DOMAIN 2; HYPOXIA-INDUCIBLE FACTORS; THERAPEUTIC TARGET; GLUTATHIONE LEVELS; CYSTINE UPTAKE; CELL-DEATH; METASTASIS; EXPRESSION; RECEPTORS; PATHWAY AB The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIF alpha subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1 alpha in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIF alpha prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1 alpha accumulation. Therefore, EglN1 senses both oxygen and cysteine. C1 [Briggs, Kimberly J.; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Briggs, Kimberly J.; Kaelin, William G., Jr.] Brigham & Womens Hosp, Boston, MA 02215 USA. [Koivunen, Peppi] Univ Oulu, Oulu Ctr Cell Matrix Res, Fac Biochem & Mol Med, Bioctr Oulu, FIN-90014 Oulu, Finland. [Cao, Shugeng; Clardy, Jon] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Backus, Keriann M.; Cravatt, Benjamin F.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Olenchock, Benjamin A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Patel, Hetalben; Gerfen, Gary J.] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. [Zhang, Qing] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Signoretti, Sabina; Richardson, Andrea L.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Witkiewicz, Agnieszka K.] Univ Texas Southwestern Med Ctr, Dept Pathol, Dallas, TX 75235 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Cao, Shugeng] Univ Hawaii, Daniel K Inouye Coll Pharm, Dept Pharmaceut Sci, Hilo, HI 96720 USA. [Richardson, Andrea L.] Johns Hopkins Med, Dept Pathol, 600 N Wolfe St, Baltimore, MD 21287 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Kaelin, WG (reprint author), Brigham & Womens Hosp, Boston, MA 02215 USA.; Kaelin, WG (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM william_kaelin@dfci.harvard.edu FU NIH; Breast Cancer Research Foundation FX We thank members of the Kaelin Laboratory for useful discussions, Gang Lu for multiple reagents and cloning advice, Jason Marineau for fractionation advice and reagents, Julie Losman for her FACS expertise, Amanda Silva for performing gavage, and Humayun Sharif and Michael Eck for generating Figure 6I. This work was supported by grants to W.G.K. from the NIH and the Breast Cancer Research Foundation and T32 and F32 NIH training grants to K.J.B. W.G.K. is an HHMI Investigator. NR 50 TC 5 Z9 5 U1 12 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 30 PY 2016 VL 166 IS 1 BP 126 EP 139 DI 10.1016/j.cell.2016.05.042 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DR9ZH UT WOS:000380254400016 PM 27368101 ER PT J AU Yassine, HN Rawat, V Mack, WJ Quinn, JF Yurko-Mauro, K Bailey-Hall, E Aisen, PS Chui, HC Schneider, LS AF Yassine, Hussein N. Rawat, Varun Mack, Wendy J. Quinn, Joseph F. Yurko-Mauro, Karin Bailey-Hall, Eileen Aisen, Paul S. Chui, Helena C. Schneider, Lon S. TI The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease SO ALZHEIMERS RESEARCH & THERAPY LA English DT Article DE APOE; Alzheimer's disease; Cerebrospinal fluid; Amyloid ID POLYUNSATURATED FATTY-ACIDS; MILD COGNITIVE IMPAIRMENT; APOLIPOPROTEIN-E GENOTYPE; DOCOSAHEXAENOIC ACID; PHOSPHOLIPASE A(2); FISH-OIL; BRAIN; TRIAL; CONSUMPTION; METABOLISM AB Background: Apolipoprotein E (APOE) epsilon 4 and low cerebrospinal fluid (CSF) amyloid-beta 42 (A beta 42) levels are predictors for developing Alzheimer's disease (AD). The results of several studies indicate an interaction between docosahexaenoic acid (DHA) consumption and cognitive outcomes by APOE genotype. Our objective in the present study was to examine whether APOE epsilon 4 genotype and low CSF A beta 42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial. Methods: Phospholipid DHA was assayed in the plasma of 384 participants and CSF of 70 participants at baseline. Forty-four of the 70 participants completed the 18-month follow-up visit after allocation to placebo (n = 15) or DHA (n = 29). Plasma and CSF DHA levels, CSF A beta 42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline A beta 42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated. Results: At baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF A beta 42 tertiles or epsilon 4 status. After 18 months of DHA supplementation, participants at the lowest A beta 42 tertile had significantly lower CSF DHA levels (p = 0.01) and lower CSF-to-plasma DHA ratios (p = 0.05) compared to the other tertiles. Baseline CSF A beta 42 levels were significantly lower in epsilon 4 carriers than in epsilon 4 noncarriers (p = 0.01). Participants carrying the epsilon 4 allele (n=25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), with a possible interaction effect between treatment and APOE genotype (p=0.07). Conclusions: APOE epsilon 4 allele and lower CSF A beta 42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD. C1 [Yassine, Hussein N.; Rawat, Varun] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Mack, Wendy J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Quinn, Joseph F.] Portland VA Med Ctr, Portland, OR USA. [Yurko-Mauro, Karin; Bailey-Hall, Eileen] DSM Nutr Prod, Dept Clin Res, Columbia, MD USA. [Aisen, Paul S.] Univ So Calif, Keck Sch Med, Alzheimers Therapeut Res Inst, Los Angeles, CA 90033 USA. [Chui, Helena C.; Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. RP Yassine, HN (reprint author), Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. EM hyassine@usc.edu FU National Heart, Lung, and Blood Institute [K23HL107389]; Alzheimer's Association [NIRG-15-361854]; National Institute of Aging [P50-AG05142-31]; National Institute on Aging [U01 AG10483] FX HNY was supported by grant K23HL107389 from National Heart, Lung, and Blood Institute and grant NIRG-15-361854 from the Alzheimer's Association. ADRC project P50-AG05142-31 (to HCC) from the National Institute of Aging supported this project. This study was supported by grant U01 AG10483 from the National Institute on Aging. The placebo and DHA study drugs were provided by DSM. DSM also provided plasma and cerebrospinal fluid measurements of fatty acids. NR 45 TC 4 Z9 4 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD JUN 30 PY 2016 VL 8 AR 25 DI 10.1186/s13195-016-0194-x PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DQ1YP UT WOS:000378997400001 PM 27358067 ER PT J AU de Jong, M Lazar, SW Hug, K Mehling, WE Holzel, BK Sack, AT Peeters, F Ashih, H Mischoulon, D Gard, T AF de Jong, Marasha Lazar, Sara W. Hug, Kiran Mehling, Wolf E. Hoelzel, Britta K. Sack, Alexander T. Peeters, Frenk Ashih, Heidi Mischoulon, David Gard, Tim TI Effects of Mindfulness-Based Cognitive Therapy on Body Awareness in Patients with Chronic Pain and Comorbid Depression SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE mindfulness-based cognitive therapy; mindfulness meditation; interoceptive awareness; body awareness; pain catastrophizing; chronic pain; depression; mediation ID RANDOMIZED CONTROLLED-TRIAL; CHRONIC NONCANCER PAIN; REPORT QIDS-SR; LOW-BACK-PAIN; INTEROCEPTIVE SENSITIVITY; PSYCHOMETRIC EVALUATION; EXPERIENTIAL AVOIDANCE; MAJOR DEPRESSION; QUICK INVENTORY; SELF-REGULATION AB Body awareness has been proposed as one of the major mechanisms of mindfulness interventions, and it has been shown that chronic pain and depression are associated with decreased levels of body awareness. We investigated the effect of Mindfulness-Based Cognitive Therapy (MBCT) on body awareness in patients with chronic pain and comorbid active depression compared to treatment as usual (TAU. N = 31). Body awareness was measured by a subset of the Multidimensional Assessment of Interoceptive Awareness (MAIA) scales deemed most relevant for the population. These included: Noticing, Not-Distracting, Attention Regulation, Emotional Awareness, and Self-Regulation. In addition, pain catastrophizing was measured by the Pain Catastrophizing Scale (PCS). These scales had adequate to high internal consistency in the current sample. Depression severity was measured by the Quick Inventory of Depressive Symptomatology Clinician rated (QIDS-C-16). Increases in the MBCT group were significantly greater than in the TAU group on the "Self-Regulation" and "Not Distracting" scales. Furthermore, the positive effect of MBCT on depression severity was mediated by "Not Distracting." These findings provide preliminary evidence that a mindfulness-based intervention may increase facets of body awareness as assessed with the MAIA in a population of pain patients with depression. Furthermore, they are consistent with a long hypothesized mechanism for mindfulness and emphasize the clinical relevance of body awareness. C1 [de Jong, Marasha; Ashih, Heidi; Mischoulon, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [de Jong, Marasha; Peeters, Frenk] Maastricht Univ, Dept Psychiat & Psychol, Sch Mental Hlth & Neurosci, Med Ctr, NL-6200 MD Maastricht, Netherlands. [de Jong, Marasha] Mondriaan, Maastricht, Netherlands. [Lazar, Sara W.; Hoelzel, Britta K.; Gard, Tim] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hug, Kiran] Univ Freiburg, Fac Med, Med Ctr, Dept Psychosomat Med, Hugstetter Str 55, D-79106 Freiburg, Germany. [Hug, Kiran] Univ Basel, Fac Psychol, Div Clin Psychol & Psychotherapy, Basel, Switzerland. [Mehling, Wolf E.] Univ Calif San Francisco, Dept Family & Community Med, Osher Ctr Integrat Med, San Francisco, CA 94143 USA. [Hoelzel, Britta K.] Tech Univ Munich, Klinikum Rechts Isar, Dept Neuroradiol, D-80290 Munich, Germany. [Sack, Alexander T.] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, NL-6200 MD Maastricht, Netherlands. [Gard, Tim] Univ Zurich, Univ Zurich Hosp, Inst Complementary & Integrat Med, Zurich, Switzerland. [Gard, Tim] Univ Zurich, Inst Biomed Engn, Translat Neuromodeling Unit, Zurich, Switzerland. [Gard, Tim] Swiss Fed Inst Technol, Zurich, Switzerland. RP Gard, T (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA.; Gard, T (reprint author), Univ Zurich, Univ Zurich Hosp, Inst Complementary & Integrat Med, Zurich, Switzerland.; Gard, T (reprint author), Univ Zurich, Inst Biomed Engn, Translat Neuromodeling Unit, Zurich, Switzerland.; Gard, T (reprint author), Swiss Fed Inst Technol, Zurich, Switzerland. EM tgard@mgh.harvard.edu RI Lazar, Sara/G-3809-2012 OI Lazar, Sara/0000-0003-1126-8363 FU Mind and Life Francisco J. Varela [2010-01-010] FX This study was funded by an anonymous bequest to the DCRP, and the Mind and Life Francisco J. Varela (Grant 2010-01-010) to TG. We would like to thank Narayan Brach for his help with Red Cap, Jim Doorley, Rosemary Walker, and Thomas Calahan for logistics, Laurie Rhoades for teaching the MBCT program, Ronald Kulich, Karsten Kueppenbender, and Egilius Spiering for patient recruitment and Lee Baer, and Alisabet J. Clain, for assistance with data base conversion and general statistical questions, and Elizabeth Hoge, Willoughby Britton, Jonathan Alpert, and Maurizio Fava for advice. We also would like to thank all participants for their efforts. NR 82 TC 1 Z9 1 U1 19 U2 25 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUN 30 PY 2016 VL 7 AR 967 DI 10.3389/fpsyg.2016.00967 PG 13 WC Psychology, Multidisciplinary SC Psychology GA DP8ZE UT WOS:000378785700001 PM 27445929 ER PT J AU Kho, AT Sharma, S Davis, JS Spina, J Howard, D McEnroy, K Moore, K Sylvia, J Qiu, WL Weiss, ST Tantisira, KG AF Kho, Alvin T. Sharma, Sunita Davis, Joshua S. Spina, Joseph Howard, Dagnie McEnroy, Kevin Moore, Kip Sylvia, Jody Qiu, Weiliang Weiss, Scott T. Tantisira, Kelan G. TI Circulating MicroRNAs: Association with Lung Function in Asthma SO PLOS ONE LA English DT Article ID AIRWAY SMOOTH-MUSCLE; ALVEOLAR EPITHELIAL-CELLS; MANAGEMENT PROGRAM CAMP; DISEASE PROGRESSION; STORAGE-CONDITIONS; ALLERGIC RHINITIS; UP-REGULATION; T-CELLS; EXPRESSION; PATHWAY AB Background MicroRNAs are key transcriptional and network regulators previously associated with asthma susceptibility. However, their role in relation to asthma severity has not been delineated. Objective We hypothesized that circulating microRNAs could serve as biomarkers of changes in lung function in asthma patients. Methods We isolated microRNAs from serum samples obtained at randomization for 160 participants of the Childhood Asthma Management Program. Using a TaqMan microRNA array containing 754 microRNA primers, we tested for the presence of known asthma microRNAs, and assessed the association of the individual microRNAs with lung function as measured by FEV1/FVC, FEV1% and FVC%. We further tested the subset of FEV1/FVC microRNAs for sex-specific and lung developmental associations. Results Of the 108 well-detected circulating microRNAs, 74 (68.5%) had previously been linked to asthma susceptibility. We found 22 (20.3%), 4 (3.7%) and 8 (7.4%) microRNAs to be associated with FEV1/FVC, FEV1% and FVC%, respectively. 8 (of 22) FEV1/FVC, 3 (of 4) FEV1% and 1 (of 8) FVC% microRNAs had functionally validated target genes that have been linked via genome wide association studies to asthma and FEV1 change. Among the 22 FEV1/FVC microRNAs, 9 (40.9%) remain associated with FEV1/FVC in boys alone in a sex-stratified analysis (compared with 3 FEV1/FVC microRNAs in girls alone), 7 (31.8%) were associated with fetal lung development, and 3 (13.6%) in both. Ontology analyses revealed enrichment for pathways integral to asthma, including PPAR signaling, G-protein coupled signaling, actin and myosin binding, and respiratory system development. Conclusions Circulating microRNAs reflect asthma biology and are associated with lung function differences in asthmatics. They may represent biomarkers of asthma severity. C1 [Kho, Alvin T.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA 02115 USA. [Kho, Alvin T.; Davis, Joshua S.; Spina, Joseph; McEnroy, Kevin; Moore, Kip; Sylvia, Jody; Qiu, Weiliang; Weiss, Scott T.; Tantisira, Kelan G.] Harvard Med Sch, Boston, MA 02115 USA. [Davis, Joshua S.; Spina, Joseph; McEnroy, Kevin; Moore, Kip; Sylvia, Jody; Qiu, Weiliang; Weiss, Scott T.; Tantisira, Kelan G.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Tantisira, Kelan G.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Davis, Joshua S.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02115 USA. [Howard, Dagnie] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Weiss, Scott T.] Partners HealthCare Syst, Partners Personalized Med, Boston, MA 02115 USA. [Sharma, Sunita] Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. RP Tantisira, KG (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Tantisira, KG (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA.; Tantisira, KG (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. EM kelan.tantisira@channing.harvard.edu FU National Institutes of Health grants [R01 HL127332, R01 HL129935, U01 HL65899, R01 HL092197, R01 NR013391, K25 HL091124, T32 HL007427] FX This work is supported by the National Institutes of Health grants R01 HL127332, R01 HL129935, U01 HL65899, R01 HL092197, R01 NR013391, K25 HL091124 (ATK) and T32 HL007427 (JSD).; This work is supported by the NIH grants R01 HL127332, R01 HL129935, U01 HL65899, R01 HL092197, R01 NR013391, K25 HL091124 (ATK) and T32 HL007427 (JSD). This manuscript is subject to the NIH public access policy. NR 82 TC 0 Z9 0 U1 5 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 30 PY 2016 VL 11 IS 6 AR e0157998 DI 10.1371/journal.pone.0157998 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0CH UT WOS:000378865200034 PM 27362794 ER PT J AU Oe, M Schumacher, S Schnyder, U Mueller-Pfeiffer, C Wilhelm, FH Kuelen, E Martin-Soelch, C AF Oe, Misari Schumacher, Sonja Schnyder, Ulrich Mueller-Pfeiffer, Christoph Wilhelm, Frank H. Kuelen, Eveline Martin-Soelch, Chantal TI Discriminative evaluative conditioning in the long-term after severe accidental injury SO PSYCHIATRY RESEARCH LA English DT Article DE Discriminative conditioning; Evaluative conditioning; Trauma; Psychophysiology; Posttraumatic stress disorder (PTSD); Learning ID POSTTRAUMATIC-STRESS-DISORDER; IMPAIRED FEAR INHIBITION; ADMINISTERED PTSD SCALE; CONTINGENCY AWARENESS; POTENTIATED STARTLE; REACTION-TIME; DSM-IV; EXTINCTION; RESPONSES; DISGUST AB Impairments in classical fear conditioning and deficits in discriminative learning are observed in post traumatic stress disorder (PTSD). However, it is unknown whether similar impairments can be found with types of discriminative learning other than classical conditioning, such as evaluative conditioning (EC), in which the valence of a stimulus can be transferred to other stimuli. In this study, we investigated whether EC is also influenced by traumatic experiences independently of presence of PTSD. We tested 14 accident survivors with remitted PTSD, 14 survivors without PTSD, and 16 non-trauma controls. We used behavioral measures, psychophysiological indicators, and subjective ratings for tasks. General effects of learning were observed across groups and conditioning/extinction. Trauma controls had slower reaction times (RTs) to the aversive conditioned stimulus compared to appetitive conditioned and neutral stimuli, as well as slower RTs and increased accuracy during conditioning than during extinction. Remitted PTSD participants showed opposite results, demonstrating decreased accuracy and slower RTs during conditioning as compared to during extinction. No discriminative effect was found in the non-trauma controls and the remitted PTSD participants. These results suggest that a traumatic experience influences EC, and that this influence differs between individuals who have and have not developed PTSD after traumatic exposure. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Oe, Misari] Kurume Univ, Sch Med, Dept Neuropsychiat, Asahi Machi 67, Kurume, Fukuoka 8300011, Japan. [Schumacher, Sonja; Schnyder, Ulrich; Mueller-Pfeiffer, Christoph] Univ Zurich, Univ Zurich Hosp, Dept Psychiat & Psychotherapy, CH-8006 Zurich, Switzerland. [Mueller-Pfeiffer, Christoph] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Wilhelm, Frank H.] Salzburg Univ, Dept Psychol, Div Clin Psychol Psychotherapy & Hlth Psychol, A-5020 Salzburg, Austria. [Kuelen, Eveline] Cantonal Hosp Tessin, Dept Internal Med, Bellinzona, Switzerland. [Martin-Soelch, Chantal] Univ Fribourg, Dept Psychol, Div Clin & Hlth Psychol, CH-1700 Fribourg, Switzerland. RP Oe, M (reprint author), Kurume Univ, Sch Med, Dept Neuropsychiat, Asahi Machi 67, Kurume, Fukuoka 8300011, Japan. EM oe_misari@kurume-u.ac.jp FU Department of Psychiatry and Psychotherapy at the University Hospital Zurich FX This study was supported by the Department of Psychiatry and Psychotherapy at the University Hospital Zurich. NR 53 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUN 30 PY 2016 VL 240 BP 144 EP 150 DI 10.1016/jpsychres.2016.04.022 PG 7 WC Psychiatry SC Psychiatry GA DP2YM UT WOS:000378359500022 PM 27107667 ER PT J AU Tsai, J Pietrzak, RH Hoff, RA Harpaz-Rotem, I AF Tsai, Jack Pietrzak, Robert H. Hoff, Rani A. Harpaz-Rotem, Ilan TI Accuracy of screening for posttraumatic stress disorder in specialty mental health clinics in the U.S. Veterans Affairs Healthcare System SO PSYCHIATRY RESEARCH LA English DT Article DE Trauma; Posttraumatic stress disorder; Epidemiology; Assessment/diagnosis; Health services ID QUALITY-OF-LIFE; PTSD CHECKLIST; AFGHANISTAN VETERANS; PSYCHOMETRIC PROPERTIES; FEMALE VETERANS; RISK-FACTORS; IRAQ; BARRIERS; COMBAT; PREVALENCE AB This study 1) describes the prevalence of positive PTSD screens among male, female, and OEF/OIF/OND veterans using various PTSD Checklist -Military version (PCL-M) criteria; 2) evaluates the sensitivity and specificity of various PCL-M criteria; and 3) identifies optimal screening criteria in predicting clinician documented PTSD diagnoses. VA electronic medical records data from 327,093 veterans during 20082012 were analyzed. Receiver operating characteristic curve analyses compared PCL-M scores against clinician-documented PTSD diagnoses. Results showed that different PCL-M scoring criteria resulted in 62.0-84.5% of veterans screening positive for PTSD compared to 40.1% with a clinician-documented PTSD diagnosis. Sensitivity of the PCL-M ranged from 73.7 to 93.5% and specificity ranged from 21.6 to 45.8% for all veterans. The optimal PCL-M cut score according to Youden's index was >= 45 for male veterans, >= 35 for female veterans, and >= 38 for OEF/OIF/OND veterans. Self-report measures like the PCL-M may be a useful screening tool for identifying probable PTSD in VA specialty clinics, but they should be calibrated for different veteran subgroups and followed by structured clinical interviews. Published by Elsevier Ireland Ltd. C1 [Tsai, Jack] US Dept Vet Affairs, New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. [Tsai, Jack; Pietrzak, Robert H.; Hoff, Rani A.; Harpaz-Rotem, Ilan] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Pietrzak, Robert H.; Hoff, Rani A.; Harpaz-Rotem, Ilan] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, West Haven, CT USA. [Hoff, Rani A.; Harpaz-Rotem, Ilan] Vet Affairs Northeast Program Evaluat Ctr, West Haven, CT USA. RP Tsai, J (reprint author), 950 Campbell Ave,151D, West Haven, CT 06516 USA. EM Jack.Tsai@yale.edu NR 38 TC 0 Z9 0 U1 3 U2 3 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 2016 VL 240 BP 157 EP 162 DI 10.1016/j.psychres.2016.04.036 PG 6 WC Psychiatry SC Psychiatry GA DP2YM UT WOS:000378359500024 PM 27107669 ER PT J AU Norton, DJ McBain, RK Pizzagalli, DA Cronin-Golom, A Chen, Y AF Norton, Daniel J. McBain, Ryan K. Pizzagalli, Diego A. Cronin-Golom, Alice Chen, Yue TI Dysregulation of visual motion inhibition in major depression SO PSYCHIATRY RESEARCH LA English DT Article DE Cognitive; Neuroscience; Motion; Vision; Center surround; Depression; Psychophysics; Mood ID AMINOBUTYRIC-ACID CONCENTRATIONS; CENTER-SURROUND INTERACTIONS; RECEPTIVE-FIELDS; OCCIPITAL CORTEX; DIRECTION SELECTIVITY; GABA CONCENTRATIONS; MEDICATION-FREE; STRIATE CORTEX; AREA; SCHIZOPHRENIA AB Individuals with depression show depleted concentrations of the inhibitory neurotransmitter GABA in occipital (visual) cortex, predicting weakened inhibition within their visual systems. Yet, visual inhibition in depression remains largely unexplored. To fill this gap, we examined the inhibitory process of center surround suppression (CSS) of visual motion in depressed individuals. Perceptual performance in discriminating the direction of motion was measured as a function of stimulus presentation time and contrast in depressed individuals (n=27) and controls (n=22). CSS was operationalized as the accuracy difference between conditions using large (7.5 degrees) and small (1.5 degrees) grating stimuli. Both depressed and control participants displayed the expected advantage in accuracy for small stimuli at high contrast. A significant interaction emerged between subject group, contrast level and presentation time, indicating that alterations of CSS in depression were modulated by stimulus conditions. At high contrast, depressed individuals showed significantly greater CSS than controls at the 66 ms presentation time (where the effect peaked in both groups). The results' specificity and dependence on stimulus features such as contrast, size and presentation time suggest that they arise from changes in early visual processing, and are not the results of a generalized deficit or cognitive bias. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Norton, Daniel J.; Cronin-Golom, Alice] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Norton, Daniel J.; Pizzagalli, Diego A.; Chen, Yue] Harvard Univ, McLean Hosp, Sch Med, Belmont, MA USA. [Norton, Daniel J.; Pizzagalli, Diego A.; Chen, Yue] Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. [Norton, Daniel J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McBain, Ryan K.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, 665 Huntington Ave, Boston, MA 02115 USA. RP Norton, DJ (reprint author), 149 13th St,10th Floor, Charlestown, MA 02129 USA. EM danieljnorton@gmail.com FU Rossano family; McLean Hospital; NRSA Grant [F31 NS074682]; NIH research Grant [R01 MH 096793] FX Funding from the Rossano family and McLean Hospital, as well as an NRSA Grant (F31 NS074682) to DJN and an NIH research Grant (R01 MH 096793) to YC are gratefully acknowledged. We thank Matthew Dibiase, Catherine Munro, Nasya Smith, Karla Sordia Lozano, and Tor Ekstrom for their help with this study. NR 42 TC 0 Z9 0 U1 1 U2 2 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 2016 VL 240 BP 214 EP 221 DI 10.1016/j.psychres.2016.04.028 PG 8 WC Psychiatry SC Psychiatry GA DP2YM UT WOS:000378359500033 PM 27111216 ER PT J AU Wisco, BE Miller, MW Wolf, EJ Kilpatrick, D Resnick, HS Badour, CL Marx, BP Keane, TM Rosen, RC Friedman, MJ AF Wisco, Blair E. Miller, Mark W. Wolf, Erika J. Kilpatrick, Dean Resnick, Heidi S. Badour, Christal L. Marx, Brian P. Keane, Terence M. Rosen, Raymond C. Friedman, Matthew J. TI The impact of proposed changes to ICD-11 on estimates of PTSD prevalence and comorbidity SO PSYCHIATRY RESEARCH LA English DT Article DE PTSD; Trauma; DSM-5; ICD-11; Diagnosis; Diagnostic criteria ID POSTTRAUMATIC-STRESS-DISORDER; DSM-IV; INTERNATIONAL CLASSIFICATION; MENTAL-DISORDERS; COMPETING MODELS; PANIC DISORDER; CRITERIA; STARTLE; REPLICATION; DIAGNOSIS AB The World Health Organization's posttraumatic stress disorder (PTSD) work group has published a proposal for the forthcoming edition of the International Classification of Diseases (ICD-11) that would yield a very different diagnosis relative to DSM-5. This study examined the impact of the proposed ICD-11 changes on PTSD prevalence relative to the ICD-10 and DSM-5 definitions and also evaluated the extent to which these changes would accomplish the stated aim of reducing the comorbidity associated with PTSD. Diagnostic prevalence estimates were compared using a U.S. national community sample and two U.S. Department of Veterans Affairs clinical samples. The ICD-11 definition yielded prevalence estimates 10-30% lower than DSM-5 and 25% and 50% lower than ICD-10 with no reduction in the prevalence of common comorbidities. Findings suggest that by constraining the diagnosis to a narrower set of symptoms, the proposed ICD-11 criteria set would substantially reduce the number of individuals with the disorder. These findings raise doubt about the extent to which the ICD-11 proposal would achieve the aim of reducing comorbidity associated with PTSD and highlight the public health and policy implications of such a redefinition. Published by Elsevier Ireland Ltd. C1 [Wisco, Blair E.] Univ N Carolina, UNCG Psychol, Dept Psychol, POB 26170, Greensboro, NC 27402 USA. [Miller, Mark W.; Wolf, Erika J.; Marx, Brian P.; Keane, Terence M.] Boston Univ, Sch Med, Dept Psychiat, Natl Ctr PTSD,VA Boston Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. [Kilpatrick, Dean; Resnick, Heidi S.; Badour, Christal L.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 67 President Stress,MSC 861, Charleston, SC 29425 USA. [Rosen, Raymond C.] New England Res Inst, 480 Pleasant St, Watertown, MA 02472 USA. [Friedman, Matthew J.] VA Natl Ctr PTSD, Geisel Sch Med Dartmouth, Natl Ctr PTSD, VA Med Ctr 116D,Dept Psychiat, 215 North Main St, White River Jct, VT 05009 USA. [Friedman, Matthew J.] VA Natl Ctr PTSD, Geisel Sch Med Dartmouth, Natl Ctr PTSD, VA Med Ctr 116D,Dept Pharmacol & Toxicol, 215 North Main St, White River Jct, VT 05009 USA. [Badour, Christal L.] Univ Kentucky, Dept Psychol, 106-B Kastle Hall, Lexington, KY 40506 USA. RP Miller, MW (reprint author), Boston Univ, Sch Med, Dept Psychiat, Natl Ctr PTSD,VA Boston Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. EM bewisco@uncg.edu; Mark.Miller5@va.gov; Erika.Wolf@va.gov; kilpatdg@musc.edu; resnickh@musc.edu; christal.badour@uky.edu; Brian.Marx@va.gov; Teriy.Keane@va.gov; RRosen@neriscience.com; matthew.friedman@va.gov FU American Psychiatric Association DSM grant; U.S. Department of Veterans Affairs; VA Merit Review grant from the National Institute of Mental Health [5I01CX000431, 1R01MH095737-01A1]; VA Clinical Sciences Research and Development Program Career Development Award from the National Institute of Mental Health [1R01MH095737-01A1]; U.S. Department of Defense [W81XWH-12-2-0117-PTSD-IIRA-INT, W81XWH-10-2-0181]; Defense Advanced Research Programs Agency [N66001-11-C-4006]; U.S. Department of Veterans Affairs [591]; APA; APA, the U.S. Department of Veterans Affairs, the U.S. Government FX Data collection was funded by an American Psychiatric Association DSM grant to Dean Kilpatrick and the U.S. Department of Veterans Affairs. Manuscript preparation was supported by a VA Merit Review grant (5I01CX000431) awarded to Mark Miller, a VA Clinical Sciences Research and Development Program Career Development Award to Erika Wolf, funding from the National Institute of Mental Health (1R01MH095737-01A1), U.S. Department of Defense (W81XWH-12-2-0117-PTSD-IIRA-INT), Defense Advanced Research Programs Agency (N66001-11-C-4006) and U.S. Department of Veterans Affairs (Cooperative Studies Program # 591) awarded to Dr. Marx, and funding from the U.S. Department of Defense (W81XWH-10-2-0181) awarded to Drs. Marx and Keane. The authors have no conflicts of interest to report. Drs. Friedman and Kilpatrick served on the Trauma/Stressor-Related and Dissociative Disorders Sub-Work Group of the Anxiety Disorder Work Group of DSM-5. Contents are solely the responsibility of the authors and views expressed do not represent those of the APA, the U.S. Department of Veterans Affairs, the U.S. Government, or other agencies supporting this research. NR 45 TC 0 Z9 0 U1 4 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUN 30 PY 2016 VL 240 BP 226 EP 233 DI 10.1016/j.psychres.2016.04.043 PG 8 WC Psychiatry SC Psychiatry GA DP2YM UT WOS:000378359500035 PM 27124207 ER PT J AU Werner, KB Griffin, MG Galovski, TE AF Werner, Kimberly B. Griffin, Michael G. Galovski, Tara E. TI Objective and subjective measurement of sleep disturbance in female trauma survivors with posttraumatic stress disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Posttraumatic stress disorder; Women; Sleep; Actigraphy ID VIETNAM COMBAT VETERANS; PSYCHIATRIC-DISORDERS; QUALITY INDEX; PTSD; ACTIGRAPHY; COMPLAINTS; INSOMNIA; EXPOSURE; HALLMARK; GENDER AB Sleep disturbance may be the most often endorsed symptom of posttraumatic stress disorder (PTSD). Much of this research is based on subjective reports from trauma survivors; however, objective measures of sleep-related impairment have yielded findings inconsistent with self-report data. More studies investigating subjective and objective assessments concordantly are needed to understand sleep impairment in PTSD. The current study examined PTSD-related sleep disturbance in a female interpersonal violence cohort with full PTSD diagnoses (N=51) assessing subjective (global and daily diary measures) and objective (actigraphy) sleep measures concurrently. PTSD severity was positively associated with global, subjective reports of sleep impairment and insomnia. Subjective measures of sleep (including global sleep impairment, insomnia, and daily sleep diary reports of total sleep time, sleep efficiency, and sleep onset latency) were moderately to strongly correlated. However, no significant correlations between subjective and objective reports of sleep impairment were found in this cohort. Analyses demonstrated an overall elevation in subjectively reported sleep impairment when compared to objective measurement assessed concurrently. Findings demonstrate a lack of agreement between subjective and objective measurements of sleep in a PTSD-positive female cohort, suggesting objective and subjective sleep impairments are distinct sleep parameters that do not necessarily directly co-vary. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Werner, Kimberly B.] Washington Univ, George Warren Brown Sch Social Work, 660 S Euclid Ave,8134, St Louis, MO 63110 USA. [Griffin, Michael G.] Univ Missouri, Dept Psychol, Ctr Trauma Recovery, 8001 Nat Bridge Rd, St Louis, MO 63121 USA. [Galovski, Tara E.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. RP Werner, KB (reprint author), Washington Univ, George Warren Brown Sch Social Work, 660 S Euclid Ave,8134, St Louis, MO 63110 USA. EM KBWerner@wustl.edu FU National Center for Complementary and Alternative Medicine Grant [AT004079]; National Institute on Drug Abuse Grant [DA15035] FX This research was completed at the University of Missouri - Saint Louis and supported by the National Center for Complementary and Alternative Medicine Grant AT004079 awarded to Tara E. Galovski, PhD. This work was also supported by National Institute on Drug Abuse Grant DA15035. NR 43 TC 0 Z9 0 U1 4 U2 6 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 2016 VL 240 BP 234 EP 240 DI 10.1016/j.psychres.2016.04.039 PG 7 WC Psychiatry SC Psychiatry GA DP2YM UT WOS:000378359500036 PM 27124208 ER PT J AU Valenza, G Greco, A Citi, L Bianchi, M Barbieri, R Scilingo, EP AF Valenza, G. Greco, A. Citi, L. Bianchi, M. Barbieri, R. Scilingo, E. P. TI Inhomogeneous Point-Processes to Instantaneously Assess Affective Haptic Perception through Heartbeat Dynamics Information SO SCIENTIFIC REPORTS LA English DT Article ID MULTISCALE ENTROPY ANALYSIS; RATE-VARIABILITY; TOUCH MASSAGE; HAIRY SKIN; STATES AB This study proposes the application of a comprehensive signal processing framework, based on inhomogeneous point-process models of heartbeat dynamics, to instantaneously assess affective haptic perception using electrocardiogram-derived information exclusively. The framework relies on inverse-Gaussian point-processes with Laguerre expansion of the nonlinear Wiener-Volterra kernels, accounting for the long-term information given by the past heartbeat events. Up to cubic-order nonlinearities allow for an instantaneous estimation of the dynamic spectrum and bispectrum of the considered cardiovascular dynamics, as well as for instantaneous measures of complexity, through Lyapunov exponents and entropy. Short-term caress-like stimuli were administered for 4.3-25 seconds on the forearms of 32 healthy volunteers (16 females) through a wearable haptic device, by selectively superimposing two levels of force, 2 N and 6 N, and two levels of velocity, 9.4 mm/s and 65 mm/s. Results demonstrated that our instantaneous linear and nonlinear features were able to finely characterize the affective haptic perception, with a recognition accuracy of 69.79% along the force dimension, and 81.25% along the velocity dimension. C1 [Valenza, G.; Barbieri, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab, Boston, MA USA. [Valenza, G.; Greco, A.; Bianchi, M.; Scilingo, E. P.] Univ Pisa, Dept Informat Engn, Pisa, Italy. [Valenza, G.; Greco, A.; Bianchi, M.; Scilingo, E. P.] Univ Pisa, Res Ctr E Piaggio, Pisa, Italy. [Citi, L.] Univ Essex, Sch Comp Sci & Elect Engn, Colchester CO4 3SQ, Essex, England. [Bianchi, M.] Ist Italiano Tecnol, Dept Adv Robot, Via Morego 30, I-16163 Genoa, Italy. RP Valenza, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab, Boston, MA USA.; Valenza, G (reprint author), Univ Pisa, Dept Informat Engn, Pisa, Italy.; Valenza, G (reprint author), Univ Pisa, Res Ctr E Piaggio, Pisa, Italy. EM g.valenza@ieee.org OI Greco, Alberto/0000-0002-4822-5562 FU European Union [601165]; ERC [291166]; European H2020 project "SoftPro: Synergy-based Open-source Foundations and Technologies for Prosthetics and RehabilitatiOn" [688857]; European Commission [689691]; Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital; Harvard Medical School, Boston, MA, USA FX The research leading to these results has received partial funding from the Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA, and European Union Seventh Framework Programme FP7/2007-2013 under Grant No. 601165 of the project "WEARHAP", and, ERC Advanced Grant No. 291166 "Soft- Hands: A Theory of Soft Synergies for a New Generation of Artificial Hands". European H2020 project "SoftPro: Synergy-based Open-source Foundations and Technologies for Prosthetics and RehabilitatiOn" (No. 688857). European Commission-Horizon 2020 Program under Grant 689691 "NEVERMIND" (NEurobehavioural predictiVE and peRsonalised Modelling of depressIve symptoms duriNg primary somatic Diseases with ICT-enabled self-management procedures). NR 40 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 30 PY 2016 VL 6 AR 28567 DI 10.1038/srep28567 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP8XS UT WOS:000378781900001 PM 27357966 ER PT J AU Manchado, E Weissmueller, S Morris, JP Chen, CC Wullenkord, R Lujambio, A de Stanchina, E Poirier, JT Gainor, JF Corcoran, RB Engelman, JA Rudin, CM Rosen, N Lowe, SW AF Manchado, Eusebio Weissmueller, Susann Morris, John P. Chen, Chi-Chao Wullenkord, Ramona Lujambio, Amaia de Stanchina, Elisa Poirier, John T. Gainor, Justin F. Corcoran, Ryan B. Engelman, Jeffrey A. Rudin, Charles M. Rosen, Neal Lowe, Scott W. TI A combinatorial strategy for treating KRAS-mutant lung cancer SO NATURE LA English DT Article ID RECEPTOR TYROSINE KINASE; MEK INHIBITION; MEDIATED REACTIVATION; SELECTIVE INHIBITOR; FEEDBACK ACTIVATION; ACQUIRED-RESISTANCE; COLON-CANCER; RAS; MODELS; POTENT AB Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients' tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer. C1 [Manchado, Eusebio; Weissmueller, Susann; Morris, John P.; Chen, Chi-Chao; Wullenkord, Ramona; Lujambio, Amaia; Lowe, Scott W.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA. [Weissmueller, Susann] Cold Spring Harbor Lab, Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Chen, Chi-Chao] Cornell Univ, Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA. [Lujambio, Amaia] Icahn Sch Med Mt Sinai, Dept Oncol Sci, Liver Canc Program, Tisch Canc Inst, New York, NY 10029 USA. [de Stanchina, Elisa; Poirier, John T.; Rudin, Charles M.; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10065 USA. [Poirier, John T.; Rudin, Charles M.; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Gainor, Justin F.; Corcoran, Ryan B.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Gainor, Justin F.; Corcoran, Ryan B.; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lowe, Scott W.] Howard Hughes Med Inst, New York, NY 10065 USA. RP Lowe, SW (reprint author), Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA.; Rosen, N (reprint author), Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10065 USA.; Rosen, N (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.; Lowe, SW (reprint author), Howard Hughes Med Inst, New York, NY 10065 USA. EM rosenn@mskcc.org; lowes@mskcc.org OI Poirier, John/0000-0001-9795-5644 FU National Cancer Institute; Center of Experimental Therapeutics; Stand Up To Cancer grant from the American Association for Cancer Research; Cancer Center Support grant; Jane Coffin Childs Memorial Fund for Medical Research; National Institutes of Health/National Cancer Institute [K99/R00]; Watson School of Biological Sciences; Bayer Foundation; EMBO Long-Term fellowship; Geoffrey Beene Cancer Research Center FX We thank M. Sanchez-Cespedes, R. Somwar, and H. Varmus for sharing cell lines; S. Tian, J. Ahn, M. Taylor, A. Shroff, and J. Plevy for technical assistance; C. J. Sherr, L. E. Dow, P Lito, T Kastenhuber, and J. Leibold for advice on experimental design and/or for editing the manuscript: and other members of the Lowe laboratory for advice and discussions. This work was supported by a program project grant from the National Cancer Institute (S.W.L.. N.R.). a grant from the Center of Experimental Therapeutics (S.W.L., N.R.), a Stand Up To Cancer grant from the American Association for Cancer Research (N.R., J.A.E., C.R.), and a Cancer Center Support grant to MSKCC. E.M. was supported by The Jane Coffin Childs Memorial Fund for Medical Research and a K99/R00 grant from the National Institutes of Health/National Cancer Institute. S.W. was supported by the Annette Kade Fellowship from the Watson School of Biological Sciences. R.W. was supported by a Carl-Duisberg Fellowship from the Bayer Foundation. A.L. was supported by an EMBO Long-Term fellowship. E.d.S. received support through the Geoffrey Beene Cancer Research Center. S.W.L. is the Geoffrey Beene Chair of Cancer Biology and a Howard Hughes Medical Institute investigator. NR 36 TC 14 Z9 14 U1 18 U2 39 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 30 PY 2016 VL 534 IS 7609 BP 647 EP + DI 10.1038/nature18600 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP7JV UT WOS:000378676000028 PM 27338794 ER PT J AU Han, PD Bloomekatz, J Ren, J Zhang, RL Grinstein, JD Zhao, L Burns, CG Burns, CE Anderson, RM Chi, NC AF Han, Peidong Bloomekatz, Joshua Ren, Jie Zhang, Ruilin Grinstein, Jonathan D. Zhao, Long Burns, C. Geoffrey Burns, Caroline E. Anderson, Ryan M. Chi, Neil C. TI Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis SO NATURE LA English DT Article ID ZEBRAFISH HEART REGENERATION; REVEALS; TRABECULATION; EXPRESSION; DIFFERENTIATION; TRANSGENESIS; PROGENITORS; INHIBITION; MUTATIONS; MIGRATION AB Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart comprises an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease(1) and non-compaction cardiomyopathies(2), it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass. Here we use advanced genetic and imaging tools in zebrafish to reveal an interplay between myocardial Notch and Erbb2 signalling that directs the spatial allocation of myocardial cells to their proper morphological positions in the ventricular wall. Although previous studies have shown that endocardial Notch signalling non-cell-autonomously promotes myocardial trabeculation through Erbb2 and bone morphogenetic protein (BMP) signalling(3), we discover that distinct ventricular cardiomyocyte clusters exhibit myocardial Notch activity that cell-autonomously inhibits Erbb2 signalling and prevents cardiomyocyte sprouting and trabeculation. Myocardial-specific Notch inactivation leads to ventricles of reduced size and increased wall thickness because of excessive trabeculae, whereas widespread myocardial Notch activity results in ventricles of increased size with a single-cell-thick wall but no trabeculae. Notably, this myocardial Notch signalling is activated non-cell-autonomously by neighbouring Erbb2-activated cardiomyocytes that sprout and form nascent trabeculae. Thus, these findings support an interactive cellular feedback process that guides the assembly of cardiomyocytes to morphologically create the ventricular myocardial wall and more broadly provide insight into the cellular dynamics of how diverse cell lineages organize to create form. C1 [Han, Peidong; Bloomekatz, Joshua; Ren, Jie; Zhang, Ruilin; Grinstein, Jonathan D.; Chi, Neil C.] Univ Calif San Diego, Dept Med, Div Cardiol, La Jolla, CA 92093 USA. [Zhao, Long; Burns, C. Geoffrey; Burns, Caroline E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Dept Med, Charlestown, MA 02129 USA. [Zhao, Long; Burns, C. Geoffrey; Burns, Caroline E.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Anderson, Ryan M.] Indiana Univ Sch Med, Ctr Diabet & Metab Dis, Dept Pediat, Indianapolis, IN 46202 USA. [Anderson, Ryan M.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Chi, Neil C.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. RP Chi, NC (reprint author), Univ Calif San Diego, Dept Med, Div Cardiol, La Jolla, CA 92093 USA.; Chi, NC (reprint author), Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. EM nchi@ucsd.edu RI Zhao, Long/A-6439-2014 FU American Heart Association [14POST20380738]; March of Dimes [1-FY14-327]; NIH/NHLBI [5R01HL127067]; National Institutes of Health FX We thank N. Tedeschi for fish care: B. Le for experimental assistance; S. Evans, D. Yelon, and Chi laboratory members for comments on the manuscript; N. Ninov and D. Stainier for plasmids; B. Link for the d2GFP BMP and d2GFP Notch reporter lines: N. Lawson for the eGFP Notch reporter line; B. Appel for the myomrdial Cerulean line; K. Poss for the myocardial CreFR and Brainbow/priZm lines; and W. Talbot for the erbb2 mutant. This work was supported in part by grants from American Heart Association (14POST20380738) to L.Z.; the March of Dimes (1-FY14-327) to RAM.; the NIH/NHLBI (5R01HL127067) to C.G.B. and C.E.B.; and the National Institutes of Health to N.C.C. NR 41 TC 4 Z9 4 U1 9 U2 17 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 30 PY 2016 VL 534 IS 7609 BP 700 EP + DI 10.1038/nature18310 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP7JV UT WOS:000378676000040 PM 27357797 ER PT J AU Kiper, POS Saito, H Gori, F Unger, S Hesse, E Yamana, K Kiviranta, R Solban, N Liu, J Brommage, R Boduroglu, K Bonafe, L Campos-Xavier, B Dikoglu, E Eastell, R Gossiel, F Harshman, K Nishimura, G Girisha, KM Stevenson, BJ Takita, H Rivolta, C Superti-Furga, A Baron, R AF Kiper, Pelin O. Simsek Saito, Hiroaki Gori, Francesca Unger, Sheila Hesse, Eric Yamana, Kei Kiviranta, Riku Solban, Nicolas Liu, Jeff Brommage, Robert Boduroglu, Koray Bonafe, Luisa Campos-Xavier, Belinda Dikoglu, Esra Eastell, Richard Gossiel, Fatma Harshman, Keith Nishimura, Gen Girisha, Katta M. Stevenson, Brian J. Takita, Hiroyuki Rivolta, Carlo Superti-Furga, Andrea Baron, Roland TI Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WNT SIGNALING PATHWAY; MINERAL DENSITY; METAPHYSEAL DYSPLASIA; BMP ANTAGONIST; BETA-CATENIN; WOMEN; OSTEOCLASTOGENESIS; CLASSIFICATION; OSTEOPOROSIS; ASSOCIATION AB BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non-vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle's disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle's disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle's disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. C1 [Kiper, Pelin O. Simsek; Bonafe, Luisa; Campos-Xavier, Belinda; Dikoglu, Esra] Univ Lausanne, Ctr Mol Dis, Lausanne, Switzerland. [Unger, Sheila] Univ Lausanne, Med Genet Serv, Lausanne, Switzerland. [Superti-Furga, Andrea] Univ Lausanne, Dept Pediat, Lausanne, Switzerland. [Harshman, Keith] Univ Lausanne, Univ Lausanne Hosp, Genom Technol Facil, Ctr Integrat Genom, Lausanne, Switzerland. [Rivolta, Carlo] Univ Lausanne, Dept Computat Biol, Unit Med Genet, Lausanne, Switzerland. [Stevenson, Brian J.] Swiss Inst Bioinformat, Lausanne, Switzerland. [Kiper, Pelin O. Simsek; Boduroglu, Koray] Hacettepe Univ, Fac Med, Dept Pediat, Unit Pediat Genet, TR-06100 Ankara, Turkey. [Saito, Hiroaki; Gori, Francesca; Hesse, Eric; Yamana, Kei; Kiviranta, Riku; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Baron, Roland] Harvard Univ, Sch Med, Dept Med, Endocrine Unit,Massachusetts Gen Hosp, 188 Longwood Ave, Boston, MA 02115 USA. [Solban, Nicolas] Acceleron Pharma, Cambridge, MA USA. [Liu, Jeff; Brommage, Robert] Lexicon Pharmaceut, The Woodlands, TX USA. [Eastell, Richard; Gossiel, Fatma] No Gen Hosp, Metab Bone Ctr, Acad Unit Bone Metab, Sheffield S5 7AU, S Yorkshire, England. [Nishimura, Gen] Tokyo Metropolitan Kiyose Childrens Hosp, Dept Radiol & Med Imaging, Kiyose, Japan. [Takita, Hiroyuki] Saga Hosp, Natl Hosp Org, Dept Orthoped, Saga, Japan. [Girisha, Katta M.] Manipal Univ, Kasturba Med Coll, Dept Med Genet, Manipal, India. RP Baron, R (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med, 188 Longwood Ave, Boston, MA 02115 USA.; Superti-Furga, A (reprint author), Lausanne Univ Hosp CHUV, Div Med Genet, CH-1011 Lausanne, Switzerland. EM asuperti@unil.ch; roland_baron@hms.harvard.edu RI Bayram, Cem/D-7403-2013; OI Bayram, Cem/0000-0001-8717-4668; Rivolta, Carlo/0000-0002-0733-9950 FU Swiss National Foundation; National Institutes of Health FX Funded by the Swiss National Foundation and the National Institutes of Health. NR 37 TC 2 Z9 2 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 30 PY 2016 VL 374 IS 26 BP 2553 EP 2562 DI 10.1056/NEJMoa1509342 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DP8DD UT WOS:000378727200007 ER PT J AU Eliott, D Papaliodis, GN Durand, ML Turbett, SE AF Eliott, Dean Papaliodis, George N. Durand, Marlene L. Turbett, Sarah E. TI Case 20-2016: A 50-Year-Old Man with Cloudy Vision, Hearing Loss, and Unsteadiness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 [Eliott, Dean; Papaliodis, George N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Ophthalmol,Massachusetts Eye & Ear Infirm, Boston, MA USA. [Durand, Marlene L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Turbett, Sarah E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Eliott, Dean; Papaliodis, George N.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Durand, Marlene L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Turbett, Sarah E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Eliott, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Ophthalmol,Massachusetts Eye & Ear Infirm, Boston, MA USA. FU Acucela; ThromboGenics; Neurotech; Ocata Therapeutics; Alcon; Alimera; Allergan; Arctic; Avalanche; Bausch Lomb; Biogen; Dutch Ophthalmic; Ophthotech; MacuLogix FX Dr. Eliott reports receiving fees for serving on an advisory board from Acucela, fees for conducting an educational seminar from ThromboGenics, grant support to his institution from Neurotech and Ocata Therapeutics, and consulting fees from Alcon, Alimera, Allergan, Arctic, Avalanche, Bausch & Lomb, Biogen, Dutch Ophthalmic, Ophthotech, MacuLogix, and ThromboGenics. No other potential conflict of interest relevant to this article was reported. NR 4 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 30 PY 2016 VL 374 IS 26 BP 2586 EP 2593 DI 10.1056/NEJMcpc1600611 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DP8DD UT WOS:000378727200012 PM 27355538 ER PT J AU Kim, T Mehta, SL Kaimal, B Lyons, K Dempsey, RJ Vemuganti, R AF Kim, TaeHee Mehta, Suresh L. Kaimal, Balarama Lyons, Kirsten Dempsey, Robert J. Vemuganti, Raghu TI Poststroke Induction of alpha-Synuclein Mediates Ischemic Brain Damage SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; brain; neuroprotection; stroke ID FOCAL CEREBRAL-ISCHEMIA; PARKINSONS-DISEASE; IN-VIVO; POSTTRANSLATIONAL MODIFICATIONS; CSP-ALPHA; RAT MODEL; NEURODEGENERATION; PHOSPHORYLATION; STROKE; OLIGOMERS AB alpha-Synuclein (alpha-Syn), one of the most abundant proteins in the CNS, is known to be a major player in the neurodegeneration observed in Parkinson's disease. We currently report that transient focal ischemia upregulates alpha-Syn protein expression and nuclear translocation in neurons of the adult rodent brain. We further show that knockdown or knock-out of alpha-Syn significantly decreases the infarction and promotes better neurological recovery in rodents subjected to focal ischemia. Furthermore, alpha-Syn knockdown significantly reduced postischemic induction of phospho-Drp1, 3-nitrotyrosine, cleaved caspase-3, and LC-3 II/I, indicating its role in modulating mitochondrial fragmentation, oxidative stress, apoptosis, and autophagy, which are known to mediate poststroke neuronal death. Transient focal ischemia also significantly upregulated serine-129 (S129) phosphorylation (p alpha-Syn) of alpha-Syn and nuclear translocation of p alpha-Syn. Furthermore, knock-out mice that lack PLK2 (the predominant kinase that mediates S129 phosphorylation) showed better functional recovery and smaller infarcts when subjected to transient focal ischemia, indicating a detrimental role of S129 phosphorylation of p alpha-Syn. In conclusion, our studies indicate that alpha-Syn is a potential therapeutic target to minimize poststroke brain damage. C1 [Kim, TaeHee; Mehta, Suresh L.; Kaimal, Balarama; Lyons, Kirsten; Dempsey, Robert J.; Vemuganti, Raghu] Univ Wisconsin, Dept Neurol Surg, 600 Highland Ave, Madison, WI 53792 USA. [Kim, TaeHee; Dempsey, Robert J.; Vemuganti, Raghu] Univ Wisconsin, Neurosci Training Program, Madison, WI 53792 USA. [Vemuganti, Raghu] Univ Wisconsin, Cellular & Mol Pathol Grad Program, Madison, WI 53792 USA. [Dempsey, Robert J.; Vemuganti, Raghu] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Vemuganti, R (reprint author), Univ Wisconsin, Dept Neurol Surg, 600 Highland Ave, Madison, WI 53792 USA. EM vemuganti@neurosurgery.wisc.edu FU U.S. Department of Veterans Affairs Merit Review Grant [I01 BX002985]; American Heart Association [15IRG23050015] FX This work was supported, in part, by the U.S. Department of Veterans Affairs Merit Review Grant (I01 BX002985). TaeHee Kim was supported by a predoctoral fellowship from the American Heart Association (15IRG23050015). We thank Dr. Kunlin Jin for providing the human brain sections. NR 63 TC 5 Z9 5 U1 1 U2 1 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 29 PY 2016 VL 36 IS 26 BP 7055 EP 7065 DI 10.1523/JNEUROSCI.1241-16.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DQ2GJ UT WOS:000379020200019 PM 27358461 ER PT J AU Ostergaard, SD Larsen, JT Dalsgaard, S Wilens, TE Mortensen, PB Agerbo, E Mors, O Petersen, L AF Ostergaard, Soren D. Larsen, Janne T. Dalsgaard, Soren Wilens, Timothy E. Mortensen, Preben B. Agerbo, Esben Mors, Ole Petersen, Liselotte TI Predicting ADHD by Assessment of Rutter's Indicators of Adversity in Infancy SO PLOS ONE LA English DT Article ID 2 GEOGRAPHICAL AREAS; DEFICIT HYPERACTIVITY DISORDER; RISK-FACTORS; INSTITUTIONAL DEPRIVATION; MENTAL-DISORDERS; SYMPTOMS; PREVALENCE; ATTAINMENT; ADJUSTMENT; CHILDREN AB Background Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with early onset. ADHD is associated with significant morbidity and mortality, partly due to delayed diagnosis. Identification of children at high risk for developing ADHD could lead to earlier diagnosis and potentially change the negative trajectory of the illness for the better. Since early psychosocial adversity is considered to be a likely etiological risk factor for ADHD, markers of this construct may be useful for early identification of children at high risk. Therefore, we sought to investigate whether Rutter's indicators of adversity (low social class, severe marital discord, large family size, paternal criminality, maternal mental disorder, and placement in out-of-home care) assessed in infancy could serve as early predictors for the development of ADHD. Methods and Findings Using data from the Danish nationwide population-based registers, we established a cohort consisting of all 994,407 children born in Denmark between January 1st 1993 and December 31st 2011 and extracted dichotomous values for the six Rutter's indicators of adversity at age 0-12 months (infancy) for each cohort member. The cohort members were followed from their second birthday and the association between the sum of Rutter's indicators of adversity (RIA-score) in infancy and subsequent development of ADHD was estimated by means of Cox regression. Also, the number needed to screen (NNS) to detect one case of ADHD based on the RIA-scores in infancy was calculated. During follow-up (9.6 million person-years), 15,857 males and 5,663 females from the cohort developed ADHD. For both males and females, there was a marked dose-response relationship between RIA-scores assessed in infancy and the risk for developing ADHD. The hazard ratios for ADHD were 11.0 (95% CI: 8.2-14.7) and 11.4 (95% CI: 7.1-18.3) respectively, for males and females with RIA-scores of 5-6, compared to males and females with RIA-scores of 0. Among males with RIA-scores of 5-6, 37.6% (95% CI: 27.0-50.7) had been diagnosed with ADHD prior to the age of 20, corresponding to a NNS of 3.0 (95% CI: 2.2-4.0). Conclusions Rutter's indicators of adversity assessed in infancy strongly predicted ADHD. This knowledge may be important for early identification of ADHD. C1 [Ostergaard, Soren D.] Aarhus Univ Hosp, Dept Clin Med, Aarhus, Denmark. [Ostergaard, Soren D.; Mors, Ole] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark. [Ostergaard, Soren D.; Larsen, Janne T.; Dalsgaard, Soren; Mortensen, Preben B.; Agerbo, Esben; Mors, Ole; Petersen, Liselotte] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark. [Larsen, Janne T.; Dalsgaard, Soren; Mortensen, Preben B.; Agerbo, Esben; Petersen, Liselotte] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark. [Wilens, Timothy E.] Harvard Med Sch, Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol, Boston, MA USA. [Wilens, Timothy E.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Mortensen, Preben B.; Agerbo, Esben] Ctr Integrated Register Based Res Aarhus Univ CIR, Aarhus, Denmark. RP Ostergaard, SD (reprint author), Aarhus Univ Hosp, Dept Clin Med, Aarhus, Denmark.; Ostergaard, SD (reprint author), Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark.; Ostergaard, SD (reprint author), Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark. EM soeoes@rm.dk OI Dalsgaard, Soren/0000-0003-4659-0969; Ostergaard, Soren Dinesen/0000-0002-8032-6208 FU Lundbeck Foundation FX The study was supported by grants from the Lundbeck Foundation (http://www.lundbeckfonden.com/). The funders of the study had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 1 Z9 1 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 29 PY 2016 VL 11 IS 6 AR e0157352 DI 10.1371/journal.pone.0157352 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0AM UT WOS:000378859400012 PM 27355346 ER PT J AU Soldevila, F Clemente, P Tajahuerce, E Uribe-Patarroyo, N Andres, P Lancis, J AF Soldevila, F. Clemente, P. Tajahuerce, E. Uribe-Patarroyo, N. Andres, P. Lancis, J. TI Computational imaging with a balanced detector SO SCIENTIFIC REPORTS LA English DT Article ID SCATTERING MEDIA; SINGLE; MICROSCOPY; CAMERA; VIDEO AB Single-pixel cameras allow to obtain images in a wide range of challenging scenarios, including broad regions of the electromagnetic spectrum and through scattering media. However, there still exist several drawbacks that single-pixel architectures must address, such as acquisition speed and imaging in the presence of ambient light. In this work we introduce balanced detection in combination with simultaneous complementary illumination in a single-pixel camera. This approach enables to acquire information even when the power of the parasite signal is higher than the signal itself. Furthermore, this novel detection scheme increases both the frame rate and the signal-to-noise ratio of the system. By means of a fast digital micromirror device together with a low numerical aperture collecting system, we are able to produce a live-feed video with a resolution of 64 x 64 pixels at 5 Hz. With advanced undersampling techniques, such as compressive sensing, we can acquire information at rates of 25 Hz. By using this strategy, we foresee real-time biological imaging with large area detectors in conditions where array sensors are unable to operate properly, such as infrared imaging and dealing with objects embedded in turbid media. C1 [Soldevila, F.; Tajahuerce, E.; Lancis, J.] Univ Jaume 1, INIT, GROC UJI, E-12071 Castellon de La Plana, Spain. [Clemente, P.] Univ Jaume 1, SCIC, E-12071 Castellon de La Plana, Spain. [Uribe-Patarroyo, N.] Harvard Univ, Sch Med, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. [Uribe-Patarroyo, N.] Massachusetts Gen Hosp, 40 Blossom St, Boston, MA 02114 USA. [Andres, P.] Univ Valencia, Fac Fis, E-46100 Burjassot, Spain. RP Soldevila, F (reprint author), Univ Jaume 1, INIT, GROC UJI, E-12071 Castellon de La Plana, Spain. EM fsoldevi@uji.es RI Lancis, Jesus/L-1484-2014 OI Soldevila, Fernando/0000-0002-7776-1276; Lancis, Jesus/0000-0002-7336-6930 FU MINECO [FIS2013-40666-P]; Generalitat Valenciana projects [PROMETEO/2012/021, ISIC/2012/013]; Universitat Jaume I [P1-1B2012-55, PREDOC/2013/32]; National Institutes of Health [P41EB015903] FX This work was supported by MINECO through project FIS2013-40666-P, and Generalitat Valenciana projects PROMETEO/2012/021 and ISIC/2012/013. Also financial support by Universitat Jaume I (project P1-1B2012-55) is acknowledged. F.S. was supported by Universitat Jaume I (PREDOC/2013/32). N.U.-P. acknowledges partial support from the National Institutes of Health (P41EB015903). NR 35 TC 3 Z9 3 U1 9 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 29 PY 2016 VL 6 AR 29181 DI 10.1038/srep29181 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ1FM UT WOS:000378946900001 PM 27353733 ER PT J AU Theoharides, TC Tsilioni, I Patel, AB Doyle, R AF Theoharides, T. C. Tsilioni, I. Patel, A. B. Doyle, R. TI Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID CORTICOTROPIN-RELEASING HORMONE; HUMAN MAST-CELLS; CONTROLLED CLINICAL-TRIAL; ENDOTHELIAL GROWTH-FACTOR; PERINATAL RISK-FACTORS; ELEVATED SERUM-LEVELS; N-ACETYLCYSTEINE; MEDIATOR RELEASE; EARLY-CHILDHOOD; IMMUNE-SYSTEM AB Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1 beta), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kappa B is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGF beta induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD. C1 [Theoharides, T. C.; Tsilioni, I.; Patel, A. B.] Tufts Univ, Sch Med, Dept Integrat Physiol & Pathobiol, Mol Immunopharmacol & Drug Discovery Lab, 136 Harrison Ave,Suite J304, Boston, MA 02111 USA. [Theoharides, T. C.; Patel, A. B.] Tufts Univ, Sackler Sch Grad Biomed Sci, Program Cell Mol & Dev Biol, Boston, MA 02111 USA. [Theoharides, T. C.] Tufts Univ, Sch Med, Dept Internal Med, Boston, MA 02111 USA. [Theoharides, T. C.] Tufts Med Ctr, Boston, MA USA. [Theoharides, T. C.] Tufts Univ, Sch Med, Dept Psychiat, Boston, MA 02111 USA. [Doyle, R.] Harvard Med Sch, Dept Child Psychiat, Massachusetts Gen Hosp, Boston, MA USA. [Doyle, R.] McLean Hosp, Boston, MA USA. RP Theoharides, TC (reprint author), Tufts Univ, Sch Med, Dept Integrat Physiol & Pathobiol, Mol Immunopharmacol & Drug Discovery Lab, 136 Harrison Ave,Suite J304, Boston, MA 02111 USA. EM theoharis.theoharides@tufts.edu FU Autism Research Institute; National Autism Association; Safe Minds; Nancy Lurie Marks Foundation; Jane Botsford Johnson Foundation FX Aspects of our work discussed were funded in part by the Autism Research Institute, the National Autism Association, Safe Minds, the Nancy Lurie Marks Foundation and The Jane Botsford Johnson Foundation. NR 214 TC 3 Z9 3 U1 11 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 28 PY 2016 VL 6 AR e844 DI 10.1038/tp.2016.77 PG 9 WC Psychiatry SC Psychiatry GA DW1QW UT WOS:000383418700001 PM 27351598 ER PT J AU DeJesus, R Moretti, F McAllister, G Wang, ZC Bergman, P Liu, SM Frias, E Alford, J Reece-Hoyes, JS Lindeman, A Kelliher, J Russ, C Knehr, J Carbone, W Beibel, M Roma, G Ng, A Tallarico, JA Porter, JA Xavier, RJ Mickanin, C Murphy, LO Hoffman, GR Nyfeler, B AF DeJesus, Rowena Moretti, Francesca McAllister, Gregory Wang, Zuncai Bergman, Phil Liu, Shanming Frias, Elizabeth Alford, John Reece-Hoyes, John S. Lindeman, Alicia Kelliher, Jennifer Russ, Carsten Knehr, Judith Carbone, Walter Beibel, Martin Roma, Guglielmo Ng, Aylwin Tallarico, John A. Porter, Jeffery A. Xavier, Ramnik J. Mickanin, Craig Murphy, Leon O. Hoffman, Gregory R. Nyfeler, Beat TI Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62 SO ELIFE LA English DT Article ID ESSENTIAL GENES; SELECTIVE AUTOPHAGY; RNAI SCREENS; HUMAN GENOME; HUMAN-CELLS; TARGET; P62/SQSTM1; UFM1; DEFICIENT; SEQUENCES AB SQSTM1 is an adaptor protein that integrates multiple cellular signaling pathways and whose expression is tightly regulated at the transcriptional and post-translational level. Here, we describe a forward genetic screening paradigm exploiting CRISPR-mediated genome editing coupled to a cell selection step by FACS to identify regulators of SQSTM1. Through systematic comparison of pooled libraries, we show that CRISPR is superior to RNAi in identifying known SQSTM1 modulators. A genome-wide CRISPR screen exposed MTOR signalling and the entire macroautophagy machinery as key regulators of SQSTM1 and identified several novel modulators including HNRNPM, SLC39A14, SRRD, PGK1 and the ufmylation cascade. We show that ufmylation regulates SQSTM1 by eliciting a cell type-specific ER stress response which induces SQSTM1 expression and results in its accumulation in the cytosol. This study validates pooled CRISPR screening as a powerful method to map the repertoire of cellular pathways that regulate the fate of an individual target protein. C1 [DeJesus, Rowena; McAllister, Gregory; Wang, Zuncai; Bergman, Phil; Liu, Shanming; Frias, Elizabeth; Alford, John; Reece-Hoyes, John S.; Lindeman, Alicia; Kelliher, Jennifer; Russ, Carsten; Tallarico, John A.; Porter, Jeffery A.; Mickanin, Craig; Murphy, Leon O.; Hoffman, Gregory R.] Novartis Inst BioMed Res, Dev & Mol Pathways, Cambridge, MA 02139 USA. [Moretti, Francesca; Knehr, Judith; Carbone, Walter; Beibel, Martin; Roma, Guglielmo; Nyfeler, Beat] Novartis Inst BioMed Res, Dev & Mol Pathways, Basel, Switzerland. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Med Sch, Gastrointestinal Unit, Boston, MA USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowal Dis, Boston, MA USA. RP Hoffman, GR (reprint author), Novartis Inst BioMed Res, Dev & Mol Pathways, Cambridge, MA 02139 USA.; Nyfeler, B (reprint author), Novartis Inst BioMed Res, Dev & Mol Pathways, Basel, Switzerland. EM hoffman@novartis.com; beat.nyfeler@novartis.com OI Carbone, Walter/0000-0001-6150-8295 FU Novartis; National Institutes of Health [R01DK097485, P30DK043351, U19A1109725] FX Novartis Rowena DeJesus Francesca Moretti Gregory McAllister Zuncai Wang Phil Bergman Shanming Liu Elizabeth Frias John Alford John S Reece-Hoyes Alicia Lindeman Jennifer Kelliher Carsten Russ Judith Knehr Walter Carbone Martin Beibel Guglielmo Roma John A Tallarico Jeffery A Porter Craig Mickanin Leon O Murphy Gregory R Hoffman Beat Nyfeler; National Institutes of Health R01DK097485 Aylwin Ng Ramnik J Xavier; National Institutes of Health P30DK043351 Aylwin Ng Ramnik J Xavier; National Institutes of Health U19A1109725 Ramnik J Xavier NR 45 TC 5 Z9 5 U1 2 U2 7 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 28 PY 2016 VL 5 AR e17290 DI 10.7554/elife.17290 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DR3PY UT WOS:000379816300001 ER PT J AU Miller, MW Sperbeck, E Robinson, ME Sadeh, N Wolf, EJ Hayes, JP Logue, M Schichman, SA Stone, A Milberg, W McGlinchey, R AF Miller, Mark W. Sperbeck, Emily Robinson, Meghan E. Sadeh, Naomi Wolf, Erika J. Hayes, Jasmeet P. Logue, Mark Schichman, Steven A. Stone, Angie Milberg, William McGlinchey, Regina TI 5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE posttraumatic stress disorder; default mode network; functional connectivity; serotonin receptor; HTR1B; HTR2A ID POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSIVE DISORDER; 1A RECEPTOR GENE; TRANSPORTER 5-HTTLPR GENOTYPE; STATE FUNCTIONAL CONNECTIVITY; BIPOLAR DISORDER; COMPREHENSIVE METAANALYSIS; ANTIDEPRESSANT TREATMENT; POSTERIOR CINGULATE; SEROTONIN RECEPTOR AB The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (START; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP x PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD. C1 [Miller, Mark W.; Sadeh, Naomi; Wolf, Erika J.; Hayes, Jasmeet P.; Logue, Mark] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. [Miller, Mark W.; Sperbeck, Emily; Sadeh, Naomi; Wolf, Erika J.; Hayes, Jasmeet P.; Logue, Mark] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Robinson, Meghan E.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA 02130 USA. [Robinson, Meghan E.; Milberg, William; McGlinchey, Regina] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA 02130 USA. [Robinson, Meghan E.; Milberg, William; McGlinchey, Regina] VA Boston Healthcare Syst, Translat Res Ctr TB & Stress Disorders, Boston, MA 02130 USA. [Robinson, Meghan E.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Logue, Mark] Boston Univ, Sch Med, Biomed Genet, Boston, MA 02118 USA. [Logue, Mark] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Schichman, Steven A.; Stone, Angie] Cent Arkansas Vet Healthcare Syst, Res Serv, Pharmacogen Anal Lab, Little Rock, AR USA. [Milberg, William; McGlinchey, Regina] Harvard Med Sch, Dept Psychiat, Boston, MA USA. RP Miller, MW (reprint author), Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. EM mark.miller5@va.gov FU National Institute of Mental Health (NIMH) [R21MH102834]; Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence at VA Boston Healthcare System [B9254-C]; United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program FX This research and preparation of this manuscript was supported by a National Institute of Mental Health (NIMH) grant awarded to MM (R21MH102834, "Neuroimaging Genetics of PTSD") and the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence (B9254-C) at VA Boston Healthcare System. This work was also supported by a Career Development Award to EW from the United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government. NR 75 TC 1 Z9 1 U1 6 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JUN 28 PY 2016 VL 10 AR 299 DI 10.3389/fnins.2016.00299 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DQ7NP UT WOS:000379394700002 PM 27445670 ER PT J AU Lee, SG Huang, MQ Obholzer, ND Sun, S Li, WY Petrillo, M Dai, P Zhou, Y Cotanche, DA Megason, SG Li, HW Chen, ZY AF Lee, Sang Goo Huang, Mingqian Obholzer, Nikolaus D. Sun, Shan Li, Wenyan Petrillo, Marco Dai, Pu Zhou, Yi Cotanche, Douglas A. Megason, Sean G. Li, Huawei Chen, Zheng-Yi TI Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration SO PLOS ONE LA English DT Article ID GROWTH-FACTOR FAMILY; INNER-EAR; LATERAL-LINE; C-MYC; GENE-EXPRESSION; DANIO-RERIO; IN-VIVO; DIFFERENTIAL EXPRESSION; EPITHELIAL TRANSITION; RECEPTOR SPECIFICITY AB Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration. C1 [Lee, Sang Goo; Huang, Mingqian; Sun, Shan; Li, Wenyan; Petrillo, Marco; Chen, Zheng-Yi] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA. [Lee, Sang Goo; Huang, Mingqian; Sun, Shan; Li, Wenyan; Petrillo, Marco; Chen, Zheng-Yi] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Obholzer, Nikolaus D.; Megason, Sean G.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Sun, Shan; Li, Wenyan; Li, Huawei] Fudan Univ, Shanghai Med Coll, Shanghai Eye & ENT Hosp, Dept Otorhinolaryngol, Shanghai 200433, Peoples R China. [Dai, Pu] Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol, Beijing 100853, Peoples R China. [Zhou, Yi] Childrens Hosp Boston, Stem Cell Program, Boston, MA USA. [Zhou, Yi] Childrens Hosp Boston, Div Pediat Hematol Oncol, Boston, MA USA. [Zhou, Yi] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cotanche, Douglas A.] Univ Massachusetts, Sch Med, Cell & Dev Biol, Worcester, MA USA. RP Chen, ZY (reprint author), Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA.; Chen, ZY (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA.; Li, HW (reprint author), Fudan Univ, Shanghai Med Coll, Shanghai Eye & ENT Hosp, Dept Otorhinolaryngol, Shanghai 200433, Peoples R China. EM hwli@shmu.edu.cn; Zheng-Yi_Chen@meei.harvard.edu FU National Institutes of Health [R01 DC06908, DC010791]; Frederick & Ines Yeatts Hair Cell Regeneration Grant; Major State Basic Research Development Program of China (973 Program) [2011cb504506]; National Natural Science Foundation of China [81230019, 81470687, 81400463] FX This work was supported by grants from National Institutes of Health (R01 DC06908 to ZYC and and DC010791 to SGM), The Frederick & Ines Yeatts Hair Cell Regeneration Grant (ZYC), The Major State Basic Research Development Program of China (973 Program) (2011cb504506) and The National Natural Science Foundation of China (nos. 81230019, 81470687, 81400463) (HL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 0 Z9 0 U1 9 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 28 PY 2016 VL 11 IS 6 AR e0157768 DI 10.1371/journal.pone.0157768 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0AH UT WOS:000378858900017 PM 27351484 ER PT J AU Hwang, SY Deng, XM Byun, S Lee, C Lee, SJ Suh, H Zhang, JM Kang, QF Zhang, T Westover, KD Mandinova, A Lee, SW AF Hwang, So-Young Deng, Xianming Byun, Sanguine Lee, Chan Lee, Seung-Joo Suh, Hyunsuk Zhang, Jianming Kang, Qiaofeng Zhang, Ting Westover, Kenneth D. Mandinova, Anna Lee, Sam W. TI Direct Targeting of beta-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/beta-Catenin Signaling SO CELL REPORTS LA English DT Article ID CANCER-CELLS; WNT PATHWAY; FUNCTIONAL INTERACTION; XENOPUS EMBRYOS; HIGH-FREQUENCY; COLON-CANCER; TCF COMPLEX; ACTIVATION; TRANSCRIPTION; INHIBITION AB The Wnt/beta-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of beta-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic beta-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/beta-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl) sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/beta-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to beta-catenin, promoting its degradation, and specifically downregulates Wnt/beta-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/beta-catenin signaling pathway. C1 [Hwang, So-Young; Byun, Sanguine; Lee, Chan; Zhang, Jianming; Mandinova, Anna; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Hwang, So-Young; Byun, Sanguine; Lee, Chan; Zhang, Jianming; Mandinova, Anna; Lee, Sam W.] Harvard Med Sch, Charlestown, MA 02129 USA. [Deng, Xianming; Kang, Qiaofeng; Zhang, Ting] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China. [Lee, Seung-Joo; Suh, Hyunsuk] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dept Biochem & Radiat Oncol, Dallas, TX 75390 USA. [Mandinova, Anna; Lee, Sam W.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Mandinova, A; Lee, SW (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA.; Mandinova, A; Lee, SW (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA.; Mandinova, A; Lee, SW (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM amandinova@mgh.harvard.edu; swlee@mgh.harvard.edu FU Korean Government Research Foundation [KRF-2008-357-E00023]; National Natural Science Foundation of China [81422045, U1405223, 21272195]; CPRIT [RP140233]; National Institutes of Health National Cancer Institute [CA195534, CA80058] FX We thank N. Tolliday and V. Kolev for help with high-throughput screening, B.H. Lee and S. Gondi for help with data analysis, and G. Heffron and W. Massefski from the NMR Facility at Harvard Medical School for NMR studies. S.-Y.H. was supported in part by the Korean Government Research Foundation (grant KRF-2008-357-E00023). X.D. was supported by grants from the National Natural Science Foundation of China (81422045, U1405223, and 21272195). K.D.W. was supported by grant CPRIT RP140233. The research was supported by the National Institutes of Health National Cancer Institute (grants CA195534 and CA80058). NR 40 TC 0 Z9 0 U1 5 U2 9 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 28 PY 2016 VL 16 IS 1 BP 28 EP 36 DI 10.1016/j.celrep.2016.05.071 PG 9 WC Cell Biology SC Cell Biology GA DQ1GY UT WOS:000378950700004 PM 27320923 ER PT J AU McLoed, AG Sherrill, TP Cheng, DS Han, W Saxon, JA Gleaves, LA Wu, PS Polosukhin, VV Karin, M Yull, FE Stathopoulos, GT Georgoulias, V Zaynagetdinov, R Blackwell, TS AF McLoed, Allyson G. Sherrill, Taylor P. Cheng, Dong-Sheng Han, Wei Saxon, Jamie A. Gleaves, Linda A. Wu, Pingsheng Polosukhin, Vasiliy V. Karin, Michael Yull, Fiona E. Stathopoulos, Georgios T. Georgoulias, Vassilis Zaynagetdinov, Rinat Blackwell, Timothy S. TI Neutrophil-Derived IL-1 beta Impairs the Efficacy of NF-kappa B Inhibitors against Lung Cancer SO CELL REPORTS LA English DT Article ID MALIGNANT PLEURAL EFFUSION; IKK-BETA; MOUSE MODEL; ACTIVATION; CARCINOGENESIS; TUMORIGENESIS; INFLAMMATION; CELLS; ADENOCARCINOMA; PROLIFERATION AB Although epithelial NF-kappa B signaling is important for lung carcinogenesis, NF-kappa B inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IK kappa beta in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-kappa B augmented pro-IL-1 beta processing by cathepsin G in neutrophils, leading to increased IL-1 beta and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-kappa B activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1 beta levels correlated with poor prognosis, and IL-1 beta increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1 beta in lung carcinogenesis and resistance to NF-kappa B inhibitors. C1 [McLoed, Allyson G.; Saxon, Jamie A.; Yull, Fiona E.; Blackwell, Timothy S.] Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37232 USA. [Sherrill, Taylor P.; Cheng, Dong-Sheng; Han, Wei; Gleaves, Linda A.; Polosukhin, Vasiliy V.; Stathopoulos, Georgios T.; Zaynagetdinov, Rinat; Blackwell, Timothy S.] Vanderbilt Univ, Dept Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA. [Wu, Pingsheng] Vanderbilt Univ, Dept Biostat, Nashville, TN 37232 USA. [Karin, Michael] Univ Calif San Diego, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, Sch Med, La Jolla, CA 92093 USA. [Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pathol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA. [Yull, Fiona E.; Blackwell, Timothy S.] Vanderbilt Ingram Canc Ctr, 691 Preston Bldg,2220 Pierce Ave, Nashville, TN 37232 USA. [Stathopoulos, Georgios T.] Univ Patras, Dept Physiol, Lab Mol Resp Carcinogenesis, Patras 26504, Greece. [Stathopoulos, Georgios T.] Univ Munich, Univ Hosp, CPC, Marchioninistr 15, D-81377 Munich, Germany. [Stathopoulos, Georgios T.] Helmholtz Zentrum Munchen, D-81377 Munich, Germany. [Stathopoulos, Georgios T.] German Ctr Lung Res DZL, D-81377 Munich, Germany. [Georgoulias, Vassilis] Univ Gen Hosp Heraklion, Dept Med Oncol, Iraklion 71110, Crete, Greece. [Blackwell, Timothy S.] US Dept Vet Affairs, Washington, DC 20420 USA. [Blackwell, Timothy S.] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA. RP Zaynagetdinov, R (reprint author), Vanderbilt Univ, Dept Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA. EM rinat.z.zaynagetdinov@vanderbilt.edu FU Cancer Initiative of North Carolina and Free to Breathe; NIH [T32HL094296]; European Research Council [FP7-IDEAS-ERC-StG-2010-260524-KRASHIMPE]; U.S. Department of Veterans Affairs; Vanderbilt-Ingram Cancer Center Spore FX This work was supported by a grant from the Lung Cancer Initiative of North Carolina and Free to Breathe (R.Z.), by NIH grant T32HL094296 (R.Z.), by European Research Council Starting Independent Investigator grant FP7-IDEAS-ERC-StG-2010-260524-KRASHIMPE (G.T.S.), by the U.S. Department of Veterans Affairs (T.S.B.), and by a Vanderbilt-Ingram Cancer Center Spore grant 2010 (T.S.B.). NR 47 TC 2 Z9 2 U1 2 U2 2 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 28 PY 2016 VL 16 IS 1 BP 120 EP 132 DI 10.1016/j.celrep.2016.05.085 PG 13 WC Cell Biology SC Cell Biology GA DQ1GY UT WOS:000378950700012 PM 27320908 ER PT J AU Deville, P Song, CM Eagle, N Blondel, VD Barabasi, AL Wang, DS AF Deville, Pierre Song, Chaoming Eagle, Nathan Blondel, Vincent D. Barabasi, Albert-Laszlo Wang, Dashun TI Scaling identity connects human mobility and social interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE human mobility; social interactions; mobile phone data; social networks; spatial networks ID NETWORKS; PREDICTABILITY; PATTERNS; COMPLEX; EPIDEMICS; WORLD; MODEL AB Massive datasets that capture human movements and social interactions have catalyzed rapid advances in our quantitative understanding of human behavior during the past years. One important aspect affecting both areas is the critical role space plays. Indeed, growing evidence suggests both our movements and communication patterns are associated with spatial costs that follow reproducible scaling laws, each characterized by its specific critical exponents. Although human mobility and social networks develop concomitantly as two prolific yet largely separated fields, we lack any known relationships between the critical exponents explored by them, despite the fact that they often study the same datasets. Here, by exploiting three different mobile phone datasets that capture simultaneously these two aspects, we discovered a new scaling relationship, mediated by a universal flux distribution, which links the critical exponents characterizing the spatial dependencies in human mobility and social networks. Therefore, the widely studied scaling laws uncovered in these two areas are not independent but connected through a deeper underlying reality. C1 [Deville, Pierre; Blondel, Vincent D.] Catholic Univ Louvain, Dept Appl Math, B-1348 Louvain La Neuve, Belgium. [Deville, Pierre; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys Biol & Comp Sci, Ctr Complex Network Res, Boston, MA 02115 USA. [Song, Chaoming] Univ Miami, Dept Phys, Coral Gables, FL 33142 USA. [Eagle, Nathan] Northeastern Univ, Coll Comp Sci, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wang, Dashun] Penn State Univ, Coll Informat Sci & Technol, University Pk, PA 16802 USA. RP Wang, DS (reprint author), Penn State Univ, Coll Informat Sci & Technol, University Pk, PA 16802 USA. EM dashunwang@gmail.com FU College of Information, Sciences, and Technology at Pennsylvania State University; Network Science Collaborative Technology Alliance - US Army Research Laboratory [W911NF-09-2-0053]; Defense Threat Reduction Agency [WMD BRBAA07-J-2-0035, BRBAA08-Per4-C-2-0033]; National Fund for Scientific Research (FNRS); Research Department of the Communaute francaise de Belgique (Large Graph Concerted Research Action) FX This work was supported by the College of Information, Sciences, and Technology at Pennsylvania State University; the Network Science Collaborative Technology Alliance sponsored by the US Army Research Laboratory under Agreement W911NF-09-2-0053; and the Defense Threat Reduction Agency Awards WMD BRBAA07-J-2-0035 and BRBAA08-Per4-C-2-0033. P.D. is supported by the National Fund for Scientific Research (FNRS) and by the Research Department of the Communaute francaise de Belgique (Large Graph Concerted Research Action). NR 62 TC 0 Z9 0 U1 13 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 28 PY 2016 VL 113 IS 26 BP 7047 EP 7052 DI 10.1073/pnas.1525443113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2LI UT WOS:000379033400039 PM 27274050 ER PT J AU Dura, B Servos, MM Barry, RM Ploegh, HL Dougan, SK Voldman, J AF Dura, Burak Servos, Mariah M. Barry, Rachel M. Ploegh, Hidde L. Dougan, Stephanie K. Voldman, Joel TI Longitudinal multiparameter assay of lymphocyte interactions from onset by microfluidic cell pairing and culture SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microfluidics; cell pairing; single-cell analysis; cell-cell interactions; multiparameter assay ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; NF-KAPPA-B; NK CELLS; CYTOKINE SECRETION; TARGET-CELLS; ACTIVATION; MECHANISMS; COMPLEX; HETEROGENEITY AB Resolving how the early signaling events initiated by cell-cell interactions are transduced into diverse functional outcomes necessitates correlated measurements at various stages. Typical approaches that rely on bulk cocultures and population-wide correlations, however, only reveal these relationships broadly at the population level, not within each individual cell. Here, we present a microfluidics-based cell-cell interaction assay that enables longitudinal investigation of lymphocyte interactions at the single-cell level through microfluidic cell pairing, on-chip culture, and multiparameter assays, and allows recovery of desired cell pairs by micromanipulation for off-chip culture and analyses. Well-defined initiation of interactions enables probing cellular responses from the very onset, permitting single-cell correlation analyses between early signaling dynamics and later-stage functional outcomes within same cells. We demonstrate the utility of this microfluidic assay with natural killer cells interacting with tumor cells, and our findings suggest a possible role for the strength of early calcium signaling in selective coordination of subsequent cytotoxicity and IFN-gamma production. Collectively, our experiments demonstrate that this new approach is well-suited for resolving the relationships between complex immune responses within each individual cell. C1 [Dura, Burak; Voldman, Joel] MIT, Res Lab Elect, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Dura, Burak; Voldman, Joel] MIT, Dept Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Dura, Burak; Voldman, Joel] MIT, Microsyst Technol Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Servos, Mariah M.; Dougan, Stephanie K.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Barry, Rachel M.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ploegh, Hidde L.; Dougan, Stephanie K.] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Ploegh, Hidde L.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA. [Dougan, Stephanie K.] Harvard Med Sch, Div Immunol, Boston, MA 02115 USA. RP Dura, B; Voldman, J (reprint author), MIT, Res Lab Elect, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Dura, B; Voldman, J (reprint author), MIT, Dept Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Dura, B; Voldman, J (reprint author), MIT, Microsyst Technol Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM dura@mit.edu; voldman@mit.edu FU Singapore-MIT Alliance; Frank Quick Faculty Research Innovation Fellowship; American Association for Cancer Research-Pancreatic Cancer Action Network FX We thank Kurt Broderick and Dennis Ward for their help with the fabrication process, Brittany A. Goods and Sarvesh Varma for their help with qPCR experiments, and Dr. J. Christopher Love for providing the automated micromanipulator setup and sharing established protocols. Master wafers for microfluidic devices were fabricated in the Microsystems Technology Laboratory at Massachusetts Institute of Technology (MIT). This research was supported by the Singapore-MIT Alliance, the Frank Quick Faculty Research Innovation Fellowship, and American Association for Cancer Research-Pancreatic Cancer Action Network. NR 52 TC 3 Z9 3 U1 7 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 28 PY 2016 VL 113 IS 26 BP E3599 EP E3608 DI 10.1073/pnas.1515364113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2LI UT WOS:000379033400006 PM 27303033 ER PT J AU Willis, NA Zhou, CS Elia, AEH Murray, JM Carr, AM Elledge, SJ Rhind, N AF Willis, Nicholas A. Zhou, Chunshui Elia, Andrew E. H. Murray, Johanne M. Carr, Antony M. Elledge, Stephen J. Rhind, Nicholas TI Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA damage; Rad3; Cds1; DDR; checkpoint ID CHECKPOINT KINASE CDS1; SCHIZOSACCHAROMYCES-POMBE; REPLICATION CHECKPOINT; PHOSPHORYLATION MOTIFS; ULTRAVIOLET-LIGHT; IN-VITRO; CHK1; ATR; ACTIVATION; STRESS AB The cellular response to DNA damage during S-phase regulates a complicated network of processes, including cell-cycle progression, gene expression, DNA replication kinetics, and DNA repair. In fission yeast, this S-phase DNA damage response (DDR) is coordinated by two protein kinases: Rad3, the ortholog of mammalian ATR, and Cds1, the ortholog of mammalian Chk2. Although several critical downstream targets of Rad3 and Cds1 have been identified, most of their presumed targets are unknown, including the targets responsible for regulating replication kinetics and coordinating replication and repair. To characterize targets of the S-phase DDR, we identified proteins phosphorylated in response to methyl methanesulfonate (MMS)-induced S-phase DNA damage in wild-type, rad3 Delta, and cds1 Delta cells by proteome-wide mass spectrometry. We found a broad range of S-phase-specific DDR targets involved in gene expression, stress response, regulation of mitosis and cytokinesis, and DNA replication and repair. These targets are highly enriched for proteins required for viability in response to MMS, indicating their biological significance. Furthermore, the regulation of these proteins is similar in fission and budding yeast, across 300 My of evolution, demonstrating a deep conservation of S-phase DDR targets and suggesting that these targets may be critical for maintaining genome stability in response to S-phase DNA damage across eukaryotes. C1 [Willis, Nicholas A.; Rhind, Nicholas] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. [Zhou, Chunshui; Elia, Andrew E. H.; Elledge, Stephen J.] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Dept Genet, Boston, MA 02115 USA. [Zhou, Chunshui] Harbin Med Univ, Med Genet Lab, Harbin 150081, Peoples R China. [Elia, Andrew E. H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Murray, Johanne M.; Carr, Antony M.] Univ Sussex, Sch Life Sci, Genome Damage & Stabil Ctr, Falmer BN1 9RQ, E Sussex, England. [Elledge, Stephen J.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. [Willis, Nicholas A.] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA. [Willis, Nicholas A.] Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA. [Willis, Nicholas A.] Harvard Med Sch, Boston, MA 02215 USA. RP Rhind, N (reprint author), Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA.; Elledge, SJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Dept Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu; nick.rhind@umassmed.edu OI Carr, Antony Michael/0000-0002-2028-2389; Rhind, Nicholas/0000-0003-1758-7736 FU NIH [GM098815, GM44664, AG011085]; Medical Research Council [G01100074]; Burroughs Wellcome Fund CAMS award FX We thank Moran Yassour and Ilan Wapinski for the scripts used for gene set enrichment analysis and Yongjie Xu and members of the A.M.C., S.J.E., and N.R. laboratories for helpful discussions. This work was supported by NIH Grants GM098815 (to N.R.) and GM44664 and AG011085 (to S.J.E.) and by Medical Research Council Grant G01100074 (to A.M.C.). A.E.H.E. is supported by a Burroughs Wellcome Fund CAMS award. S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 62 TC 1 Z9 1 U1 3 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 28 PY 2016 VL 113 IS 26 BP E3676 EP E3685 DI 10.1073/pnas.1525620113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2LI UT WOS:000379033400014 PM 27298342 ER PT J AU Zhou, CS Elia, AEH Naylor, ML Dephoure, N Ballif, BA Goel, G Xu, QK Ng, A Chou, DM Xavier, RJ Gygi, SP Elledge, SJ AF Zhou, Chunshui Elia, Andrew E. H. Naylor, Maria L. Dephoure, Noah Ballif, Bryan A. Goel, Gautam Xu, Qikai Ng, Aylwin Chou, Danny M. Xavier, Ramnik J. Gygi, Steven P. Elledge, Stephen J. TI Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA damage; proteomics; checkpoint; phosphatidyl inositol; TOR ID SACCHAROMYCES-CEREVISIAE; CHECKPOINT PATHWAYS; GENOME STABILITY; MISMATCH REPAIR; PROTEIN-KINASE; HUMAN-CELLS; RAD53; REPLICATION; MECHANISMS; COMPLEX AB The DNA damage response (DDR) is regulated by a protein kinase signaling cascade that orchestrates DNA repair and other processes. Identifying the substrate effectors of these kinases is critical for understanding the underlying physiology and mechanism of the response. We have used quantitative mass spectrometry to profile DDR-dependent phosphorylation in budding yeast and genetically explored the dependency of these phosphorylation events on the DDR kinases MEC1, RAD53, CHK1, and DUN1. Based on these screens, a database containing many novel DDR-regulated phosphorylation events has been established. Phosphorylation of many of these proteins has been validated by quantitative peptide phospho-immunoprecipitation and examined for functional relevance to the DDR through large-scale analysis of sensitivity to DNA damage in yeast deletion strains. We reveal a link between DDR signaling and themetabolic pathways of inositol phosphate and phosphatidyl inositol synthesis, which are required for resistance to DNA damage. We also uncover links between the DDR and TOR signaling as well as translation regulation. Taken together, these data shed new light on the organization of DDR signaling in budding yeast. C1 [Zhou, Chunshui; Elia, Andrew E. H.; Naylor, Maria L.; Xu, Qikai; Chou, Danny M.; Elledge, Stephen J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Genet, Div Genet, Boston, MA 02115 USA. [Zhou, Chunshui] Harbin Med Univ, Med Genet Lab, Harbin 150081, Peoples R China. [Elia, Andrew E. H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Dephoure, Noah; Gygi, Steven P.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Ballif, Bryan A.] Univ Vermont, Dept Biol, Burlington, VT 05405 USA. [Goel, Gautam; Ng, Aylwin; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Elledge, Stephen J.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Elledge, SJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Genet, Div Genet, Boston, MA 02115 USA.; Gygi, SP (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.; Elledge, SJ (reprint author), Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. EM steven_gygi@hms.harvard.edu; selledge@genetics.med.harvard.edu FU Burroughs Wellcome Fund Career Award for Medical Scientists; K12 Paul Calabresi Award for Oncology; NIH [GM44644, AG011085, GM67945, P30DK043351] FX We thank W. Haas, J. Villen, B. Zhai, M. Li, D. Lee, and T. Xu for their advice. A.E.H.E is supported by a Burroughs Wellcome Fund Career Award for Medical Scientists and a K12 Paul Calabresi Award for Oncology. This work was supported by NIH Grants GM44644 and AG011085 (to S.J.E.), GM67945 (to S.P.G.), and P30DK043351 (to R.J.X). S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 44 TC 3 Z9 3 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 28 PY 2016 VL 113 IS 26 BP E3667 EP E3675 DI 10.1073/pnas.1602827113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2LI UT WOS:000379033400013 PM 27298372 ER PT J AU Bellmunt, J Zhou, CW Mullane, SA Werner, L Taplin, ME Fay, AP Choueiri, TK Orsola, A Takeda, DY Hahn, WC Kim, J Sonpavde, G Bowden, M AF Bellmunt, Joaquim Zhou, Chensheng Willa Mullane, Stephanie A. Werner, Lillian Taplin, Mary-Ellen Fay, Andre P. Choueiri, Toni K. Orsola, Anna Takeda, David Y. Hahn, William C. Kim, Jaegil Sonpavde, Guru Bowden, Michaela TI Association of tumour microRNA profiling with outcomes in patients with advanced urothelial carcinoma receiving first-line platinum-based chemotherapy SO BRITISH JOURNAL OF CANCER LA English DT Article DE miRNA; urothelial carcinoma; platinum; response ID CISPLATIN-BASED CHEMOTHERAPY; INVASIVE BLADDER-CANCER; LONG-TERM-SURVIVAL; GENE-EXPRESSION; CELL CARCINOMA; UP-REGULATION; MIR-372; COMBINATION; PROGRESSION; METASTASIS AB Background: Tumour expression of selected microRNAs (miRs) correlates with cisplatin efficacy in multiple cancers. We investigated the role of selected miRs in patients receiving cisplatin-based therapy for advanced urothelial carcinoma (UC). Methods: RNA was extracted from formalin-fixed paraffin-embedded tumour from 83 advanced UC patients who received cisplatin. A miR panel based on relevance for platinum sensitivity and UC was studied by quantitative reverse transcription quantitative PCR (RT-qPCR). Association of progression-free survival (PFS) with miR expression was analysed using cox regression. Selected TFs were chosen by association with the panel of miRs using the Transcription Regulation algorithm (GeneGo MetaCore+MetaDrug version 6.23 build 67496). Bladder cancer (BC) cell lines were used to investigate the previously described role of miR-21 mediating cisplatin sensitivity. Results: The 83 patients had a median PFS of 8 months. In multivariate analysis, higher levels of E2F1 (P = 0.01, HR: 1.95 (1.14, 3.33)), miR-21 (P = 0.01, HR: 2.01 (1.17, 3.45)) and miR-372 (P = 0.05, HR: 1.70 (1.00, 2.89)) were associated with a shorter PFS. In the 8 BC cell lines, miR-21 was not shown to be necessary nor sufficient for modulating cisplatin sensitivity. Conclusions: In metastatic UC patients treated with cisplatin-based therapy, high primary tumour levels of E2F1, miR-21 and miR-372 are associated with poor PFS independent of clinical prognostic factors. The in vitro study could not confirm miR-21 levels role in modulating platinum sensitivity. C1 [Bellmunt, Joaquim; Zhou, Chensheng Willa; Mullane, Stephanie A.; Werner, Lillian; Taplin, Mary-Ellen; Fay, Andre P.; Choueiri, Toni K.; Orsola, Anna; Takeda, David Y.; Hahn, William C.; Bowden, Michaela] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Bellmunt, Joaquim; Choueiri, Toni K.; Takeda, David Y.; Hahn, William C.] Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Bellmunt, Joaquim; Taplin, Mary-Ellen; Choueiri, Toni K.; Takeda, David Y.; Hahn, William C.] Harvard Univ, Dept Med Oncol, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. [Hahn, William C.; Kim, Jaegil] Eli & Edythe L Broad Inst, 415 Main St, Cambridge, MA 02142 USA. [Sonpavde, Guru] Univ Alabama Birmingham, Dept Med Oncol, 1720 2nd Ave S, Birmingham, AL 35233 USA. RP Bellmunt, J (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA.; Bellmunt, J (reprint author), Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA 02115 USA.; Bellmunt, J (reprint author), Harvard Univ, Dept Med Oncol, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. EM joaquim_bellmunt@dfci.harvard.edu FU Spanish Health Ministry Grant 'Fondo de Investigacion Sanitaria' [FIS PI10/02112]; Whole Foods Golf Classic; Friends of Dana-Farber; Retired Professional Fire Fighters Cancer Fund; [RTICC 06/0020/19] FX This work has been supported by FIS PI10/02112 (microRNAS) (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. 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. Also a private donation in the memory of Rich Beaudoin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 0 Z9 0 U1 1 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 28 PY 2016 VL 115 IS 1 BP 12 EP 19 DI 10.1038/bjc.2016.146 PG 8 WC Oncology SC Oncology GA DQ0HR UT WOS:000378880400003 PM 27351382 ER PT J AU Turner, EL Metcalfe, C Donovan, JL Noble, S Sterne, JAC Lane, JA Walsh, EI Hill, EM Down, L Ben-Shlomo, Y Oliver, SE Evans, S Brindle, P Williams, NJ Hughes, LJ Davies, CF Ng, SY Neal, DE Hamdy, FC Albertsen, P Reid, CM Oxley, J McFarlane, J Robinson, MC Adolfsson, J Zietman, A Baum, M Koupparis, A Martin, RM AF Turner, Emma L. Metcalfe, Chris Donovan, Jenny L. Noble, Sian Sterne, Jonathan A. C. Lane, J. Athene Walsh, Eleanor I. Hill, Elizabeth M. Down, Liz Ben-Shlomo, Yoav Oliver, Steven E. Evans, Simon Brindle, Peter Williams, Naomi J. Hughes, Laura J. Davies, Charlotte F. Ng, Siaw Yein Neal, David E. Hamdy, Freddie C. Albertsen, Peter Reid, Colette M. Oxley, Jon McFarlane, John Robinson, Mary C. Adolfsson, Jan Zietman, Anthony Baum, Michael Koupparis, Anthony Martin, Richard M. TI Contemporary accuracy of death certificates for coding prostate cancer as a cause of death: Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee SO BRITISH JOURNAL OF CANCER LA English DT Article DE cluster randomised controlled trial; screening; prostate cancer; prostate cancer mortality; cause of death; death certification; sensitivity; specificity ID CLUSTER RANDOMIZED-TRIAL; SCREENING TRIAL; MEN; MORTALITY; DESIGN; CAP AB Background: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes. Methods: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015). Results: Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis. Conclusions: UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials. C1 [Turner, Emma L.; Metcalfe, Chris; Donovan, Jenny L.; Noble, Sian; Sterne, Jonathan A. C.; Lane, J. Athene; Walsh, Eleanor I.; Hill, Elizabeth M.; Down, Liz; Ben-Shlomo, Yoav; Davies, Charlotte F.; Martin, Richard M.] Univ Bristol, Sch Social & Community Med, Canynge Hall,39 Whatley Rd, Bristol BS8 2PS, Avon, England. [Oliver, Steven E.] Univ York, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Oliver, Steven E.] Hull York Med Sch, York YO10 5DD, N Yorkshire, England. [Evans, Simon; McFarlane, John] Royal United Hosp, Urol Dept, Combe Pk, Bath BA1 3NG, Avon, England. [Brindle, Peter] Avon Primary Care Res Collaborat, South Plaza,Marlborough St, Bristol BS1 3NX, Avon, England. [Williams, Naomi J.] Univ Bristol, Royal Hallamshire Hosp, Sch Social & Community Med, Sheffield S10 2JF, S Yorkshire, England. [Hughes, Laura J.] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Box 279 S4, Cambridge CB2 0QQ, England. [Ng, Siaw Yein] Univ Bristol, Sch Social & Community Med, Freeman Hosp, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England. [Neal, David E.; Hamdy, Freddie C.] John Radcliffe Hosp, Nuffield Dept Surg Sci, Oxford OX3 9DU, England. [Albertsen, Peter] Univ Connecticut, Hlth Ctr, Farmington, CT USA. [Albertsen, Peter] St Francis Hosp & Med Ctr, Hartford, CT USA. [Reid, Colette M.] Bristol Haematol & Oncol Ctr, Dept Palliat Med, Bristol BS2 8ED, Avon, England. [Oxley, Jon] North Bristol NHS Trust, Southmead Hosp, Dept Cellular Pathol, Bristol BS10 5NB, Avon, England. [Robinson, Mary C.] Royal Victoria Infirm, Dept Cellular Pathol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Adolfsson, Jan] Karolinska Inst, Dept Clin Sci, Stokholm, Sweden. [Zietman, Anthony] Massachusetts Gen Hosp, Harvard Med Sch, Harvard Radiat Oncol Program, Boston, MA USA. [Baum, Michael] UCL, Dept Surg, Gower St, London WC1E 6BT, England. [Koupparis, Anthony] North Bristol NHS Trust, Southmead Hosp, Dept Urol, Bristol BS10 5NB, Avon, England. [Martin, Richard M.] Univ Bristol, Integrat Epidemiol Unit, Sch Social & Community Med, MRC, Oakfield House, Bristol BS8 2BN, Avon, England. RP Turner, EL (reprint author), Univ Bristol, Sch Social & Community Med, Canynge Hall,39 Whatley Rd, Bristol BS8 2PS, Avon, England. EM emma.turner@bristol.ac.uk FU Cancer Research UK; UK Department of Health [C11043/A4286, C18281/A8145, C18281/A11326, C18281/A15064]; UK National Institute for Health Research (NIHR) and Health Technology Assessment Programme [96/20/06, 96/20/99]; Oxford NIHR Biomedical Research Centre; Surgical Interventional Trials Unit; Cancer Research UK through Oxford Cancer Research Centre; University of Bristol; University of Oxford FX We acknowledge the contribution of the CAP trial group. Investigators: RMM (Lead PI), JLD (PI), DEN (PI), FCH (PI), ELT (trial Co-ordinator), CM (statistician), JACS (statistician) and SN (health economist), JAL. Research staff: EMH, SYN, NJW, LD (data manager), EW (data manager), Joanna Thorn (health economist), CFD, LJH, Mari-Anne Rowlands and Lindsey Bell. Management committee: ELT (Chair), RMM, JLD, CM, JACS, SN, YBS, JAL, SEO, PB and SE. Trial steering committee: MB (Chair), PA, Tracy Roberts, MCR, JA, David Dearnaley, AZ, Fritz Schroder, Tim Peters, Peter Holding, Teresa Lennon, Sue Bonnington, Malcolm Mason, JO, RMM, JLD, DEN, FCH, ELT and JAL. Data monitoring committee: Lars Holmberg (Chair), Robert Pickard, Simon Thompson and Usha Menon. Cause of Death Committee: PA (Chair), CMR, JMF, JO, MCR, JA, MB, AZ, Amit Bahl and AK. Administrative staff: Marta Tazewell and Genevieve Hatton-Brown. We wish to extend our thanks to Pete Shiarly for the development of bespoke databases. We also wish to acknowledge the contribution of all members of the ProtecT study research groups. Thanks are extended to the Cancer Registries and staff at the Health and Social Care Information Centre. We would also like to thank all the men who participated in this study. The CAP trial is funded by Cancer Research UK and the UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326 and C18281/A15064). The ProtecT trial is funded by the UK National Institute for Health Research (NIHR) and Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The views and opinions expressed herein are our own and do not necessarily reflect those of the Department of Health. We acknowledge the tremendous contribution of all the ProtecT study participants, investigators, researchers, data monitoring committee and trial steering committee (Chair: Michael Baum). We acknowledge the support from the Oxford NIHR Biomedical Research Centre through the Surgical Innovation and Evaluation Theme, and the Surgical Interventional Trials Unit, and Cancer Research UK through the Oxford Cancer Research Centre. Professors Donovan, Hamdy and Neal are NIHR Senior Investigators. CAP is sponsored by the University of Bristol and is registered at Current Controlled Trials (ISRCTN92187251). ProtecT trial is sponsored by the University of Oxford and is registered at Current Controlled Trials (ISRCTN20141297) and Clinical Trials.Gov (NCT02044172). NR 14 TC 4 Z9 4 U1 1 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 28 PY 2016 VL 115 IS 1 BP 90 EP 94 DI 10.1038/bjc.2016.162 PG 5 WC Oncology SC Oncology GA DQ0HR UT WOS:000378880400014 PM 27253172 ER PT J AU MacKintosh, FR Sprenkle, PC Walter, LC Rawson, L Karnes, RJ Morrell, CH Kattan, MW Nawaf, CB Neville, TB AF MacKintosh, F. Roy Sprenkle, Preston C. Walter, Louise C. Rawson, Lori Karnes, R. Jeffrey Morrell, Christopher H. Kattan, Michael W. Nawaf, Cayce B. Neville, Thomas B. TI Age and Prostate-Specific Antigen Level Prior to Diagnosis Predict Risk of Death from Prostate Cancer SO FRONTIERS IN ONCOLOGY LA English DT Article DE prostate cancer; prostate-specific antigen; life expectancy; older men; death risk ID PREVENTION TRIAL; MORTALITY; CALCULATORS; VALIDATION; ERSPC; MEN; PSA AB A single early prostate-specific antigen (PSA) level has been correlated with a higher likelihood of prostate cancer diagnosis and death in younger men. PSA testing in older men has been considered of limited utility. We evaluated prostate cancer death in relation to age and PSA level immediately prior to prostate cancer diagnosis. Using the Veterans Affairs database, we identified 230,081 men aged 50-89 years diagnosed with prostate cancer and at least one prior PSA test between 1999 and 2009. Prostate cancer-specific death over time was calculated for patients stratified by age group (e.g., 50-59 years, through 80-89 years) and PSA range at diagnosis (10 ranges) using Kaplan-Meier methods. Risk of 10-year prostate cancer mortality across age and PSA was compared using log-rank tests with a Bonferroni adjustment for multiple testing. 10.5% of men diagnosed with prostate cancer died of cancer during the 10-year study period (mean follow-up = 3.7 years). Higher PSA values prior to diagnosis predict a higher risk of death in all age groups (p < 0.0001). Within the same PSA range, older age groups are at increased risk for death from prostate cancer (p < 0.0001). For PSA of 7-10 ng/mL, cancer-specific death, 10 years after diagnosis, increased from 7% for age 50-59 years to 51% for age 80-89 years. Men older than 70 years are more likely to die of prostate cancer at any PSA level than younger men, suggesting prostate cancer remains a significant problem among older men (even those aged 80+) and deserves additional study. C1 [MacKintosh, F. Roy; Rawson, Lori] VA Sierra Nevada Hlth Care Syst, Reno, NV USA. [Sprenkle, Preston C.] Yale Univ, Sch Med, VA Connecticut Healthcare Syst, New Haven, CT USA. [Walter, Louise C.] Univ Calif San Francisco, San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA 94143 USA. [Karnes, R. Jeffrey] Mayo Clin, Rochester, MN USA. [Morrell, Christopher H.] Loyola Univ Maryland, Baltimore, MD USA. [Kattan, Michael W.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Nawaf, Cayce B.] Yale Univ, Sch Med, Dept Urol, New Haven, CT USA. [Neville, Thomas B.] Soar BioDynam Inc, Incline Village, NV USA. RP Sprenkle, PC (reprint author), Yale Univ, Sch Med, VA Connecticut Healthcare Syst, New Haven, CT USA. EM preston.sprenkle@yale.edu NR 28 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 28 PY 2016 VL 6 AR 157 DI 10.3389/fonc.2016.00157 PG 7 WC Oncology SC Oncology GA DP7CM UT WOS:000378656600001 PM 27446803 ER PT J AU Tagde, A Rajabi, H Stroopinsky, D Gali, R Alam, M Bouillez, A Kharbanda, S Stone, R Avigan, D Kufe, D AF Tagde, Ashujit Rajabi, Hasan Stroopinsky, Dina Gali, Reddy Alam, Maroof Bouillez, Audrey Kharbanda, Surender Stone, Richard Avigan, David Kufe, Donald TI MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia SO ONCOTARGET LA English DT Article DE MUC1-C; DNMT1; DNA methylation; decitabine; CDH1 ID E-CADHERIN; HEMATOLOGICAL MALIGNANCIES; STEM-CELLS; ONCOPROTEIN; CANCER; DNMT3A; METHYLATION; EXPRESSION; PATHWAY; HYPOMETHYLATION AB Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML); however, the regulation of DNA methyltransferase 1 (DNMT1), which is responsible for maintenance of DNA methylation patterns, has largely remained elusive. MUC1-C is a transmembrane oncoprotein that is aberrantly expressed in AML stem-like cells. The present studies demonstrate that targeting MUC1-C with silencing or a pharmacologic inhibitor GO-203 suppresses DNMT1 expression. In addition, MUC1 expression positively correlates with that of DNMT1 in primary AML cells, particularly the CD34+/ CD38- population. The mechanistic basis for this relationship is supported by the demonstration that MUC1-C activates the NF-kappa B p65 pathway, promotes occupancy of the MUC1-C/NF-kappa B complex on the DNMT1 promoter and drives DNMT1 transcription. We also show that targeting MUC1-C substantially reduces gene promoter-specific DNA methylation, and derepresses expression of tumor suppressor genes, including CDH1, PTEN and BRCA1. In support of these results, we demonstrate that combining GO-203 with the DNMT1 inhibitor decitabine is highly effective in reducing DNMT1 levels and decreasing AML cell survival. These findings indicate that (i) MUC1-C is an attractive target for the epigentic reprogramming of AML cells, and (ii) targeting MUC1-C in combination with decitabine is a potentially effective clinical approach for the treatment of AML. C1 [Tagde, Ashujit; Rajabi, Hasan; Alam, Maroof; Bouillez, Audrey; Kharbanda, Surender; Stone, Richard; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Stroopinsky, Dina; Avigan, David] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Gali, Reddy] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA.; Avigan, D (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM davigan@bidmc.harvard.edu; donald_kufe@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health [CA100707, CA97098, CA166480] FX Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA100707, CA97098 and CA166480. NR 51 TC 3 Z9 3 U1 6 U2 22 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 28 PY 2016 VL 7 IS 26 BP 38974 EP 38987 DI 10.18632/oncotarget.9777 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700001 PM 27259275 ER PT J AU Mitra, S Federico, L Zhao, W Dennison, J Sarkar, TR Zhang, F Takiar, V Cheng, KW Mani, S Lee, JS Mills, GB AF Mitra, Shreya Federico, Lorenzo Zhao, Wei Dennison, Jennifer Sarkar, Tapasree Roy Zhang, Fan Takiar, Vinita Cheng, Kwai W. Mani, Sendurai Lee, Ju Seog Mills, Gordon B. TI Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT SO ONCOTARGET LA English DT Article DE Rab25; Rab coupling protein; breast cancer; luminal B; claudin low ID EPITHELIAL-MESENCHYMAL TRANSITION; SQUAMOUS-CELL CARCINOMA; CANINE KIDNEY-CELLS; ALPHA-5-BETA-1 INTEGRIN; 3D MICROENVIRONMENTS; MOLECULAR PORTRAITS; THERAPEUTIC TARGET; EXPRESSION; TRAFFICKING; METASTASIS AB The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions. C1 [Mitra, Shreya; Federico, Lorenzo; Zhao, Wei; Dennison, Jennifer; Zhang, Fan; Lee, Ju Seog; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Sarkar, Tapasree Roy] Texas A&M Univ, Ctr Stat Bioinformat, College Stn, TX USA. [Takiar, Vinita] Univ Cincinnati, Dept Radiat Oncol, Cincinnati, OH USA. [Cheng, Kwai W.] Michael & DeBakey Med Ctr, Cardiac Catheterizat Lab, Houston, TX USA. [Mani, Sendurai] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. RP Mitra, S (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. EM smitra@mdanderson.org RI Mani, Sendurai/A-7244-2009 OI Mani, Sendurai/0000-0002-5918-4276 FU Susan G Komen Postdoctoral Fellowship Grant [KG101340]; American Cancer Grant [CA0099031 08, CA16672]; Komen Foundation [KG08169404]; GlaxoSmithKline TRIUMPH post-doctoral fellowship FX This project was supported by4 funds from Susan G Komen Postdoctoral Fellowship Grant (KG101340) awarded to S.M and the American Cancer Grant (CA0099031 08 and CA16672) and Komen Foundation. (KG08169404) granted to G.B.M. J.B.D. was supported by a GlaxoSmithKline TRIUMPH post-doctoral fellowship. NR 67 TC 0 Z9 0 U1 8 U2 9 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 28 PY 2016 VL 7 IS 26 BP 40252 EP 40265 DI 10.18632/oncotarget.9730 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700100 PM 27259233 ER PT J AU Zhou, YB Shen, JK Hornicek, FJ Kan, QC Duan, ZF AF Zhou, Yubing Shen, Jacson K. Hornicek, Francis J. Kan, Quancheng Duan, Zhenfeng TI The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer SO ONCOTARGET LA English DT Review DE CDK11; CDKs inhibitor; cell cycle; therapeutic target; cancer therapy ID ADVANCED BREAST-CANCER; RNA-POLYMERASE-II; SISTER-CHROMATID COHESION; PROTEIN-KINASE; CELL-CYCLE; INDUCED APOPTOSIS; TERMINAL DOMAIN; GENE PROMOTER; IN-VIVO; TARGETS AB Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment. C1 [Zhou, Yubing; Kan, Quancheng; Duan, Zhenfeng] Zhengzhou Univ, Dept Pharm, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China. [Zhou, Yubing; Shen, Jacson K.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. RP Kan, QC; Duan, ZF (reprint author), Zhengzhou Univ, Dept Pharm, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China.; Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. EM qckan19632012@163.com; zduan@mgh.harvard.edu FU Joint Research Fund devoted to clinical pharmacy and precision medicine; National Natural Science Foundation of China [81402266, 81372875]; Gattegno fund; Wechsler fund; China Scholarship Council FX This work was supported by a Joint Research Fund devoted to clinical pharmacy and precision medicine (Z.D and Q.K). Support has also been provided by the National Natural Science Foundation of China (No.: 81402266 and 81372875), the Gattegno and Wechsler funds. Dr. Zhou is supported by a scholarship from the China Scholarship Council. NR 100 TC 0 Z9 0 U1 9 U2 11 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 28 PY 2016 VL 7 IS 26 BP 40846 EP 40859 DI 10.18632/oncotarget.8519 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP6NV UT WOS:000378614700143 PM 27049727 ER PT J AU Hsu, JC Maddox, TM Kennedy, K Katz, DF Marzec, LN Lubitz, SA Gehi, AK Turakhia, MP Marcus, GM AF Hsu, Jonathan C. Maddox, Thomas M. Kennedy, Kevin Katz, David F. Marzec, Lucas N. Lubitz, Steven A. Gehi, Anil K. Turakhia, Mintu P. Marcus, Gregory M. TI Aspirin Instead of Oral Anticoagulant Prescription in Atrial Fibrillation Patients at Risk for Stroke SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aspirin; CHADS(2) score; CHA(2)DS(2)-VASc score; thromboembolism ID ANTITHROMBOTIC THERAPY; PRACTICE GUIDELINES; PREDICTING STROKE; AMERICAN-COLLEGE; WARFARIN USE; MANAGEMENT; REGISTRY; METAANALYSIS; OUTPATIENTS; PREVENTION AB BACKGROUND Oral anticoagulation (OAC), rather than aspirin, is recommended in patients with atrial fibrillation (AF) at moderate to high risk of stroke. OBJECTIVES This study sought to examine patient and practice-level factors associated with prescription of aspirin alone compared with OAC in AF patients at intermediate to high stroke risk in real-world cardiology practices. METHODS The authors identified 2 cohorts of outpatients with AF and intermediate to high thromboembolic risk (CHADS2 score >= 2 and CHA(2)DS(2)-VASc >= 2) enrolled in the American College of Cardiology PINNACLE (Practice Innovation and Clinical Excellence) registry between 2008 and 2012. Using hierarchical modified Poisson regression models adjusted for patient and practice characteristics, the authors examined the prevalence and predictors of aspirin alone versus OAC prescription in AF patients at risk for stroke. RESULTS Of 210,380 identified patients with CHADS2 score >= 2 on antithrombotic therapy, 80,371 (38.2%) were treated with aspirin alone, and 130,009 (61.8%) were treated with warfarin or non-vitamin K antagonist OACs. In the cohort of 294,642 patients with CHA(2)DS(2)-VASc >= 2, 118,398 (40.2%) were treated with aspirin alone, and 176,244 (59.8%) were treated with warfarin or non-vitamin K antagonist OACs. After multivariable adjustment, hypertension, dyslipidemia, coronary artery disease, prior myocardial infarction, unstable and stable angina, recent coronary artery bypass graft, and peripheral arterial disease were associated with prescription of aspirin only, whereas male sex, higher body mass index, prior stroke/transient ischemic attack, prior systemic embolism, and congestive heart failure were associated with more frequent prescription of OAC. CONCLUSIONS In a large, real-world cardiac outpatient population of AF patients with a moderate to high risk of stroke, more than 1 in 3 were treated with aspirin alone without OAC. Specific patient characteristics predicted prescription of aspirin therapy over OAC. (C) 2016 by the American College of Cardiology Foundation. C1 [Hsu, Jonathan C.] Univ Calif San Diego, Dept Med, Div Cardiol, Cardiac Electrophysiol Sect, 9444 Med Ctr Dr,MC7411, La Jolla, CA 92037 USA. [Maddox, Thomas M.] Univ Colorado, Sch Med, VA Eastern Colorado Hlth Care Syst, Denver, CO USA. [Kennedy, Kevin] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Katz, David F.; Marzec, Lucas N.] Univ Colorado, Sch Med, Denver, CO USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Gehi, Anil K.] Univ N Carolina, Chapel Hill, NC USA. [Turakhia, Mintu P.] Stanford Univ, Sch Med, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Marcus, Gregory M.] Univ Calif San Francisco, Dept Med, Div Cardiol, Sect Cardiac Electrophysiol, San Francisco, CA 94143 USA. RP Hsu, JC (reprint author), Univ Calif San Diego, Dept Med, Div Cardiol, Cardiac Electrophysiol Sect, 9444 Med Ctr Dr,MC7411, La Jolla, CA 92037 USA. EM Jonathan.Hsu@ucsd.edu FU American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR); Bristol-Myers Squibb; Pfizer Inc.; Biotronik; Biosense Webster; National Institutes of Health (NIH); Doris Duke Charitable Foundation; Veterans Affairs; Gilead Sciences; iRhythm; Medtronic; Janssen Pharmaceuticals; SentreHeart; NIH; PCORI; Pfizer; Rhythm Diagnostic Systems FX This research was supported by the American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR). The views expressed in this paper represent those of the authors, and do not necessarily represent the official views of the NCDR or its associated professional societies identified at www.ncdr.com.; PINNACLE Registry is an initiative of the American College of Cardiology Foundation. Bristol-Myers Squibb and Pfizer Inc. are Founding Sponsors of the PINNACLE Registry. Dr. Hsu has received honoraria from St. Jude Medical, Medtronic, Biotronik, Janssen Pharmaceutical, and Bristol-Myers Squibb; has received research support from Biotronik and Biosense Webster. Dr. Lubitz has received grants from the National Institutes of Health (NIH) and the Doris Duke Charitable Foundation. Dr. Gehi has received speaker honoraria from Medtronic, Zoll Medical, St. Jude Medical, and Biotronik. Dr. Turakhia has received research support from the Veterans Affairs, Gilead Sciences, iRhythm, Medtronic, Janssen Pharmaceuticals, and SentreHeart; is a consultant to Janssen Pharmaceuticals, Medtronic, St. Jude Medical, and Precision Health Economics; and has equity ownership in thryva and Zipline. Dr. Marcus has received research support from the NIH, PCORI, Medtronic, Pfizer, Rhythm Diagnostic Systems, and SentreHeart; and is a consultant for and has equity ownership in InCarda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 26 TC 11 Z9 12 U1 4 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 28 PY 2016 VL 67 IS 25 BP 2913 EP 2923 DI 10.1016/j.jacc.2016.03.581 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO8SI UT WOS:000378053500001 PM 27339487 ER PT J AU Semigran, MJ AF Semigran, Marc J. TI Chemotherapy to Treat Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE bortezomib; congestive heart failure; cyclophosphamide; infiltrative cardiomyopathy; light chain; melphalan ID STEM-CELL TRANSPLANTATION; HIGH-DOSE MELPHALAN; AL AMYLOIDOSIS; CARDIAC AMYLOIDOSIS; CYCLOPHOSPHAMIDE; DEXAMETHASONE; PROGRESSION; BORTEZOMIB; SURVIVAL C1 [Semigran, Marc J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Semigran, Marc J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Semigran, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Bigelow 800,Fruit St, Boston, MA 02114 USA. EM msemigran@partners.org NR 12 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 28 PY 2016 VL 67 IS 25 BP 2949 EP 2951 DI 10.1016/j.jacc.2016.05.003 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO8SI UT WOS:000378053500006 PM 27339492 ER PT J AU Hainline, B Drezner, JA Baggish, A Harmon, KG Emery, MS Myerburg, RJ Sanchez, E Molossi, S Parsons, JT Thompson, PD AF Hainline, Brian Drezner, Jonathan A. Baggish, Aaron Harmon, Kimberly G. Emery, Michael S. Myerburg, Robert J. Sanchez, Eduardo Molossi, Silvana Parsons, John T. Thompson, Paul D. TI Interassociation Consensus Statement on Cardiovascular Care of College Student-Athletes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac arrest; electrocardiogram; emergency action plan; pre-participation screening; student-athlete; sudden cardiac death ID AMERICAN-HEART-ASSOCIATION; SUDDEN CARDIAC-ARREST; AUTOMATED EXTERNAL DEFIBRILLATORS; OF-CARDIOLOGY-FOUNDATION; SCIENTIFIC STATEMENT; DISQUALIFICATION RECOMMENDATIONS; HIGH-SCHOOL; CARDIOPULMONARY-RESUSCITATION; CLINICAL CARDIOLOGY; SEATTLE CRITERIA AB Cardiovascular evaluation and care of college student-athletes is gaining increasing attention from both the public and medical communities. Emerging strategies include screening of the general athlete population, recommendations of permissible levels of participation by athletes with identified cardiovascular conditions, and preparation for responding to unanticipated cardiac events in athletic venues. The primary focus has been sudden cardiac death and the utility of screening with or without advanced cardiac screening. The National Collegiate Athletic Association convened a multi-disciplinary task force to address cardiovascular concerns in collegiate student-athletes and to develop consensus for an interassociation statement. This document summarizes the task force deliberations and follow-up discussions, and includes available evidence on cardiovascular risk, pre-participation evaluation, and the recognition of and response to cardiac arrest. Future recommendations for cardiac research initiatives, education, and collaboration are also provided. (C) 2016 by the American College of Cardiology Foundation. C1 [Hainline, Brian; Parsons, John T.] Natl Collegiate Athlet Assoc, Sport Sci Inst, POB 6222, Indianapolis, IN 46206 USA. [Drezner, Jonathan A.; Harmon, Kimberly G.] Univ Washington, Dept Family Med, Seattle, WA 98195 USA. [Baggish, Aaron] Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. [Emery, Michael S.] Indiana Univ Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA. [Myerburg, Robert J.] Univ Miami, Miller Sch Med, Div Cardiol, Miami, FL 33136 USA. [Sanchez, Eduardo] Amer Heart Assoc, Dallas, TX USA. [Molossi, Silvana] Baylor Coll Med, Dept Pediat, Div Pediat Cardiol, Houston, TX 77030 USA. [Thompson, Paul D.] Hartford Hosp, Div Cardiol, Hartford, CT 06115 USA. RP Hainline, B (reprint author), Natl Collegiate Athlet Assoc, Sport Sci Inst, POB 6222, Indianapolis, IN 46206 USA. EM bhainline@ncaa.org FU NCAA Sport Science Institute; Genomas; Roche; Sanofi; Regeneron; Esperion; Amarin; Pfizer FX Funding for the multidisciplinary task force, held at the National Collegiate Athletic Association (NCAA) headquarters in September 2014, was provided by the NCAA Sport Science Institute. The task force included representatives from the following affiliations: American Academy of Pediatrics' Council on Sports Medicine and Physical Fitness; National Athletic Trainers' Association; College Athletic Trainers' Society; American Medical Society for Sports Medicine; American College of Cardiology Sports and Exercise Cardiology Leadership Council; National Federation of State High School Associations; American Orthopaedic Society for Sports Medicine; NCAA Student-Athlete Advisory Council; American Osteopathic Academy of Sports Medicine, National Strength and Conditioning Association; Collegiate Strength and Conditioning Coaches Association; American Heart Association; NCAA Committee on Competitive Safeguards and Medical Aspects of Sports; and the American College of Sports Medicine. Dr. Thompson has received research support from Genomas, Roche, Sanofi, Regeneron, Esperion, Amarin, and Pfizer; has served as a consultant for Amgen, Regeneron, Merck, Esperion, and Sanofi; has received speaker honoraria from Merck, AstraZeneca, Regeneron, Sanofi, and Amgen; owns stock in AbbVie, Abbott Labs, CVS, General Electric, Johnson & Johnson, Medtronic, and JA Willey; and has provided expert legal testimony on exercise-related cardiac events and statin myopathy. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 76 TC 12 Z9 12 U1 3 U2 8 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 28 PY 2016 VL 67 IS 25 BP 2981 EP 2995 DI 10.1016/j.jacc.2016.03.527 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO8SI UT WOS:000378053500011 PM 27090220 ER PT J AU Murphy, SA Cannon, CP Blazing, MA Giugliano, RP Tershakovec, AM Braunwald, E AF Murphy, Sabina A. Cannon, Christopher P. Blazing, Michael A. Giugliano, Robert P. Tershakovec, Andrew M. Braunwald, Eugene TI REPLY: Adding Ezetimibe to Simvastatin for the Secondary Prevention of Cardiovascular Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Murphy, Sabina A.] Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. RP Murphy, SA (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM smurphy15@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 28 PY 2016 VL 67 IS 25 BP 3025 EP 3026 DI 10.1016/j.jacc.2016.03.580 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO8SI UT WOS:000378053500022 PM 27339506 ER PT J AU Yeboah, A Cohen, RI Faulknor, R Schloss, R Yarmush, ML Berthiaume, F AF Yeboah, Agnes Cohen, Rick I. Faulknor, Renea Schloss, Rene Yarmush, Martin L. Berthiaume, Francois TI The development and characterization of SDF1 alpha-elastin-like-peptide nanoparticles for wound healing SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Stromal cell-derived factor-1 (SDF1); Elastin like peptides (ELP); Nanoparticles; Wound healing; Skin ID CELL-DERIVED FACTOR-1-ALPHA; ENDOTHELIAL PROGENITOR CELLS; ELASTIN-LIKE POLYPEPTIDES; FACTOR-I; FUSION PROTEIN; MYOCARDIAL-INFARCTION; GROWTH-FACTOR; CXCR4; NEOVASCULARIZATION; EXPRESSION AB Chronic skin wounds are characterized by poor re-epithelialization, angiogenesis and granulation. Previous work has demonstrated that topical stromal cell-derived growth factor-1 (SDF1) promotes neovascularization, resulting in faster re-epithelialization of skin wounds in diabetic mice. However, the clinical usefulness of such bioactive peptides is limited because they are rapidly degraded in the wound environment due to high levels of proteases. Here, we describe the development of a recombinant fusion protein comprised of SDF1 and an elastin-like peptide that confers the ability to self-assemble into nanoparticles. The fusion protein and recombinant human SDF1 showed similar binding characteristics, as indicated by the measured equilibrium dissociation constant (K-d) for the binding of free SDF1 or the fusion protein to the CXCR4 receptor. The biological activity of SDF1-ELP, as measured by intracellular calcium release in HL60 cells was dose dependent, and also very similar to that of free SDF1. In contrast, the biological activity of SDF1-ELP in vivo was significantly superior to that of free SDF1. When applied to full thickness skin wounds in diabetic mice, wounds treated with SDF1-ELP nanoparticles were 95% closed by day 21, and fully closed by day 28, while wounds treated with free SDF1, ELP alone, or vehicle were only 80% closed by day 21, and took 42 days to fully close. In addition, the SDF1-ELP nanoparticles significantly increased the epidermal and dermal layer of the healed wound, as compared to the other groups. These results indicate that SDF1-ELP fusion protein nanoparticles are promising agents for the treatment of chronic skin wounds. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yeboah, Agnes] Rutgers State Univ, Dept Chem & Biochem Engn, 98 Brett Rd, Piscataway, NJ 08854 USA. [Cohen, Rick I.; Faulknor, Renea; Schloss, Rene; Yarmush, Martin L.; Berthiaume, Francois] Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. [Yarmush, Martin L.] Massachusetts Gen Hosp, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA. [Yarmush, Martin L.] Shriners Burns Hosp, 51 Blossom St, Boston, MA 02114 USA. RP Berthiaume, F (reprint author), Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA.; Yarmush, ML (reprint author), Massachusetts Gen Hosp, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA.; Yarmush, ML (reprint author), Shriners Burns Hosp, 51 Blossom St, Boston, MA 02114 USA. EM yarmush@rci.rutgers.edu; fberthia@rci.rutgers.edu FU Shriners Hospitals for Children; New Jersey Commission for Spinal Cord Research [CSCR15IRG010]; National Institutes of Health; Schlumberger Faculty FX This work was partially supported by the Shriners Hospitals for Children and the New Jersey Commission for Spinal Cord Research (CSCR15IRG010). Agnes Yeboah was supported by a National Institutes of Health-funded biotechnology training fellowship, and a Schlumberger Faculty for the Future fellowship. We would like to thank Dr. Jafar Al-Sharab for helping with the TEM measurements, and the School of Environmental and Biological Sciences for allowing us to use their Biacore equipment, and also for helping with the experiments. Our sincere thanks also go to the School of Marine and Coastal Sciences, Rutgers University, for the use of their spectrophotometer, the Center for Advanced Biotechnology and Medicine, Rutgers University, for the use of their circular dichroism equipment, the Material Science Engineering Department and the Ernest Mario School of Pharmacy, Rutgers University for the use of their Zetasizer equipment, and the Digital Imaging and Histology Core at the Rutgers-New Jersey Medical School Cancer Center for their histological staining services. NR 45 TC 3 Z9 3 U1 8 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD JUN 28 PY 2016 VL 232 BP 238 EP 247 DI 10.1016/j.jconrel.2016.04.020 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DN9LL UT WOS:000377401000024 PM 27094603 ER PT J AU Pikman, Y Puissant, A Alexe, G Furman, A Chen, LYM Frumm, SM Ross, L Fenouille, N Bassil, CF Lewis, CA Ramos, A Gould, J Stone, RM DeAngelo, DJ Galinsky, I Clish, CB Kung, AL Hemann, MT Vander Heiden, MG Banerji, V Stegmaier, K AF Pikman, Yana Puissant, Alexandre Alexe, Gabriela Furman, Andrew Chen, Liying M. Frumm, Stacey M. Ross, Linda Fenouille, Nina Bassil, Christopher F. Lewis, Caroline A. Ramos, Azucena Gould, Joshua Stone, Richard M. DeAngelo, Daniel J. Galinsky, Ilene Clish, Clary B. Kung, Andrew L. Hemann, Michael T. Vander Heiden, Matthew G. Banerji, Versha Stegmaier, Kimberly TI Targeting MTH FD2 in acute myeloid leukemia SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INTERNAL TANDEM DUPLICATION; POOR-PROGNOSIS; METHYLENETETRAHYDROFOLATE DEHYDROGENASE; SUCCINATE-DEHYDROGENASE; CONNECTIVITY MAP; CLASS DISCOVERY; IDH2 MUTATIONS; CANCER-CELLS; DNA-DAMAGE; GENE AB Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML. C1 [Pikman, Yana; Puissant, Alexandre; Alexe, Gabriela; Furman, Andrew; Chen, Liying M.; Frumm, Stacey M.; Ross, Linda; Bassil, Christopher F.; Banerji, Versha; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Stone, Richard M.; DeAngelo, Daniel J.; Galinsky, Ilene; Vander Heiden, Matthew G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Pikman, Yana; Puissant, Alexandre; Alexe, Gabriela; Furman, Andrew; Chen, Liying M.; Frumm, Stacey M.; Ross, Linda; Bassil, Christopher F.; Banerji, Versha; Stegmaier, Kimberly] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. [Alexe, Gabriela; Gould, Joshua; Clish, Clary B.; Vander Heiden, Matthew G.; Stegmaier, Kimberly] MIT, Broad Inst, Cambridge, MA 02142 USA. [Alexe, Gabriela; Gould, Joshua; Clish, Clary B.; Vander Heiden, Matthew G.; Stegmaier, Kimberly] Harvard Univ, Cambridge, MA 02142 USA. [Alexe, Gabriela] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Fenouille, Nina; Lewis, Caroline A.; Ramos, Azucena; Hemann, Michael T.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. [Banerji, Versha] CancerCare Manitoba, Res Inst Oncol & Hematol, Winnipeg, MB R3E 0V9, Canada. [Banerji, Versha] Univ Manitoba, Winnipeg, MB R3E 0V9, Canada. [Puissant, Alexandre] INSERM, U1065, Team 2, C3M, F-06204 Nice, France. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.; Stegmaier, K (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA.; Stegmaier, K (reprint author), MIT, Broad Inst, Cambridge, MA 02142 USA.; Stegmaier, K (reprint author), Harvard Univ, Cambridge, MA 02142 USA. EM kimberly_stegmaier@dfci.harvard.edu RI PUISSANT, ALEXANDRE/O-9575-2016; OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; Kung, Andrew/0000-0002-9091-488X FU National Cancer Institute [R01 CA140292, R21 CA198028]; National Heart, Lung, and Blood Institute [5T32 HL07574-32]; National Institute of Child Health and Human Development grant [5K12HD052896-09]; Lauri Strauss Leukemia Foundation; Lady Tata Memorial Trust International Award; Boston Children's Hospital Career Development Award; Children's Leukemia Research Association; Cubans Curing Children's Cancers (4C's Fund); Project Cupid; When Everyone Survives; Post MD NCIC/Terry Fox Research Fellowship; CancerCare Manitoba Foundation; University of Mannitoba; Library of Integrated Cellular Signatures [U54HG006093, U54HL127366] FX This research was supported by National Cancer Institute grants R01 CA140292; K. Stegmaier) and R21 CA198028 (M. Vander Heiden), National Heart, Lung, and Blood Institute grant 5T32 HL07574-32 (Y. Pikman), the National Institute of Child Health and Human Development grant 5K12HD052896-09 (Y. Pikman), the Lauri Strauss Leukemia Foundation (Y. Pikman), Lady Tata Memorial Trust International Award (Y. Pikman), Boston Children's Hospital Career Development Award (Y. Pikman), Children's Leukemia Research Association (K. Stegmaier), Cubans Curing Children's Cancers (4C's Fund; K. Stegmaier), Project Cupid (K. Stegmaier), When Everyone Survives (K. Stegmaier), Post MD NCIC/Terry Fox Research Fellowship (V. Banerji), CancerCare Manitoba Foundation, the University of Mannitoba (V. Banerji), and the Library of Integrated Cellular Signatures grants U54HG006093 and U54HL127366. K. Stegmaier is a Leukemia and Lymphoma Society Scholar, A. Puissant is a Leukemia and Lymphoma Society Fellow, and Y. Pikman an Alex's Lemonade Stand Young Investigator Award Recipient. NR 64 TC 3 Z9 3 U1 2 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUN 27 PY 2016 VL 213 IS 7 BP 1285 EP 1306 DI 10.1084/jem.20151574 PG 22 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VA UT WOS:000380849800015 PM 27325891 ER PT J AU Yu, Y Moncal, KK Li, JQ Peng, WJ Rivero, I Martin, JA Ozbolat, IT AF Yu, Yin Moncal, Kazim K. Li, Jianqiang Peng, Weijie Rivero, Iris Martin, James A. Ozbolat, Ibrahim T. TI Three-dimensional bioprinting using self-assembling scalable scaffold-free "tissue strands" as a new bioink SO SCIENTIFIC REPORTS LA English DT Article ID CARTILAGE; CELLS; FABRICATION; CONSTRUCTS AB Recent advances in bioprinting have granted tissue engineers the ability to assemble biomaterials, cells, and signaling molecules into anatomically relevant functional tissues or organ parts. Scaffold-free fabrication has recently attracted a great deal of interest due to the ability to recapitulate tissue biology by using self-assembly, which mimics the embryonic development process. Despite several attempts, bioprinting of scale-up tissues at clinically-relevant dimensions with closely recapitulated tissue biology and functionality is still a major roadblock. Here, we fabricate and engineer scaffold-free scalable tissue strands as a novel bioink material for robotic-assisted bioprinting technologies. Compare to 400 mu m-thick tissue spheroids bioprinted in a liquid delivery medium into confining molds, near 8 cm-long tissue strands with rapid fusion and self-assemble capabilities are bioprinted in solid form for the first time without any need for a scaffold or a mold support or a liquid delivery medium, and facilitated native-like scale-up tissues. The prominent approach has been verified using cartilage strands as building units to bioprint articular cartilage tissue. C1 [Yu, Yin] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Yu, Yin] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Moncal, Kazim K.; Peng, Weijie; Ozbolat, Ibrahim T.] Penn State Univ, Dept Engn Sci & Mech, State Coll, PA USA. [Moncal, Kazim K.; Peng, Weijie; Ozbolat, Ibrahim T.] Penn State Univ, Huck Inst Life Sci, State Coll, PA USA. [Li, Jianqiang; Rivero, Iris] Iowa State Univ, Ind & Mfg Syst Engn, Ames, IA USA. [Martin, James A.] Univ Iowa, Dept Orthopaed & Rehabil, Iowa City, IA USA. RP Ozbolat, IT (reprint author), Penn State Univ, Dept Engn Sci & Mech, State Coll, PA USA.; Ozbolat, IT (reprint author), Penn State Univ, Huck Inst Life Sci, State Coll, PA USA. EM ito1@psu.edu FU National Science Foundation [1600118, 1349716]; Grow Iowa Value Funds; Engineering Science and Mechanics Department at the Pennsylvania State University; China Scholarship Council [201308360128] FX This research has been supported by National Science Foundation Awards #1600118, CAREER #1349716, Grow Iowa Value Funds, the start-up funds from Engineering Science and Mechanics Department at the Pennsylvania State University and the China Scholarship Council award #201308360128. The authors thank Dr. Adil Akkouch and Melanie Laverman from The University of Iowa for their assistance with SEM imaging and typesetting, respectively. NR 30 TC 4 Z9 4 U1 20 U2 43 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 27 PY 2016 VL 6 AR 28714 DI 10.1038/srep28714 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP4YE UT WOS:000378502400001 PM 27346373 ER PT J AU Jacobs, IJ Parmar, M Skates, SJ Menon, U AF Jacobs, Ian J. Parmar, Mahesh Skates, Steven J. Menon, Usha TI Ovarian cancer screening: UKCTOCS trial Reply SO LANCET LA English DT Letter ID RANDOMIZED CONTROLLED-TRIAL; MORTALITY; PROSTATE C1 [Jacobs, Ian J.; Menon, Usha] UCL, Dept Womens Canc, Inst Womens Hlth, London W1T 7DN, England. [Jacobs, Ian J.] Univ New S Wales, Sydney, NSW, Australia. [Jacobs, Ian J.] Univ Manchester, Inst Human Dev, Ctr Womens Hlth, Manchester, Lancs, England. [Parmar, Mahesh] UCL, MRC, Clin Trials Unit, London, England. [Skates, Steven J.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Skates, Steven J.] Harvard Univ, Sch Med, Boston, MA USA. RP Menon, U (reprint author), UCL, Dept Womens Canc, Inst Womens Hlth, London W1T 7DN, England. EM u.menon@ucl.ac.uk FU Cancer Research UK [C1479/A2884]; Department of Health; Medical Research Council [G0801228, G9901012]; NCI NIH HHS [CA152990] NR 5 TC 2 Z9 2 U1 3 U2 4 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 25 PY 2016 VL 387 IS 10038 BP 2603 EP 2604 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DP3JX UT WOS:000378390500027 PM 27353822 ER PT J AU Wynn, ML Yates, JA Evans, CR Van Wassenhove, LD Wu, ZF Bridges, S Bao, LW Fournier, C Ashrafzadeh, S Merrins, MJ Satin, LS Schnell, S Burant, CF Merajver, SD AF Wynn, Michelle L. Yates, Joel A. Evans, Charles R. Van Wassenhove, Lauren D. Wu, Zhi Fen Bridges, Sydney Bao, Liwei Fournier, Chelsea Ashrafzadeh, Sepideh Merrins, Matthew J. Satin, Leslie S. Schnell, Santiago Burant, Charles F. Merajver, Sofia D. TI RhoC GTPase Is a Potent Regulator of Glutamine Metabolism and N-Acetylaspartate Production in Inflammatory Breast Cancer Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE breast cancer; glutamine; hypoxia-inducible factor (HIF); Rho (Rho GTPase); tumor metabolism; N-acetylaspartate ID KINASE TYPE M2; PYRUVATE-KINASE; TUMOR-GROWTH; REDUCTIVE CARBOXYLATION; LUNG-CANCER; E-CADHERIN; IN-VIVO; HYPOXIA; OVEREXPRESSION; PROTEIN AB Inflammatory breast cancer (IBC) is an extremely lethal cancer that rapidly metastasizes. Although the molecular attributes of IBC have been described, little is known about the underlying metabolic features of the disease. Using a variety of metabolic assays, including C-13 tracer experiments, we found that SUM149 cells, the primary in vitro model of IBC, exhibit metabolic abnormalities that distinguish them from other breast cancer cells, including elevated levels of N-acetylaspartate, a metabolite primarily associated with neuronal disorders and gliomas. Here we provide the first evidence of N-acetylaspartate in breast cancer. We also report that the oncogene RhoC, a driver of metastatic potential, modulates glutamine and N-acetylaspartate metabolism in IBC cells in vitro, revealing a novel role for RhoC as a regulator of tumor cell metabolism that extends beyond its well known role in cytoskeletal rearrangement. C1 [Wynn, Michelle L.; Yates, Joel A.; Evans, Charles R.; Wu, Zhi Fen; Bridges, Sydney; Bao, Liwei; Fournier, Chelsea; Ashrafzadeh, Sepideh; Burant, Charles F.; Merajver, Sofia D.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Wynn, Michelle L.; Schnell, Santiago] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Satin, Leslie S.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Van Wassenhove, Lauren D.] Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA. [Merrins, Matthew J.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Merrins, Matthew J.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Merajver, SD (reprint author), Univ Michigan, Dept Internal Med, Ctr Canc 7217, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM smerajve@umich.edu OI Burant, Charles/0000-0001-9189-5003 FU National Institutes of Health [U24 DK097153] FX This work utilized core services of the Michigan Regional Comprehensive Metabolomics Resource Core, supported by National Institutes of Health Grant U24 DK097153. We thank Firas Midani for help with natural abundance correction algorithms and Mariana Rodriguez Ortiz for help with figure preparation. NR 51 TC 2 Z9 2 U1 5 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 24 PY 2016 VL 291 IS 26 BP 13715 EP 13729 DI 10.1074/jbc.M115.703959 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR2YZ UT WOS:000379771100026 PM 27129239 ER PT J AU Drehmer, JE Hipple, B Nabi-Burza, E Ossip, DJ Chang, YC Rigotti, NA Winickoff, JP AF Drehmer, Jeremy E. Hipple, Bethany Nabi-Burza, Emara Ossip, Deborah J. Chang, Yuchiao Rigotti, Nancy A. Winickoff, Jonathan P. TI Proactive enrollment of parents to tobacco quitlines in pediatric practices is associated with greater quitline use: a cross-sectional study SO BMC PUBLIC HEALTH LA English DT Article DE Smoking; Tobacco; Pediatrics; Family practice; Parent; Smoking cessation; Secondhand smoke; Tobacco control; Quitline; Telephone counseling ID SMOKING-CESSATION; NICOTINE REPLACEMENT; CONTROL INTERVENTION; RANDOMIZED-TRIAL; NORTH-AMERICA; SMOKERS; CHILDREN; ACCEPTABILITY; FEASIBILITY; REFERRALS AB Background: Every U.S. state has a free telephone quitline that tobacco users can access to receive cessation assistance, yet referral rates for parents in the pediatric setting remain low. This study evaluates, within pediatric offices, the impact of proactive enrollment of parents to quitlines compared to provider suggestion to use the quitline and identifies other factors associated with parental quitline use. Methods: As part of a cluster randomized controlled trial (Clinical Effort Against Secondhand Smoke Exposure), research assistants completed post-visit exit interviews with parents in 20 practices in 16 states. Parents' quitline use was assessed at a 12-month follow-up interview. A multivariable analysis was conducted for quitline use at 12 months using a logistic regression model with generalized estimating equations to account for provider clustering. Self-reported cessation rates were also compared among quitline users based on the type of referral they received at their child's doctor's office. Results: Of the 1980 parents enrolled in the study, 1355 (68 %) completed a 12-month telephone interview and of those 139 (10 %) reported talking with a quitline (15 % intervention versus 6 % control; p < .0001). Parents who were Hispanic (aOR 2.12 (1.22, 3.70)), black (aOR 1.57 (1.14, 2.16)), planned to quit smoking in the next 30 days (aOR 2.32 (1.47, 3.64)), and had attended an intervention practice (aOR 2.37 (1.31, 4.29)) were more likely to have talked with a quitline. Parents who only received a suggestion from a healthcare provider to use the quitline (aOR 0.45 (0.23, 0.90)) and those who were not enrolled and did not receive a suggestion (aOR 0.33 (0.17, 0.64)) were less likely to talk with a quitline than those who were enrolled in the quitline during the baseline visit. Self-reported cessation rates among quitline users were similar regardless of being proactively enrolled (19 %), receiving only a suggestion (25 %), or receiving neither a suggestion nor an enrollment (17 %) during a visit (p = 0.47). Conclusions: These results highlight the enhanced clinical effectiveness of not just recommending the quitline to parents but also offering them enrollment in the quitline at the time of their child's visit to the pediatric office. C1 [Drehmer, Jeremy E.; Hipple, Bethany; Nabi-Burza, Emara; Winickoff, Jonathan P.] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Res & Policy, Div Gen Acad Pediat, 125 Nashua St,Suite 860, Boston, MA 02114 USA. [Drehmer, Jeremy E.; Hipple, Bethany; Nabi-Burza, Emara; Chang, Yuchiao; Rigotti, Nancy A.; Winickoff, Jonathan P.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Ossip, Deborah J.] Univ Rochester, Med Ctr, Dept Publ Hlth Sci, Rochester, NY 14642 USA. [Chang, Yuchiao; Rigotti, Nancy A.; Winickoff, Jonathan P.] Harvard Univ, Sch Med, Boston, MA USA. RP Drehmer, JE (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Res & Policy, Div Gen Acad Pediat, 125 Nashua St,Suite 860, Boston, MA 02114 USA.; Drehmer, JE (reprint author), Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. EM jdrehmer@mgh.harvard.edu OI Drehmer, Jeremy/0000-0002-5022-5836 FU National Institutes of Health NCI grant [R01-CA127127]; National Institute on Drug Abuse; Agency for Healthcare Research and Quality; Flight Attendant Medical Research Institute; Pediatric Research in Office Settings (PROS) Network from the HRSA MCHB [HRSA 5-UA6-10-001]; Pediatric Research in Office Settings (PROS) Network from the AAP FX This study was supported by the National Institutes of Health NCI grant R01-CA127127 (to Dr. Winickoff), National Institute on Drug Abuse, and the Agency for Healthcare Research and Quality. This study was also partially supported by a grant from the Flight Attendant Medical Research Institute to the AAP Julius B. Richmond Center, and the Pediatric Research in Office Settings (PROS) Network, which receives core funding from the HRSA MCHB (HRSA 5-UA6-10-001) and the AAP. The funders had no role in the design or conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review and approval of the manuscript. NR 36 TC 0 Z9 0 U1 0 U2 1 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 24 PY 2016 VL 16 AR 520 DI 10.1186/s12889-016-3147-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6FH UT WOS:000378591800001 PM 27342141 ER PT J AU Prabhu, SD Frangogiannis, NG AF Prabhu, Sumanth D. Frangogiannis, Nikolaos G. TI The Biological Basis for Cardiac Repair After Myocardial Infarction From Inflammation to Fibrosis SO CIRCULATION RESEARCH LA English DT Review DE chemokines; cytokines; fibrosis; immune cells; inflammation; myocytes, cardiac; myocardial infarction ID NF-KAPPA-B; ISCHEMIA-REPERFUSION INJURY; ACUTE CORONARY SYNDROME; TOLL-LIKE RECEPTOR-2; MOBILITY GROUP BOX-1; REGULATES FIBROBLAST PHENOTYPE; MARROW-DERIVED CELLS; KILLER T-CELLS; IN-VIVO; HEART-FAILURE AB In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-a) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-beta family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure. C1 [Prabhu, Sumanth D.] Univ Alabama Birmingham, Div Cardiovasc Dis, 311 Tinsley Harrison Tower,1900 Univ Blvd, Birmingham, AL 35294 USA. [Prabhu, Sumanth D.] Birmingham VAMC, Med Serv, Birmingham, AL USA. [Frangogiannis, Nikolaos G.] Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Dept Med, 1300 Morris Pk Ave,Forchheimer G46B, Bronx, NY 10461 USA. RP Prabhu, SD (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, 311 Tinsley Harrison Tower,1900 Univ Blvd, Birmingham, AL 35294 USA.; Frangogiannis, NG (reprint author), Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Dept Med, 1300 Morris Pk Ave,Forchheimer G46B, Bronx, NY 10461 USA. EM sprabhu@uab.edu; nikolaos.frangogiannis@einstein.yu.edu FU BLRD VA [I01 BX002706]; NHLBI NIH HHS [R01 HL076246, R01 HL085440, R01 HL125735]; NIDDK NIH HHS [P30 DK020541, P30 DK079626] NR 271 TC 20 Z9 22 U1 12 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 24 PY 2016 VL 119 IS 1 BP 91 EP 112 DI 10.1161/CIRCRESAHA.116.303577 PG 22 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DP4WA UT WOS:000378496500014 PM 27340270 ER PT J AU McAlpine, CS Swirski, FK AF McAlpine, Cameron S. Swirski, Filip K. TI Circadian Influence on Metabolism and Inflammation in Atherosclerosis SO CIRCULATION RESEARCH LA English DT Review DE atherosclerosis; circadian rhythm; inflammation; metabolism; life style ID OBSTRUCTIVE SLEEP-APNEA; REV-ERB-ALPHA; SMOOTH-MUSCLE-CELLS; CORONARY-HEART-DISEASE; AMBULATORY BLOOD-PRESSURE; HEMATOPOIETIC STEM-CELLS; LOW-DENSITY-LIPOPROTEIN; CLOCK GENE-EXPRESSION; HUMAN BONE-MARROW; HIGH-FAT DIET AB Many aspects of human health and disease display daily rhythmicity. The brain's suprachiasmic nucleus, which interprets recurring external stimuli, and autonomous molecular networks in peripheral cells together, set our biological circadian clock. Disrupted or misaligned circadian rhythms promote multiple pathologies including chronic inflammatory and metabolic diseases such as atherosclerosis. Here, we discuss studies suggesting that circadian fluctuations in the vessel wall and in the circulation contribute to atherogenesis. Data from humans and mice indicate that an impaired molecular clock, disturbed sleep, and shifting light-dark patterns influence leukocyte and lipid supply in the circulation and alter cellular behavior in atherosclerotic lesions. We propose that a better understanding of both local and systemic circadian rhythms in atherosclerosis will enhance clinical management, treatment, and public health policy. C1 Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP McAlpine, CS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM csmcalpine@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL095612, R01 HL128264] NR 178 TC 2 Z9 2 U1 6 U2 24 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 24 PY 2016 VL 119 IS 1 BP 131 EP 141 DI 10.1161/CIRCRESAHA.116.308034 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DP4WA UT WOS:000378496500016 PM 27340272 ER PT J AU Long, MT Pedley, A Massaro, JM Hoffmann, U Fox, CS AF Long, Michelle T. Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI The Association between Non-Invasive Hepatic Fibrosis Markers and Cardiometabolic Risk Factors in the Framingham Heart Study SO PLOS ONE LA English DT Article ID FATTY LIVER-DISEASE; INCREASED ARTERIAL STIFFNESS; PULSE PRESSURE; NONALCOHOLIC STEATOHEPATITIS; DIAGNOSIS; BIOPSY; ADULTS AB Background & Aims Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular related death, particularly in those with hepatic fibrosis. We determined the prevalence of predicted fibrosis based on non-invasive fibrosis markers and the association of hepatic fibrosis with cardiovascular risk factors. Methods Cross-sectional study of 575 Framingham Heart Study participants with NAFLD based on computed tomography. We determined the prevalence of predicted fibrosis based on the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), the Fibrosis-4 score (FIB4), and the NAFLD Fibrosis Score (NFS). Using multivariable logistic regression models, we examined the association between low, indeterminate, or high risk for fibrosis according to the NFS and various cardiometabolic risk factors. Results The predicted risk of fibrosis was 12%, 4%, 5%, and 32% for the NFS, FIB4, APRI, and AST/ALT ratio, respectively. In multivariable models, participants with a high risk for advanced fibrosis by the NFS had a wider pulse pressure (adjusted mean difference = 6.87 mm Hg; p = 0.0002) and an increased odds of hypertension (OR 2.92; p = 0.007) compared to those with low risk of fibrosis. There were no statistically significant differences between other cardiovascular risk factors for those with a high versus low risk of fibrosis. Conclusions The AST/ALT ratio, APRI, and NFS give widely disparate predictions of liver fibrosis. Participants with a high risk for fibrosis based on NFS had wider pulse pressure and increased odds of hypertension. Whether modifying these risk factors impacts cardiovascular endpoints in NAFLD patients remains unknown. C1 [Long, Michelle T.] Boston Univ, Sch Med, Div Gastroenterol, Boston Med Ctr, Boston, MA 02118 USA. [Long, Michelle T.; Pedley, Alison; Massaro, Joseph M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pedley, Alison] Merck Res Labs, Kenilworth, NJ USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. RP Long, MT (reprint author), Boston Univ, Sch Med, Div Gastroenterol, Boston Med Ctr, Boston, MA 02118 USA.; Long, MT (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM mtlong@bu.edu OI Long, Michelle/0000-0001-6131-3981 FU Boston University School of Medicine; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; Division of Intramural Research of the National Heart, Lung, and Blood Institute FX This work was supported by the Boston University School of Medicine and the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195 and HHSN268201500001I), and the Division of Intramural Research of the National Heart, Lung, and Blood Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Alison Pedley is an employee of Merck. The funder provided support in the form of salaries for authors [AP], 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 these authors are articulated in the 'author contributions' section. NR 31 TC 2 Z9 2 U1 2 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 24 PY 2016 VL 11 IS 6 AR e0157517 DI 10.1371/journal.pone.0157517 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3KZ UT WOS:000378393600008 PM 27341207 ER PT J AU Lelegren, M Liu, YH Ross, C Tardif, S Salmon, AB AF Lelegren, Matthew Liu, Yuhong Ross, Corinna Tardif, Suzette Salmon, Adam B. TI Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate SO PATHOBIOLOGY OF AGING AND AGE-RELATED DISEASES LA English DT Article DE healthspan; protein chaperone; proteasome; immunoproteasome; autophagy ID GENETICALLY HETEROGENEOUS MICE; EXTENDS LIFE-SPAN; PROTEIN HOMEOSTASIS; MAMMALIAN TARGET; OXIDATIVE-STRESS; AUTOPHAGY; LONGEVITY; IMMUNOPROTEASOME; PROTEASOME; RESISTANCE AB Background: Inhibition of mechanistic target of rapamycin (mTOR) has emerged as a viable means to lengthen lifespan and healthspan in mice, although it is still unclear whether these benefits will extend to other mammalian species. We previously reported results from a pilot experiment wherein common marmosets (Callithrix jacchus) were treated orally with rapamycin to reduce mTOR signaling in vivo in line with previous reports in mice and humans. Further, long-term treatment did not significantly alter body weight, daily activity, blood lipid concentrations, or glucose metabolism in this cohort. Methods: In this study, we report on the molecular consequences of rapamycin treatment in marmosets on mechanisms that regulate protein homeostasis (proteostasis) in vivo. There is growing appreciation for the role of proteostasis in longevity and for the role that mTOR plays in regulating this process. Tissue samples of liver and skeletal muscle from marmosets in our pilot cohort were assessed for expression and activity of components of the ubiquitin-proteasome system, macroautophagy, and protein chaperones. Results: Rapamycin treatment was associated with increased expression of PSMB5, a core subunit of the 20S proteasome, but not PSMB8 which is involved in the formation of the immunoproteasome, in the skeletal muscle and liver. Surprisingly, proteasome activity measured in these tissues was not affected by rapamycin. Rapamycin treatment was associated with an increased expression of mitochondria-targeted protein chaperones in skeletal muscle, but not liver. Finally, autophagy was increased in skeletal muscle and adipose, but not liver, from rapamycin-treated marmosets. Conclusions: Overall, these data show tissue-specific upregulation of some, but not all, components of the proteostasis network in common marmosets treated with a pharmaceutical inhibitor of mTOR. C1 [Lelegren, Matthew; Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Lelegren, Matthew; Liu, Yuhong; Ross, Corinna; Tardif, Suzette; Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX USA. [Ross, Corinna; Tardif, Suzette] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX USA. [Ross, Corinna] Texas A&M Univ, Dept Biol, San Antonio, TX USA. [Ross, Corinna; Tardif, Suzette] Texas Biomed Res Inst, Southwest Natl Primate Res Ctr, San Antonio, TX USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX USA. RP Salmon, AB (reprint author), 15355 Lambda Dr, San Antonio, TX USA. EM salmona@uthscsa.edu FU NIA NIH HHS [R01 AG050797, T35 AG038048]; NIH HHS [P51 OD011133] NR 52 TC 1 Z9 2 U1 1 U2 1 PU CO-ACTION PUBLISHING PI JARFALLA PA RIPVAGEN 7, JARFALLA, SE-175 64, SWEDEN EI 2001-0001 J9 PATHOBIOL AGING AGE JI Pathobiol. Aging Age-relat. Dis. PD JUN 23 PY 2016 VL 6 AR 31793 DI 10.3402/pba.v6.31793 PG 9 WC Pathology SC Pathology GA DT4EX UT WOS:000381434000001 PM 27341957 ER PT J AU Shen, EX Wang, MJ Xie, HR Zou, RQ Lin, QW Lai, LL Li, FJ Liang, ZM Xu, YR Zhou, MH AF Shen, Erxia Wang, Mengjie Xie, Hairui Zou, Ruqiong Lin, Qiwen Lai, Lili Li, Fujun Liang, Zhimei Xu, Yanran Zhou, Maohua TI Existence of Th22 in children and evaluation of IL-22+CD4+T, Th17, and other T cell effector subsets from healthy children compared to adults SO BMC IMMUNOLOGY LA English DT Article DE Interleukin-22; Children; Adults; Memory T cells; CD4 T helper ID CYTOKINE PRODUCTION; INTERLEUKIN 22; HELPER TYPE-1; CD4(+); IL-22; DISTINCT; LINEAGE; INFLAMMATION; POPULATIONS; PROFILES AB Background: Children are prone to get infections, especially in the respiratory system and the gut mainly because their immune system is immature. T cells significantly contribute to the prevention of infections, and different helper T cell (Th) subsets play different anti-pathogen roles. Interleukin (IL)-22 producing by T-helper 22 cells (Th22) play an important role in host defense against Gram-negative bacterial organisms in gut and lung. T-helper 17 cells (Th17) protect against extracelluar bacteria and fungi especially at the epithelial surface. However, there is no report comparing IL-22 producing T cells and Th17 cells in healthy young children to adults. Methods: Flow cytometry (FCM) was used to observe whether Th22 subset existed in the peripheral blood of healthy young children. Meanwhile, we determined the frequencies of Th subsets including Th17, Th1 and Th2, cytotoxic T (Tc) 1 subset, CD4+ and CD8+ memory T cells in the peripheral blood of both young children and adults. Results: In the present study, we demonstrated that Th22 subset existed in peripheral blood of children, with IL-22 mainly secreted by CD4 + CD45RO+ memory T cells. Moreover, we observed that IL-22 + CD4 + T cells and Th subsets including Th17, Th1, and Th2 frequencies of young children (1-6 years old) were significantly lower than adults. While the Th1 frequency from Group A (1-3 years old) was markedly lower than that from Group B (4-6 years old). No significant differences of Th17 or IL-22 + CD4 + T cells frequencies were observed between these two groups. In addition, Tc1 subset frequencies were also remarkably lower in young children than in adults. Furthermore, lower frequencies of CD45RO+ memory CD4+ and CD8+ T cells in young children than in adults, and significant correlation between CD45RO+ memory CD4 + T cells and IL-22 + CD4 + T cells, Th1, Th17 were observed. Conclusions: Th22 subset exists in the peripheral blood of young children. Compared with adults, there are lower frequencies of IL-22 + CD4 + T cells, as well as Th1, Th17, Th2 and Tc1 subsets in the peripheral blood of young children. C1 [Shen, Erxia; Wang, Mengjie; Zou, Ruqiong; Li, Fujun; Liang, Zhimei; Xu, Yanran] Guangzhou Med Univ, Sch Basic Sci, Sinofrench Hoffmann Inst, Dept Pathogen Biol & Immunol, Guangzhou 510182, Guangdong, Peoples R China. [Shen, Erxia] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Xie, Hairui; Lai, Lili] Yuexiu Dist Childrens Hosp Guangzhou, Guangzhou 510115, Guangdong, Peoples R China. [Lin, Qiwen] Guangzhou Blood Ctr, Guangzhou 510095, Guangdong, Peoples R China. [Zhou, Maohua] Acad Med Sci, Guangdong Gen Hosp, Dept Lab Med, Guangzhou 510080, Guangdong, Peoples R China. RP Shen, EX (reprint author), Guangzhou Med Univ, Sch Basic Sci, Sinofrench Hoffmann Inst, Dept Pathogen Biol & Immunol, Guangzhou 510182, Guangdong, Peoples R China.; Shen, EX (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Zhou, MH (reprint author), Acad Med Sci, Guangdong Gen Hosp, Dept Lab Med, Guangzhou 510080, Guangdong, Peoples R China. EM erxia_shen@yahoo.com; zmhuagz@126.com FU Science and Technology Planning Project of Guangdong Province, China [2013B021800189, 2014A070713041]; National Natural Science Foundation of China [31500712]; Guangzhou city-level key disciplines and specialties of Immunology [B127007] FX This work was Supported by Science and Technology Planning Project of Guangdong Province, China (No. 2013B021800189, No. 2014A070713041), National Natural Science Foundation of China (No. 31500712), and the Guangzhou city-level key disciplines and specialties of Immunology (No. B127007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 1 Z9 1 U1 4 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD JUN 23 PY 2016 VL 17 AR 20 DI 10.1186/s12865-016-0158-8 PG 8 WC Immunology SC Immunology GA DQ6HU UT WOS:000379306100001 PM 27338754 ER PT J AU Mazahery, H Conlon, C Beck, KL Kruger, MC Stonehouse, W Camargo, CA Meyer, BJ Tsang, B Mugridge, O von Hurst, PR AF Mazahery, Hajar Conlon, Cathryn Beck, Kathryn L. Kruger, Marlena C. Stonehouse, Welma Camargo, Carlos A., Jr. Meyer, Barbara J. Tsang, Bobby Mugridge, Owen von Hurst, Pamela R. TI Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial SO TRIALS LA English DT Article DE Autism; ASD; Vitamin D; Omega-3 fatty acids; Supplements ID ABERRANT BEHAVIOR CHECKLIST; DOCOSAHEXAENOIC ACID SUPPLEMENTATION; POLYUNSATURATED FATTY-ACIDS; GASTROINTESTINAL PROBLEMS; YOUNG-ADULTS; D DEFICIENCY; D-RECEPTOR; BRAIN; COMBINATION; PEDIATRICS AB Background: There is strong mechanistic evidence to suggest that vitamin D and omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs), specifically docosahexaenoic acid (DHA), have the potential to significantly improve the symptoms of autism spectrum disorder (ASD). However, there are no trials that have measured the effect of both vitamin D and n-3 LCPUFA supplementation on autism severity symptoms. The objective of this 2 x 2 factorial trial is to investigate the effect of vitamin D, n-3 LCPUFAs or a combination of both on core symptoms of ASD. Methods/design: Children with ASD living in New Zealand (n = 168 children) will be randomised to one of four treatments daily: vitamin D (2000 IU), n-3 LCPUFAs (722 mg DHA), vitamin D (2000 IU) + n-3 LCPUFAs (722 mg DHA) or placebo for 12 months. All researchers, participants and their caregivers will be blinded until the data analysis is completed, and randomisation of the active/placebo capsules and allocation will be fully concealed from all mentioned parties. The primary outcome measures are the change in social-communicative functioning, sensory processing issues and problem behaviours between baseline and 12 months. A secondary outcome measure is the effect on gastrointestinal symptoms. Baseline data will be used to assess and correct basic nutritional deficiencies prior to treatment allocation. For safety measures, serum 25-hydroxyvitamin D 25(OH) D and calcium will be monitored at baseline, 6 and 12 months, and weekly compliance and gastrointestinal symptom diaries will be completed by caregivers throughout the study period. Discussion: To our knowledge there are no randomised controlled trials assessing the effects of both vitamin D and DHA supplementation on core symptoms of ASD. If it is shown that either vitamin D, DHA or both are effective, the trial would reveal a non-invasive approach to managing ASD symptoms. C1 [Mazahery, Hajar; Conlon, Cathryn; Beck, Kathryn L.; Kruger, Marlena C.; Mugridge, Owen; von Hurst, Pamela R.] Massey Univ, Sch Food & Nutr, Inst Food Sci & Technol, Auckland, New Zealand. [Stonehouse, Welma] CSIRO, Food Nutr & Bioprod, Adelaide, SA, Australia. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Meyer, Barbara J.] Univ Wollongong, Sch Med, Illawarra, NSW 2522, Australia. [Tsang, Bobby] North Shore Hosp, Waitemata Dist Hlth Board, Auckland, New Zealand. RP von Hurst, PR (reprint author), Massey Univ, Sch Food & Nutr, Inst Food Sci & Technol, Auckland, New Zealand. EM p.r.vonhurst@massey.ac.nz RI Stonehouse, Welma/H-2316-2013 FU Massey University Strategic Innovation Fund, Massey University, New Zealand FX Partial funding for the study was provided by Massey University Strategic Innovation Fund, Massey University, New Zealand to cover the pilot study in 2015. Additional support has been provided by Douglas Nutrition, Pty. Ltd., NZ who are supplying the active supplement and identical-appearing placebo, but who have no input into study design, implementation, data management, statistical analysis or reporting of results. NR 87 TC 0 Z9 0 U1 13 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD JUN 23 PY 2016 VL 17 AR 295 DI 10.1186/s13063-016-1428-8 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DQ1WI UT WOS:000378990700001 PM 27334138 ER PT J AU Levman, J Takahashi, E AF Levman, Jacob Takahashi, Emi TI Pre-Adult MRI of Brain Cancer and Neurological injury: Multivariate Analyses SO FRONTIERS IN PEDIATRICS LA English DT Review DE multivariate analysis; machine learning; fetal; neonatal; pediatric; MRI; review ID ARTERIAL ISCHEMIC-STROKE; CONGENITAL HEART-DISEASE; WHITE-MATTER INJURY; PRETERM INFANTS; THERAPEUTIC HYPOTHERMIA; PROGNOSTIC-FACTORS; PREMATURE NEWBORNS; PILOCYTIC ASTROCYTOMAS; DIABETIC-KETOACIDOSIS; CORTICAL DEVELOPMENT AB Brain cancer and neurological injuries, such as stroke, are life-threatening conditions for which further research is needed to overcome the many challenges associated with providing optimal patient care. Multivariate analysis (MVA) is a class of pattern recognition technique involving the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of neuroimaging challenges, including identifying variables associated with patient outcomes; understanding an injury's etiology, development, and progression; creating diagnostic tests; assisting in treatment monitoring; and more. Compared to adults, imaging of the developing brain has attracted less attention from MVA researchers, however, remarkable MVA growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to brain injury and cancer in neurological fetal, neonatal, and pediatric magnetic resonance imaging (MRI). With a wide variety of MRI modalities providing physiologically meaningful biomarkers and new biomarker measurements constantly under development, MVA techniques hold enormous potential toward combining available measurements toward improving basic research and the creation of technologies that contribute to improving patient care. C1 [Levman, Jacob; Takahashi, Emi] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med,Div Newborn Med, Boston, MA 02115 USA. [Levman, Jacob; Takahashi, Emi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Levman, J (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med,Div Newborn Med, Boston, MA 02115 USA.; Levman, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM jacob.levman@childrens.harvard.edu NR 109 TC 0 Z9 0 U1 4 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PD JUN 23 PY 2016 VL 4 AR UNSP 65 DI 10.3389/fped.2016.00065 PG 13 WC Pediatrics SC Pediatrics GA DP5PC UT WOS:000378548500001 PM 27446888 ER PT J AU Glykys, J Staley, KJ AF Glykys, Joseph Staley, Kevin J. TI Developmental Decrease of Neuronal Chloride Concentration Is Independent of Trauma in Thalamocortical Brain Slices SO PLOS ONE LA English DT Article ID EXCITATORY ACTIONS; NETWORK ACTIVITY; IN-VITRO; GABA; INJURY; MECHANISM; MATRIX; CORTEX; METALLOPROTEINASES; RECORDINGS AB The intraneuronal chloride concentration ([Cl-](i)) is paramount for determining the polarity of signaling at GABA(A) synapses in the central nervous system. Sectioning hippocampal brain slices increases [Cl-](i) in the superficial layers. It is not known whether cutting trauma also increases [Cl-](i) in the neocortex and thalamus, and whether the effects of trauma change during development. We used Cl- imaging to study the [Cl-](i) vs. the distance from the cut surface in acute thalamocortical slices from mice at developmental ages ranging from postnatal day 5 (P5) to P20. We demonstrate: 1) [Cl-](i) is higher in the most superficial areas in both neocortical and thalamic brain slices at all ages tested and, 2) there is a developmental decrease in [Cl-](i) that is independent of acute trauma caused by brain slicing. We conclude that [Cl-](i) has a developmental progression during P5-20 in both the neocortex and thalamus. However, in both brain regions and during development the neurons closest to the slicing trauma have an elevated [Cl-](i) . C1 [Glykys, Joseph; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Div Child Neurol, Boston, MA 02114 USA. [Glykys, Joseph; Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Glykys, J (reprint author), Massachusetts Gen Hosp, Dept Neurol, Div Child Neurol, Boston, MA 02114 USA.; Glykys, J (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM jglykys@mgh.harvard.edu FU National Institute of Health/National Institute of Neurological Disorders and Stroke [K08 1K08NS091248, 5R01NS40109-14] FX JG was supported by the National Institute of Health/National Institute of Neurological Disorders and Stroke K08 1K08NS091248. KS was supported by the National Institute of Health/National Institute of Neurological Disorders and Stroke 5R01NS40109-14. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 0 Z9 0 U1 2 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 23 PY 2016 VL 11 IS 6 AR e0158012 DI 10.1371/journal.pone.0158012 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3JL UT WOS:000378389200089 PM 27337272 ER PT J AU Waljee, AK Wiitala, WL Govani, S Stidham, R Saini, S Hou, J Feagins, LA Khan, N Good, CB Vijan, S Higgins, PDR AF Waljee, Akbar K. Wiitala, Wyndy L. Govani, Shail Stidham, Ryan Saini, Sameer Hou, Jason Feagins, Linda A. Khan, Nabeel Good, Chester B. Vijan, Sandeep Higgins, Peter D. R. TI Corticosteroid Use and Complications in a US Inflammatory Bowel Disease Cohort SO PLOS ONE LA English DT Article ID HEALTH-CARE-SYSTEM; ULCERATIVE-COLITIS; CROHNS-DISEASE; NETWORK METAANALYSIS; OSTEOPOROSIS; QUALITY; AZATHIOPRINE; GUIDELINES; FRACTURES; EFFICACY AB Background and Aims Corticosteroids are effective for the short-term treatment of inflammatory bowel disease (IBD). Long-term use, however, is associated with significant adverse effects. To define the: (1) frequency and duration of corticosteroid use, (2) frequency of escalation to corticosteroid-sparing therapy, (3) rate of complications related to corticosteroid use, (4) rate of appropriate bone density measurements (dual energy X-ray absorptiometry [ DEXA] scans), and (5) factors associated with escalation and DEXA scans. Methods Retrospective review of Veterans Health Administration (VHA) data from 2002-2010. Results Of the 30,456 Veterans with IBD, 32% required at least one course of corticosteroids during the study time period, and 17% of the steroid users had a prolonged course. Among these patients, only 26.2% underwent escalation of therapy. Patients visiting a gastroenterology (GI) physician were significantly more likely to receive corticosteroid-sparing medications. Factors associated with corticosteroid-sparing medications included younger age (OR = 0.96 per year, 95% CI: 0.95, 0.97), male gender (OR = 2.00,95% CI: 1.16,3.46), GI visit during the corticosteroid evaluation period (OR = 8.01,95% CI: 5.85,10.95) and the use of continuous corticosteroids vs. intermittent corticosteroids (OR = 2.28,95% CI: 1.33,3.90). Rates of complications per 1000 person-years after IBD diagnosis were higher among corticosteroid users (venous thromboembolism [VTE] 9.0%; fragility fracture 2.6%; Infections 54.3) than non-corticosteroid users (VTE 4.9%; fragility fracture 1.9%; Infections 26.9). DEXA scan utilization rates among corticosteroid users were only 7.8%. Conclusions Prolonged corticosteroid therapy for the treatment of IBD is common and is associated with significant harm to patients. Patients with prolonged use of corticosteroids for IBD should be referred to gastroenterology early and universal efforts to improve the delivery of high quality care should be undertaken. C1 [Waljee, Akbar K.; Wiitala, Wyndy L.; Saini, Sameer; Vijan, Sandeep] VA Ann Arbor Hlth Care Syst, VA Ctr Clin Management Res, Ann Arbor, MI USA. [Waljee, Akbar K.; Govani, Shail; Stidham, Ryan; Saini, Sameer; Vijan, Sandeep; Higgins, Peter D. R.] Univ Michigan Hlth Syst, Div Gastroenterol & Hepatol, Dept Internal Med, Ann Arbor, MI USA. [Hou, Jason] Michael E DeBakey VA Med Ctr, Houston VA HSR&D Ctr Excellence, Dept Internal Med, Div Gastroenterol & Hepatol, Houston, TX USA. [Hou, Jason] Baylor Coll Med, Med Ctr, Dept Med, Houston, TX 77030 USA. [Feagins, Linda A.] VA North Texas Hlth Care Syst, Div Gastroenterol & Hepatol, Dept Internal Med, Dallas, TX USA. [Feagins, Linda A.] Univ Texas SW Med Ctr Dallas, Div Gastroenterol, Dallas, TX 75390 USA. [Feagins, Linda A.] Univ Texas SW Med Ctr Dallas, Div Hepatol, Dallas, TX 75390 USA. [Khan, Nabeel] Philadelphia VA Med Ctr, Div Gastroenterol, Dept Internal Med, Philadelphia, PA USA. [Khan, Nabeel] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Good, Chester B.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Good, Chester B.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. RP Waljee, AK (reprint author), VA Ann Arbor Hlth Care Syst, VA Ctr Clin Management Res, Ann Arbor, MI USA.; Waljee, AK (reprint author), Univ Michigan Hlth Syst, Div Gastroenterol & Hepatol, Dept Internal Med, Ann Arbor, MI USA. EM awaljee@med.umich.edu FU Veteran's Health Administration Health Services Research and Development Career Development Award (CDA-2) [1IK2HX000775]; National Institutes of Health Research Project Grant Program (R01) [GM097117] FX A.K.W.'s research is funded by a Veteran's Health Administration Health Services Research and Development Career Development Award (CDA-2) 1IK2HX000775. P.D.R.H.'s research is supported by National Institutes of Health Research Project Grant Program (R01) GM097117. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2016 VL 11 IS 6 AR e0158017 DI 10.1371/journal.pone.0158017 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3JL UT WOS:000378389200091 PM 27336296 ER PT J AU Anderson, MA Deng, J Seymour, JF Tam, C Kim, SY Fein, J Yu, LJ Brown, JR Westerman, D Si, EG Majewski, IJ Segal, D Enschede, SLH Huang, DCS Davids, MS Letai, A Roberts, AW AF Anderson, Mary Ann Deng, Jing Seymour, John F. Tam, Constantine Kim, Su Young Fein, Joshua Yu, Lijian Brown, Jennifer R. Westerman, David Si, Eric G. Majewski, Ian J. Segal, David Enschede, Sari L. Heitner Huang, David C. S. Davids, Matthew S. Letai, Anthony Roberts, Andrew W. TI The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; TARGETING BCL2; IN-VIVO; CANCER; IBRUTINIB; ABT-199; FAMILY; MITOCHONDRIA; ACTIVATION; MUTATIONS AB BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug. C1 [Anderson, Mary Ann; Si, Eric G.; Majewski, Ian J.; Segal, David; Huang, David C. S.; Roberts, Andrew W.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Canc & Haematol Div, Parkville, Vic 3050, Australia. [Anderson, Mary Ann; Seymour, John F.; Tam, Constantine; Huang, David C. S.; Roberts, Andrew W.] Univ Melbourne, Fac Med Dent & Hlth Sci, Parkville, Vic 3052, Australia. [Anderson, Mary Ann; Roberts, Andrew W.] Royal Melbourne Hosp, Dept Clin Hematol & Bone Marrow Transplantat, Parkville, Vic 3050, Australia. [Deng, Jing; Fein, Joshua; Yu, Lijian; Brown, Jennifer R.; Davids, Matthew S.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Seymour, John F.; Tam, Constantine; Westerman, David] Peter MacCallum Canc Ctr, Dept Haematol, East Melbourne, Vic, Australia. [Kim, Su Young; Enschede, Sari L. Heitner] AbbVie, N Chicago, IL USA. RP Roberts, AW (reprint author), Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3050, Australia. EM roberts@wehi.edu.au RI Roberts, Andrew/C-6736-2012 OI Roberts, Andrew/0000-0002-7341-5720 FU AbbVie; Genentech/Roche; Webster bequest; Australian National Health and Medical Research Council [1016647, 1016701, 9000220]; Leukemia and Lymphoma Society [7001-13]; Victorian Cancer Agency; Cancer Council Victoria; Australian Cancer Research Foundation; Victorian State Government Operational Infrastructure Support grant; National Cancer Institute, National Institutes of Health [CA129974]; American Society of Clinical Oncology Career Development Award FX This work was supported by AbbVie, in collaboration with Genentech/Roche. Venetoclax (ABT-199/GDC-0199) is being developed through collaboration between AbbVie and Genentech/Roche. M.A.A. was supported by a fellowship from the Webster bequest. Work in the labs of D.C.S.H. and A.W.R. was supported by scholarships, fellowships, and grants from the Australian National Health and Medical Research Council (research fellowships [A.W.R. and D.C.S.H.], program grants 1016647 and 1016701, and Independent Research Institutes Infrastructure Support Scheme grant 9000220); the Leukemia and Lymphoma Society (SCOR grants 7001-13); the Victorian Cancer Agency; the Cancer Council Victoria; the Australian Cancer Research Foundation; and a Victorian State Government Operational Infrastructure Support grant. This work was supported by a grant from the National Cancer Institute, National Institutes of Health (CA129974) (A.L.). M.S.D. is supported by an American Society of Clinical Oncology Career Development Award. NR 36 TC 12 Z9 12 U1 2 U2 7 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 23 PY 2016 VL 127 IS 25 BP 3215 EP 3224 DI 10.1182/blood-2016-01-688796 PG 10 WC Hematology SC Hematology GA DP2RK UT WOS:000378337700015 PM 27069256 ER PT J AU Tai, YT Acharya, C An, G Moschetta, M Zhong, MY Feng, XY Cea, M Cagnetta, A Wen, K van Eenennaam, H van Elsas, A Qiu, LG Richardson, P Munshi, N Anderson, KC AF Tai, Yu-Tzu Acharya, Chirag An, Gang Moschetta, Michele Zhong, Mike Y. Feng, Xiaoyan Cea, Michele Cagnetta, Antonia Wen, Kenneth van Eenennaam, Hans van Elsas, Andrea Qiu, Lugui Richardson, Paul Munshi, Nikhil Anderson, Kenneth C. TI APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment SO BLOOD LA English DT Article ID CELL MATURATION ANTIGEN; CHRONIC LYMPHOCYTIC-LEUKEMIA; KAPPA-B PATHWAY; DRUG-RESISTANCE; PLASMA-CELLS; MONOCLONAL-ANTIBODY; IMMUNE CHECKPOINT; POOR-PROGNOSIS; STROMAL CELLS; T-CELLS AB Here we show that overexpression or activation of B-cell maturation antigen(BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-kappa B signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor beta, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01Afurther decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-kappa B pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM. C1 [Tai, Yu-Tzu; Acharya, Chirag; An, Gang; Moschetta, Michele; Zhong, Mike Y.; Feng, Xiaoyan; Cea, Michele; Cagnetta, Antonia; Wen, Kenneth; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Tai, Yu-Tzu; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [van Eenennaam, Hans; van Elsas, Andrea] Aduro Biotech Europe, Oss, Netherlands. [Qiu, Lugui] Chinese Acad Med Sci, Inst Hematol, Dept Lymphoma & Myeloma, Tianjin Cord Blood Bank, Tianjin, Peoples R China. [Qiu, Lugui] Peking Union Med Coll, Tianjin, Peoples R China. RP Tai, YT (reprint author), Dana Farber Canc Inst, Dept Med Oncol, M551,450 Brookline Ave, Boston, MA 02215 USA. EM yu-tzu_tai@dfci.harvard.edu FU National Institutes of Health, National Cancer Institute [RO1050947, R01-CA178264, PO1-CA078378]; Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence SPORE in Multiple Myeloma [P50CA100707]; BioNovion FX This work was supported by National Institutes of Health, National Cancer Institute grants RO1050947, R01-CA178264, PO1-CA078378, and the Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence SPORE in Multiple Myeloma P50CA100707. K.C.A. is an American Cancer Society Clinical Research Professor. Fellowship support provided by BioNovion. NR 75 TC 5 Z9 5 U1 2 U2 6 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 23 PY 2016 VL 127 IS 25 BP 3225 EP 3236 DI 10.1182/blood-2016-01-691162 PG 12 WC Hematology SC Hematology GA DP2RK UT WOS:000378337700016 PM 27127303 ER PT J AU Yang, G Buhrlage, SJ Tan, L Liu, X Chen, J Xu, L Tsakmaklis, N Chen, JJG Patterson, CJ Brown, JR Castillo, JJ Zhang, W Zhang, XF Liu, S Cohen, P Hunter, ZR Gray, N Treon, SP AF Yang, Guang Buhrlage, Sara J. Tan, Li Liu, Xia Chen, Jie Xu, Lian Tsakmaklis, Nicholas Chen, Jiaji G. Patterson, Christopher J. Brown, Jennifer R. Castillo, Jorge J. Zhang, Wei Zhang, Xiaofeng Liu, Shuai Cohen, Philip Hunter, Zachary R. Gray, Nathanael Treon, Steven P. TI HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib SO BLOOD LA English DT Article ID TYROSINE KINASE INHIBITOR; B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; L265P SOMATIC MUTATION; WALDENSTROMS MACROGLOBULINEMIA; MULTIPLE-MYELOMA; ACTIVATION; RESISTANCE; EXPRESSION; LYN AB Activating mutations in MYD88 are present in similar to 95% of patients with Waldenstrom macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCLcell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCKwas a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88. C1 [Yang, Guang; Liu, Xia; Chen, Jie; Xu, Lian; Tsakmaklis, Nicholas; Chen, Jiaji G.; Patterson, Christopher J.; Castillo, Jorge J.; Hunter, Zachary R.; Treon, Steven P.] Dana Farber Canc Inst, Dept Med Oncol, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Yang, Guang; Liu, Xia; Chen, Jie; Xu, Lian; Tsakmaklis, Nicholas; Chen, Jiaji G.; Patterson, Christopher J.; Brown, Jennifer R.; Castillo, Jorge J.; Hunter, Zachary R.; Treon, Steven P.] Harvard Univ, Sch Med, 450 Brookline Ave,M546, Boston, MA 02215 USA. [Buhrlage, Sara J.; Tan, Li; Gray, Nathanael] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhang, Wei; Zhang, Xiaofeng; Liu, Shuai] Univ Massachusetts, Dept Chem, Boston, MA 02125 USA. [Cohen, Philip] Univ Dundee, MRC, Prot Phosphorylat & Ubiquitylat Unit, Coll Life Sci, Dundee, Scotland. RP Treon, SP (reprint author), Harvard Univ, Sch Med, 450 Brookline Ave,M546, Boston, MA 02215 USA.; Treon, SP (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,M546, Boston, MA 02215 USA. EM steven_treon@dfci.harvard.edu OI Hunter, Zachary/0000-0002-1689-1691 FU Leukemia and Lymphoma Society; Edward and Linda Nelson Fund for WM Research; Bauman Family Trust; Tannenhauser Family Foundation; International Waldenstrom's Macroglobulinemia Foundation FX The authors gratefully acknowledge the generous support of Peter Bing, the International Waldenstrom's Macroglobulinemia Foundation, the Leukemia and Lymphoma Society, the Edward and Linda Nelson Fund for WM Research, the Bauman Family Trust, the Tannenhauser Family Foundation, and the WM patients who provided samples for these studies. The authors also acknowledge the kind gift of Thomas Smithgall for providing the HCK inhibitor-resistant mutant construct used in these studies. NR 43 TC 4 Z9 4 U1 2 U2 6 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 23 PY 2016 VL 127 IS 25 BP 3237 EP 3252 DI 10.1182/blood-2016-01-695098 PG 16 WC Hematology SC Hematology GA DP2RK UT WOS:000378337700017 PM 27143257 ER PT J AU Lorenzo, ME Carter, JB Barnes, JA Nazarian, RM AF Lorenzo, Mayra E. Carter, Joi B. Barnes, Jeffrey A. Nazarian, Rosalynn M. TI Case 19-2016: A 65-Year-Old Man with End-Stage Renal Disease and a Pruritic Rash SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID T-CELL LEUKEMIA/LYMPHOMA; CUTANEOUS MANIFESTATIONS; LYMPHOMA; SKIN; LEUKAEMIA/LYMPHOMA; FEATURES C1 [Lorenzo, Mayra E.; Carter, Joi B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Barnes, Jeffrey A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lorenzo, Mayra E.; Carter, Joi B.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Barnes, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Nazarian, Rosalynn M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Lorenzo, ME (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA.; Lorenzo, ME (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. 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 23 PY 2016 VL 374 IS 25 BP 2478 EP 2488 DI 10.1056/NEJMcpc1512457 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DP1TG UT WOS:000378271700012 PM 27332907 ER PT J AU Abdelghany, MT Baggett, MV AF Abdelghany, Mazin T. Baggett, Meridale V. TI Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Abdelghany, Mazin T.; Baggett, Meridale V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Abdelghany, MT (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mabdelghany@partners.org NR 4 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 23 PY 2016 VL 374 IS 25 BP 2497 EP 2497 DI 10.1056/NEJMc1603180 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DP1TG UT WOS:000378271700016 PM 27332912 ER PT J AU Stanford, FC Alfaris, N Misra, M AF Stanford, Fatima C. Alfaris, Nasreen Misra, Madhusmita TI Metformin versus Placebo in Obese Pregnant Women without Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Stanford, Fatima C.; Alfaris, Nasreen; Misra, Madhusmita] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Stanford, FC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM fstanford@mgh.harvard.edu OI Stanford, Fatima/0000-0003-4616-533X NR 5 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 23 PY 2016 VL 374 IS 25 BP 2501 EP 2501 DI 10.1056/NEJMc1603067 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DP1TG UT WOS:000378271700022 PM 27332918 ER PT J AU Brackett, CM Furlani, RE Anderson, RG Krishnamurthy, A Melander, RJ Moskowitz, SM Ernst, RK Melander, C AF Brackett, Christopher M. Furlani, Robert E. Anderson, Ryan G. Krishnamurthy, Aparna Melander, Roberta J. Moskowitz, Samuel M. Ernst, Robert K. Melander, Christian TI Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity SO TETRAHEDRON LA English DT Article DE Antibiotic adjuvant; 2-Aminoimidazole; Colistin; ESKAPE pathogens; Acinetobacter baumannii; Pseudomonas aeruginosa ID CYSTIC-FIBROSIS PATIENTS; POLYMYXIN RESISTANCE; BETA-LACTAMS; ANTIBIOTICS AB We recently reported a 2-aminoimidazole-based antibiotic adjuvant that reverses colistin resistance in two species of Gram-negative bacteria. Mechanistic studies in Acinetobacter baumannii demonstrated that this compound downregulated the PmrAB two-component system and abolished a lipid A modification that is required for colistin resistance. We now report the synthesis and evaluation of two separate libraries of substituted 2-aminoimidazole analogues based on this parent compound. From these libraries, a new small molecule was identified that lowers the minimum inhibitory concentration of colistin by up to 32-fold greater than the parent compound while also displaying less inherent bacterial toxicity, thereby minimizing the likelihood of resistance evolution. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Brackett, Christopher M.; Furlani, Robert E.; Anderson, Ryan G.; Krishnamurthy, Aparna; Melander, Roberta J.; Melander, Christian] N Carolina State Univ, Dept Chem, Box 8204, Raleigh, NC 27695 USA. [Moskowitz, Samuel M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Moskowitz, Samuel M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ernst, Robert K.] Univ Maryland, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA. RP Melander, C (reprint author), N Carolina State Univ, Dept Chem, Box 8204, Raleigh, NC 27695 USA. EM ccmeland@ncsu.edu FU National Institutes of Health [GM055769, AI067653]; Cystic Fibrosis Foundation [MOSKOW13P0] FX The authors would like to thank the National Institutes of Health (GM055769 to C.M, AI067653 to S.M.M) and the Cystic Fibrosis Foundation (MOSKOW13P0 to S.M.M.) for their generous support of this work. NR 18 TC 1 Z9 1 U1 3 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD JUN 23 PY 2016 VL 72 IS 25 BP 3549 EP 3553 DI 10.1016/j.tet.2015.09.019 PG 5 WC Chemistry, Organic SC Chemistry GA DO4BA UT WOS:000377725600002 PM 27429479 ER PT J AU Crommentuijn, MHW Kantar, R Noske, DP Vandertop, WP Badr, CE Wurdinger, T Maguire, CA Tannous, BA AF Crommentuijn, Matheus H. W. Kantar, Rami Noske, David P. Vandertop, W. Peter Badr, Christian E. Wurdinger, Thomas Maguire, Casey A. Tannous, Bakhos A. TI Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model SO MOLECULAR THERAPY-ONCOLYTICS LA English DT Article ID APOPTOSIS-INDUCING LIGAND; HEPATOCELLULAR-CARCINOMA GROWTH; TRAIL-INDUCED APOPTOSIS; MALIGNANT GLIOMA-CELLS; GENE-THERAPY; ADENOASSOCIATED VIRUS; PROLONGS SURVIVAL; NUDE-MICE; FACTOR-IX; IN-VIVO AB Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken beta-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors. C1 [Crommentuijn, Matheus H. W.; Kantar, Rami; Badr, Christian E.; Maguire, Casey A.; Tannous, Bakhos A.] Massachusetts Gen Hosp, Ctr Neurosci, Dept Neurol, Expt Therapeut & Mol Imaging Lab, Boston, MA 02114 USA. [Crommentuijn, Matheus H. W.; Kantar, Rami; Badr, Christian E.; Wurdinger, Thomas; Maguire, Casey A.; Tannous, Bakhos A.] Harvard Med Sch, Program Neurosci, Boston, MA 02114 USA. [Crommentuijn, Matheus H. W.; Noske, David P.; Vandertop, W. Peter; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Neuro oncol Res Grp, Dept Neurosurg, Amsterdam, Netherlands. RP Tannous, BA (reprint author), Massachusetts Gen Hosp, Ctr Neurosci, Dept Neurol, Expt Therapeut & Mol Imaging Lab, Boston, MA 02114 USA.; Tannous, BA (reprint author), Harvard Med Sch, Program Neurosci, Boston, MA 02114 USA. EM btannous@hms.harvard.edu FU National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS) [R01NS064983]; American Brain Tumor Association Discovery Grant; KWF Kankerbestrijding (Dutch Cancer Society); NIH/NINDS [P30NS045776] FX This study was supported by grants from the National Institutes of Health (NIH), the National Institute of Neurological Disorders and Stroke (NINDS) R01NS064983 (B.A.T.) and the American Brain Tumor Association Discovery Grant (C.A.M.). The authors acknowledge the support from 1S10RR025504 Shared Instrumentation Grant IVIS imaging system that was used to acquire imaging data. M.H.W.C. was supported by a scholarship from KWF Kankerbestrijding (Dutch Cancer Society). The authors would like to thank Kevin Conway for the production of lentivirus vectors at the MGH Vector Core, Charlestown, MA, USA (supported by NIH/NINDS P30NS045776; BAT). NR 54 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 2372-7705 J9 Mol Ther-Oncolytics JI Mol. Ther.-Oncolytics PD JUN 22 PY 2016 VL 3 AR UNSP 16017 DI 10.1038/mto.2016.17 PG 8 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA EE2WS UT WOS:000389446500001 PM 27382645 ER PT J AU Wang, PF Gaitanaros, S Lee, S Bathe, M Shih, WM Ke, YG AF Wang, Pengfei Gaitanaros, Stavros Lee, Seungwoo Bathe, Mark Shih, William M. Ke, Yonggang TI Programming Self-Assembly of DNA Origami Honeycomb Two-Dimensional Lattices and Plasmonic Metamaterials SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NANOSCALE SHAPES; FINITE-SIZE; FOLDING DNA; NANOSTRUCTURES; ARRAYS; DELIVERY; NANOTUBES; CRYSTALS; NANOPARTICLES; DESIGN AB Scaffolded DNA origami has proven to be a versatile method for generating functional nanostructures with prescribed sub-100 nm shapes. Programming DNA-origami tiles to form large-scale 2D lattices that span hundreds of nanometers to the micrometer scale could provide an enabling platform for diverse applications ranging from metamaterials to surface-based biophysical assays. Toward this end, here we design a family of hexagonal DNA-origami tiles using computer aided design and demonstrate successful self-assembly of micrometer-scale 2D honeycomb lattices and tubes by controlling their geometric and mechanical properties including their interconnecting strands. Our results offer insight into programmed self-assembly of low-defect supra-molecular DNA-origami 2D lattices and tubes. In addition, we demonstrate that these DNA-origami hexagon tiles and honeycomb lattices are versatile platforms for assembling optical metamaterials via programmable spatial arrangement of gold nanoparticles (AuNPs) into cluster and superlattice geometries. C1 [Wang, Pengfei; Ke, Yonggang] Georgia Inst Technol, Wallance H Coulter Dept Biomed Engn, Atlanta, GA 30322 USA. [Wang, Pengfei; Ke, Yonggang] Emory Univ, Atlanta, GA 30322 USA. [Gaitanaros, Stavros; Bathe, Mark] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lee, Seungwoo] Sungkyunkwan Univ SKKU, SKKU Adv Inst Nanotechnol, Suwon 16419, South Korea. [Lee, Seungwoo] Sungkyunkwan Univ SKKU, Sch Chem Engn, Suwon 16419, South Korea. [Shih, William M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Wyss Inst Biol Inspired Engn, 44 Binney St, Boston, MA 02115 USA. [Shih, William M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. [Shih, William M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Ke, YG (reprint author), Georgia Inst Technol, Wallance H Coulter Dept Biomed Engn, Atlanta, GA 30322 USA.; Ke, YG (reprint author), Emory Univ, Atlanta, GA 30322 USA. EM yonggang.ke@emory.edu FU Wallace H. Coulter Department of Biomedical Engineering Faculty Startup Grant; Winship Cancer Institute Billi and Bernie Marcus Research Award; Wyss Institute Faculty Grant; ONR [N000014091118, N000141010241, N000141410609]; NSF DMREF [1435964]; NIH [1DP2OD004641]; NSF CMMI [1334109]; Basic Science Research Program (the National Research Foundation of Korea) [2009-0083540, NRF-2014R1A1A2057763] FX This work is supported by a Wallace H. Coulter Department of Biomedical Engineering Faculty Startup Grant and a Winship Cancer Institute Billi and Bernie Marcus Research Award to Y.K., by a Wyss Institute Faculty Grant, ONR Grants N000014091118 and N000141010241, NSF DMREF Grant 1435964, and an NIH Director's New Innovator Award 1DP2OD004641 to W.M.S., by ONR Grant N000141410609 and NSF CMMI 1334109 to M.B., and by the Basic Science Research Program (the National Research Foundation of Korea, 2009-0083540 and NRF-2014R1A1A2057763) to S.L. NR 66 TC 5 Z9 5 U1 52 U2 113 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 22 PY 2016 VL 138 IS 24 BP 7733 EP 7740 DI 10.1021/jacs.6b03966 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DP6CN UT WOS:000378584600047 PM 27224641 ER PT J AU Skoge, M Wong, E Hamza, B Bae, A Martel, J Kataria, R Keizer-Gunnink, I Kortholt, A Van Haastert, PJM Charras, G Janetopoulos, C Irimia, D AF Skoge, Monica Wong, Elisabeth Hamza, Bashar Bae, Albert Martel, Joseph Kataria, Rama Keizer-Gunnink, Ineke Kortholt, Arjan Van Haastert, Peter J. M. Charras, Guillaume Janetopoulos, Christopher Irimia, Daniel TI A Worldwide Competition to Compare the Speed and Chemotactic Accuracy of Neutrophil-Like Cells SO PLOS ONE LA English DT Article ID DICTYOSTELIUM-DISCOIDEUM; LEUKOCYTE MIGRATION; EUKARYOTIC CHEMOTAXIS; HL-60 CELLS; CYCLIC-AMP; G-PROTEINS; CHEMOATTRACTANT; RECEPTORS; PHOSPHORYLATION; PHAGOCYTOSIS AB Chemotaxis is the ability to migrate towards the source of chemical gradients. It underlies the ability of neutrophils and other immune cells to hone in on their targets and defend against invading pathogens. Given the importance of neutrophil migration to health and disease, it is crucial to understand the basic mechanisms controlling chemotaxis so that strategies can be developed to modulate cell migration in clinical settings. Because of the complexity of human genetics, Dictyostelium and HL60 cells have long served as models system for studying chemotaxis. Since many of our current insights into chemotaxis have been gained from these two model systems, we decided to compare them side by side in a set of winner-take-all races, the Dicty World Races. These worldwide competitions challenge researchers to genetically engineer and pharmacologically enhance the model systems to compete in microfluidic racecourses. These races bring together technological innovations in genetic engineering and precision measurement of cell motility. Fourteen teams participated in the inaugural Dicty World Race 2014 and contributed cell lines, which they tuned for enhanced speed and chemotactic accuracy. The race enabled large-scale analyses of chemotaxis in complex environments and revealed an intriguing balance of speed and accuracy of the model cell lines. The successes of the first race validated the concept of using fun-spirited competition to gain insights into the complex mechanisms controlling chemotaxis, while the challenges of the first race will guide further technological development and planning of future events. C1 [Skoge, Monica] Princeton Univ, Joseph Henry Labs Phys, Princeton, NJ 08544 USA. [Skoge, Monica] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Wong, Elisabeth; Hamza, Bashar; Martel, Joseph; Irimia, Daniel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr,Shriners Burns Hosp, Boston, MA 02115 USA. [Bae, Albert] Max Planck Inst Dynam & Self Org, Gottingen, Germany. [Martel, Joseph] Wentworth Inst Technol, Dept Biomed Engn, Boston, MA USA. [Kataria, Rama; Keizer-Gunnink, Ineke; Kortholt, Arjan; Van Haastert, Peter J. M.] Univ Groningen, Dept Cell Biochem, Groningen, Netherlands. [Charras, Guillaume] UCL, London Ctr Nanotechnol, London, England. [Charras, Guillaume] UCL, Dept Cell & Dev Biol, London, England. [Janetopoulos, Christopher] Allegheny Univ Hlth Sci, Philadelphia, PA 19102 USA. RP Irimia, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr,Shriners Burns Hosp, Boston, MA 02115 USA. EM dirimia@hms.harvard.edu FU National Institutes of Health grant [GM092804]; Office for Science & Technology of the Embassy of France in the United States of America through the program "Life Sciences: inventing - creating - having fun"; Biological and Biotechnological Sciences Research Council Grant [BB/F021402]; K2 Therapeutics; Micromedicine; Formedium; MatTeck FX Microfabrication work was performed at the BioMEMS Research Center (EB002503) at the Massachusetts General Hospitals. Additional support was available through National Institutes of Health grant GM092804 and from the Office for Science & Technology of the Embassy of France in the United States of America through the program "Life Sciences: inventing - creating - having fun". GC was supported by Biological and Biotechnological Sciences Research Council Grant BB/F021402. The prize for the winners of the Dicty World Race 2014 was sponsored by K2 Therapeutics, Micromedicine, Formedium, and MatTeck and individual contributors, through the experiment.com platform for science research crowdfunding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Microfabrication work was performed at the BioMEMS Research Center (EB002503) at the Massachusetts General Hospitals. Additional support was available through National Institutes of Health grant GM092804 and from the Office for Science & Technology of the Embassy of France in the United States of America through the program "Life Sciences: inventing-creating-having fun". GC was supported by Biological and Biotechnological Sciences Research Council Grant BB/F021402. The prize for the winners of the Dicty World Race 2014 was sponsored by K2 Therapeutics, Micromedicine, Formedium, and MatTeck and individual contributors, through the experiment.com platform for science research crowdfunding. We are also very thankful to all the scientist participants who sent us cells and contributed to the success of our endeavor. NR 67 TC 1 Z9 1 U1 4 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 22 PY 2016 VL 11 IS 6 AR e0154491 DI 10.1371/journal.pone.0154491 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP0WX UT WOS:000378212800003 PM 27332963 ER PT J AU Zeng, C Guo, XY Long, JR Kuchenbaecker, KB Droit, A Michailidou, K Ghoussaini, M Kar, S Freeman, A Hopper, JL Milne, RL Bolla, MK Wang, Q Dennis, J Agata, S Ahmed, S Aittomaki, K Andrulis, IL Anton-Culver, H Antonenkova, NN Arason, A Arndt, V Arun, BK Arver, B Bacot, F Barrowdale, D Baynes, C Beeghly-Fadiel, A Benitez, J Bermisheva, M Blomqvist, C Blot, WJ Bogdanova, NV Bojesen, SE Bonanni, B Borresen-Dale, AL Brand, JS Brauch, H Brennan, P Brenner, H Broeks, A Bruning, T Burwinkel, B Buys, SS Cai, QY Caldes, T Campbell, I Carpenter, J Chang-Claude, J Choi, JY Claes, KBM Clarke, C Cox, A Cross, SS Czene, K Daly, MB de la Hoya, M De Leeneer, K Devilee, P Diez, O Domchek, SM Doody, M Dorfling, CM Dork, T dos-Santos-Silva, I Dumont, M Dwek, M Dworniczak, B Egan, K Eilber, U Einbeigi, Z Ejlertsen, B Ellis, S Frost, D Lalloo, F Fasching, PA Figueroa, J Flyger, H Friedlander, M Friedman, E Gambino, G Gao, YT Garber, J Garcia-Closas, M Gehrig, A Damiola, F Lesueur, F Mazoyer, S Stoppa-Lyonnet, D Giles, GG Godwin, AK Goldgar, DE Gonzalez-Neira, A Greene, MH Guenel, P Haeberle, L Haiman, CA Hallberg, E Hamann, U Hansen, TVO Hart, S Hartikainen, JM Hartman, M Hassan, N Healey, S Hogervorst, FBL Verhoef, S Hendricks, CB Hillemanns, P Hollestelle, A Hulick, PJ Hunter, DJ Imyanitov, EN Isaacs, C Ito, H Jakubowska, A Janavicius, R Jaworska-Bieniek, K Jensen, UB John, EM Beauparlant, CJ Jones, M Kabisch, M Kang, D Karlan, BY Kauppila, S Kerin, MJ Khan, S Khusnutdinova, E Knight, JA Konstantopoulou, I Kraft, P Kwong, A Laitman, Y Lambrechts, D Lazaro, C Le Marchand, L Lee, CN Lee, MH Lester, J Li, JM Liljegren, A Lindblom, A Lophatananon, A Lubinski, J Mai, PL Mannermaa, A Manoukian, S Margolin, S Marme, F Matsuo, K McGuffog, L Meindl, A Menegaux, F Montagna, M Muir, K Mulligan, AM Nathanson, KL Neuhausen, SL Nevanlinna, H Newcomb, PA Nord, S Nussbaum, RL Offit, K Olah, E Olopade, OI Olswold, C Osorio, A Papi, L Park-Simon, TW Paulsson-Karlsson, Y Peeters, S Peissel, B Peterlongo, P Peto, J Pfeiler, G Phelan, CM Presneau, N Radice, P Rahman, N Ramus, SJ Rashid, MU Rennert, G Rhiem, K Rudolph, A Salani, R Sangrajrang, S Sawyer, EJ Schmidt, MK Schmutzler, RK Schoemaker, MJ Schurmann, P Seynaeve, C Shen, CY Shrubsole, MJ Shu, XO Sigurdson, A Singer, CF Slager, S Soucy, P Southey, M Steinemann, D Swerdlow, A Szabo, CI Tchatchou, S Teixeira, MR Teo, SH Terry, MB Tessier, DC Teule, A Thomassen, M Tihomirova, L Tischkowitz, M Toland, AE Tung, N Turnbull, C van den Ouweland, AMW van Rensburg, EJ ven den Berg, D Vijai, J Wang-Gohrke, S Weitzel, JN Whittemore, AS Winqvist, R Wong, TY Wu, AH Yannoukakos, D Yu, JC Pharoah, PDP Hall, P Chenevix-Trench, G Dunning, AM Simard, J Couch, FJ Antoniou, AC Easton, DF Zheng, W AF Zeng, Chenjie Guo, Xingyi Long, Jirong Kuchenbaecker, Karoline B. Droit, Arnaud Michailidou, Kyriaki Ghoussaini, Maya Kar, Siddhartha Freeman, Adam Hopper, John L. Milne, Roger L. Bolla, Manjeet K. Wang, Qin Dennis, Joe Agata, Simona Ahmed, Shahana Aittomaki, Kristiina Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arason, Adalgeir Arndt, Volker Arun, Banu K. Arver, Brita Bacot, Francois Barrowdale, Daniel Baynes, Caroline Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina Blomqvist, Carl Blot, William J. Bogdanova, Natalia V. Bojesen, Stig E. Bonanni, Bernardo Borresen-Dale, Anne-Lise Brand, Judith S. Brauch, Hiltrud Brennan, Paul Brenner, Hermann Broeks, Annegien Bruening, Thomas Burwinkel, Barbara Buys, Saundra S. Cai, Qiuyin Caldes, Trinidad Campbell, Ian Carpenter, Jane Chang-Claude, Jenny Choi, Ji-Yeob Claes, Kathleen B. M. Clarke, Christine Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. de la Hoya, Miguel De Leeneer, Kim Devilee, Peter Diez, Orland Domchek, Susan M. Doody, Michele Dorfling, Cecilia M. Doerk, Thilo dos-Santos-Silva, Isabel Dumont, Martine Dwek, Miriam Dworniczak, Bernd Egan, Kathleen Eilber, Ursula Einbeigi, Zakaria Ejlertsen, Bent Ellis, Steve Frost, Debra Lalloo, Fiona Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Friedlander, Michael Friedman, Eitan Gambino, Gaetana Gao, Yu-Tang Garber, Judy Garcia-Closas, Montserrat Gehrig, Andrea Damiola, Francesca Lesueur, Fabienne Mazoyer, Sylvie Stoppa-Lyonnet, Dominique Giles, Graham G. Godwin, Andrew K. Goldgar, David E. Gonzalez-Neira, Anna Greene, Mark H. Guenel, Pascal Haeberle, Lothar Haiman, Christopher A. Hallberg, Emily Hamann, Ute Hansen, Thomas V. O. Hart, Steven Hartikainen, Jaana M. Hartman, Mikael Hassan, Norhashimah Healey, Sue Hogervorst, Frans B. L. Verhoef, Senno Hendricks, Carolyn B. Hillemanns, Peter Hollestelle, Antoinette Hulick, Peter J. Hunter, David J. Imyanitov, Evgeny N. Isaacs, Claudine Ito, Hidemi Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna Jensen, Uffe Birk John, Esther M. Beauparlant, Charles Joly Jones, Michael Kabisch, Maria Kang, Daehee Karlan, Beth Y. Kauppila, Saila Kerin, Michael J. Khan, Sofia Khusnutdinova, Elza Knight, Julia A. Konstantopoulou, Irene Kraft, Peter Kwong, Ava Laitman, Yael Lambrechts, Diether Lazaro, Conxi Le Marchand, Loic Lee, Chuen Neng Lee, Min Hyuk Lester, Jenny Li, Jingmei Liljegren, Annelie Lindblom, Annika Lophatananon, Artitaya Lubinski, Jan Mai, Phuong L. Mannermaa, Arto Manoukian, Siranoush Margolin, Sara Marme, Frederik Matsuo, Keitaro McGuffog, Lesley Meindl, Alfons Menegaux, Florence Montagna, Marco Muir, Kenneth Mulligan, Anna Marie Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Newcomb, Polly A. Nord, Silje Nussbaum, Robert L. Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Olswold, Curtis Osorio, Ana Papi, Laura Park-Simon, Tjoung-Won Paulsson-Karlsson, Ylva Peeters, Stephanie Peissel, Bernard Peterlongo, Paolo Peto, Julian Pfeiler, Georg Phelan, Catherine M. Presneau, Nadege Radice, Paolo Rahman, Nazneen Ramus, Susan J. Rashid, Muhammad Usman Rennert, Gad Rhiem, Kerstin Rudolph, Anja Salani, Ritu Sangrajrang, Suleeporn Sawyer, Elinor J. Schmidt, Marjanka K. Schmutzler, Rita K. Schoemaker, Minouk J. Schuermann, Peter Seynaeve, Caroline Shen, Chen-Yang Shrubsole, Martha J. Shu, Xiao-Ou Sigurdson, Alice Singer, Christian F. Slager, Susan Soucy, Penny Southey, Melissa Steinemann, Doris Swerdlow, Anthony Szabo, Csilla I. Tchatchou, Sandrine Teixeira, Manuel R. Teo, Soo H. Terry, Mary Beth Tessier, Daniel C. Teule, Alex Thomassen, Mads Tihomirova, Laima Tischkowitz, Marc Toland, Amanda E. Tung, Nadine Turnbull, Clare van den Ouweland, Ans M. W. van Rensburg, Elizabeth J. ven den Berg, David Vijai, Joseph Wang-Gohrke, Shan Weitzel, Jeffrey N. Whittemore, Alice S. Winqvist, Robert Wong, Tien Y. Wu, Anna H. Yannoukakos, Drakoulis Yu, Jyh-Cherng Pharoah, Paul D. P. Hall, Per Chenevix-Trench, Georgia Dunning, Alison M. Simard, Jacques Couch, Fergus J. Antoniou, Antonis C. Easton, Douglas F. Zheng, Wei CA EMBRACE GEMO Study Collaborators HEBON KConFab AOCS Investigators TI Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus SO BREAST CANCER RESEARCH LA English DT Article DE Fine-scale mapping; Genetic risk factor; PTHLH; CCDC91; Breast cancer; BRAC1 mutation carriers ID HORMONE-RELATED PROTEIN; GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; SUSCEPTIBILITY LOCI; GENETIC MODIFIERS; OVARIAN-CANCER; LOCALIZATION; METASTASIS; EXPRESSION; ENHANCERS AB Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk. C1 [Zeng, Chenjie; Guo, Xingyi; Long, Jirong; Beeghly-Fadiel, Alicia; Blot, William J.; Cai, Qiuyin; Shrubsole, Martha J.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. [Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Barrowdale, Daniel; Ellis, Steve; Frost, Debra; McGuffog, Lesley; Pharoah, Paul D. 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[HEBON] Netherlands Canc Inst, Coordinating Ctr, Hereditary Breast & Ovarian Canc Res Grp Netherla, Amsterdam, Netherlands. [Hendricks, Carolyn B.] Suburban Hosp, Bethesda, MD USA. [Hendricks, Carolyn B.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Duarte, CA USA. [Hollestelle, Antoinette; Seynaeve, Caroline] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hulick, Peter J.] NorthShore Univ HealthSyst, Ctr Med Genet, Evanston, IL USA. [Hunter, David J.; Kraft, Peter] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Hunter, David J.; Kraft, Peter] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Jakubowska, Anna; Jaworska-Bieniek, Katarzyna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Janavicius, Ramunas] State Res Inst, Ctr Innovat Med, Vilnius, Lithuania. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, Aarhus N, Denmark. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Beauparlant, Charles Joly] Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Beauparlant, Charles Joly] Univ Laval, Quebec City, PQ, Canada. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kauppila, Saila] Univ Oulu, Oulu Univ Hosp, Dept Pathol, Oulu, Finland. [Kerin, Michael J.] Natl Univ Ireland, Sch Med, Galway, Ireland. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Khusnutdinova, Elza] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Konstantopoulou, Irene] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Lambrechts, Diether] Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lazaro, Conxi] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI USA. [Lee, Min Hyuk] Soonchunhyang Univ & Hosp, Dept Surg, Seoul, South Korea. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Manoukian, Siranoush; Peissel, Bernard] INT, Fdn IRCCS Ist Ricovero Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka, Japan. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Newcomb, Polly A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med Genet, San Francisco, CA 94143 USA. [Offit, Kenneth; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Osorio, Ana] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Papi, Laura] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy. [Paulsson-Karlsson, Ylva] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Peeters, Stephanie] Univ Hosp Gasthuisberg, Leuven, Belgium. [Peterlongo, Paolo] Fdn Ist FIRC Italian Fdn Canc Res Oncol Mol, IFOM, Milan, Italy. [Pfeiler, Georg] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Pfeiler, Georg] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Radice, Paolo] INT, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Sect Canc Genet, London, England. [Ramus, Susan J.] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Rashid, Muhammad Usman] SKMCH & RC, Dept Basic Sci, Lahore, Pakistan. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, Haifa, Israel. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, CIO, CMMC, Cologne, Germany. [Salani, Ritu] Ohio State Univ, Coll Med, Obstet & Gynecol, Columbus, OH 43210 USA. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Singer, Christian F.] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Soucy, Penny] Ctr Hosp Univ Quebec Res Ctr, Quebec City, PQ, Canada. [Soucy, Penny] Univ Laval, Quebec City, PQ, Canada. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia. [Steinemann, Doris] Hannover Med Sch, Hannover, Germany. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Szabo, Csilla I.] NHGRI, NIH, Bethesda, MD 20892 USA. [Tchatchou, Sandrine] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Teule, Alex] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Genet Counseling Unit, Barcelona, Spain. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Odense C, Denmark. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Tischkowitz, Marc] McGill Univ, Program Canc Genet, Dept Human Genet, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Tischkowitz, Marc] Univ Cambridge, Sch Med, Cambridge, England. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Offit, Kenneth; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA. [Winqvist, Robert] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Winqvist, Robert] Ctr NordLab Oulu, Northern Finland Lab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore, Singapore. [Yannoukakos, Drakoulis] Aristotle Univ Thessaloniki, Sch Med, Papageorgiou Hosp, Dept Med Oncol, Thessaloniki, Greece. [Yu, Jyh-Cherng] Natl Taiwan Univ Hosp, Dept Surg, Taipei, Taiwan. [Chenevix-Trench, Georgia; KConFab] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Chenevix-Trench, Georgia; AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Inst, Melbourne, Vic, Australia. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Peissel, Bernard/E-8187-2017; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Bruning, Thomas/G-8120-2015; manoukian, siranoush/E-7132-2017; Hartikainen, Jaana/E-6256-2015; Osorio, Ana/I-4324-2014; Li, Jingmei/I-2904-2012; Teo, Soo-hwang/H-2353-2014; Dork, Thilo/J-8620-2012; Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Nord, Silje/R-5212-2016; Khusnutdinova, Elza/A-4810-2013; Brenner, Hermann/B-4627-2017 OI Peissel, Bernard/0000-0001-9233-3571; Khan, Sofia/0000-0003-4185-8882; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166; Evans, Gareth/0000-0002-8482-5784; Bruning, Thomas/0000-0001-9560-5464; manoukian, siranoush/0000-0002-6034-7562; Osorio, Ana/0000-0001-8124-3984; Li, Jingmei/0000-0001-8587-7511; Zheng, Wei/0000-0003-1226-070X; Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572 FU charity Against Breast Cancer [1121258]; Deutsche Krebshilfe; NHMRC; National Breast Cancer Foundation, Cancer Australia; National Institute of Health (USA); Breakthrough Breast Cancer; Institute of Cancer Research; NHS; National Cancer Institute grants [CA 27469]; GOG Statistical and Data Center [CA 37517]; GOG Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program; NCI; ISCIII (Spain) [RD12/00369/0006, 12/00539]; European Regional Development FEDER funds; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756, NKI 2007-3839, 2009 4363]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005, 2014-187.WO76]; BBMRI [NWO 184.021.007/CP46]; Transcan [JTC 2012]; Singapore Breast Cancer Study; HUKM-HKL; Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HIR/MOHE/06]; Cancer Research Initiatives Foundation; NIH [R37CA070867]; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C8620/A8372, C8620/A8857]; European Community Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978, R01 CA77398]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; BBMRI-NL; Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; Cancer Institute NSW; National Breast Cancer Foundation; Breast Cancer Research Trust, UK; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK; Oxford Biomedical Research Centre; US Military Acquisition (ACQ) Activity, Era of Hope Award [W81XWH-05-1-0204]; Institute of Cancer Research (UK); Medical Research Council (UK) Clinical Research Fellowship; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securit, Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council and Herlev Hospital; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/ 00923, PI12/00070]; California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section [103885]; Lon V Smith Foundation [LVS39420]; Against Breast Cancer Registered Charity [1121258]; Baden Wrettemberg Minister of Sciences, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany grants [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation; Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine; Evangelische Kliniken Bonn gGmbH; Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe e. V. [70492]; Hannover Medical School; Helsinki University Central Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry of Health, Labor and Welfare of Japan; Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry Health, Labor and Welfare of Japan; National Cancer Center Research and Development Fund; Takeda Health Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; German Federal Ministry of Research and Education [RUS08/017]; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations and strategic funding of the University of Eastern Finland; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; California Breast Cancer Research Program [1RB-0287, 3 PB-0102, 5 PB-0018, 10 PB-0098]; California Department of Health; National Cancer Institute Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Italian Association for Cancer Research (AIRC); Italian citizens [5/1000]; NIH grants [CA128978, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839]; Ting Tsung and Wei Fong Chao Foundation; VicHealth and Cancer Council Victoria; Australian NHMRC grants [209057, 251553, 504711]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; K.G. Jebsen Centre for Breast Cancer Research; Research Council of Norway grant [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346]; Norwegian Cancer Society; NIH grant [R01CA100374, CA87969, R01CA64277, R01CA148667, R37CA70867]; Finnish Cancer Foundation; Center of Excellence grant [251314]; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) programme through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; National Cancer Institute Thailand; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Stefanie Spielman Breast Cancer fund; OSU Comprehensive Cancer Center; Hellenic Cooperative Oncology Group research grant [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program; Research Excellence II; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Institute of Cancer Research (ICR), London; Massachusetts [R01CA47305]; Wisconsin [R01 CA47147]; New Hampshire centres [R01CA69664]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; U.S. Department of Health and Human Services; National Cancer Institute [CA164920]; Lithuania (BFBOCC-LT), Research Council of Lithuania grant [LIG-07/2012]; Cancer Association of South Africa (CANSA); Morris and Horowitz Families Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08]; RTICC [06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA) [SAF2010-20493]; Office of the Director, National Institutes of Health; Fondazione IRCCS Istituto Nazionale Tumori [5x1000]; FiorGen Foundation for Pharmacogenomics; Cancer Research UK grants [C1287/A10118, C12292/A11174]; NHMRC Program Grant; Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology [SYN11_10_19 NBCA]; NIHR grant; NIHR support; Royal Marsden NHS Foundation Trust; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC); German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; French National Institute of Cancer (INCa); Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI) [P30-CA051008]; Fisher Center for Familial Cancer Research; Swing For the Cure; GOA grant [BOF10/GOA/019]; Ghent University Hospital; Helsinki University Hospital Research Fund; Dutch Cancer Society grants [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research grant [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant NWO [184.021.007/CP46]; Hong Kong Hereditary Breast Cancer Family Registry; Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Research Grants [KTIA-OTKA CK-80745, OTKA K-112228]; Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/OP-9]; ICO: contract grant sponsor; ISCIIIRETIC [RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" programme; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Ministero della Salute and Istituto Oncologico Veneto grant [5x1000]; Liga Portuguesa Contra o Cancro; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; MH CZ - DRO (MMCI) [00209805]; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Charles University in Prague project [UNCE204024]; Andrew Sabin Research Fund; Intramural Research Program of the US National Cancer Institute, NIH; Westat Inc, Rockville [NO2-CP-11019-50, N02-CP-65504]; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), NY; Russian Federation for Basic Research [13-04-92613, 14-04-93959, 15-04-01744]; National Cancer Institute grants; Tissue Bank [CA 27469]; NRG Oncology Statistical and Data Center [CA 37517]; NRG Oncology's Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program, NCI; Ohio State University Comprehensive Cancer Center; ITT (Istituto Toscano Tumori) grants; Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HlR/MOHE/06]; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; Jonsson Comprehensive Cancer Center Foundation; UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA; Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Ovarian Cancer Research Fund (OCRF) grant [258807]; Ann Schreiber Program of Excellence award from the Ovarian Cancer Research Fund [POE/USC/01.12]; National Institute of Health [5 U19 CA148112-02]; Cancer Center Support Grant from the National Cancer Institute [P30 CA014089]; Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004]; [5U01CA113916]; [R01CA140323] FX We thank all the individuals who took part in these studies and all the researchers, study staff, clinicians and other healthcare providers, technicians and administrative staff who have enabled this work to be carried out. In particular, we would like to thank Terence Jack Martin (St Vincents Institute, Melbourne, Australia) for carefully reviewing this manuscript. COGS would not have been possible without the contributions of the following: Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Lesley McGuffog, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCFS wishes to thank Maggie Angelakos, Judi Maskiell and Gillian Dite. ABCS wishes to thank Sten Cornelissen, Richard van Hien, Linde Braaf, Frans Hogervorst, Senno Verhoef, Laura van t Veer, Emiel Rutgers, C Ellen van der Schoot and Femke Atsma. ABCTB wishes to thank Christine Clarke, Rosemary Balleine, Robert Baxter, Stephen Braye, Jane Carpenter, Jane Dahlstrom, John Forbes, Soon Lee, Debbie Marsh, Adrienne Morey, Nirmala Pathmanathan, Rodney Scott, Allan Spigelman, Nicholas Wilcken and Desmond Yip. Samples are made available to researchers on a non-exclusive basis. The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special thanks also go to the Thai Ministry of Public Health (MOPH), doctors and nurses who helped with the data collection process. Finally, the ACP study would like to thank Dr. Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Dr. Pornthep Siriwanarungsan, the Department Director-General of Disease Control who have supported the study throughout. BBCS wishes to thank Eileen Williams, Elaine Ryder-Mills and Kara Sargus. BIGGS wishes to thank Niall McInerney, Gabrielle Colleran, Andrew Rowan and Angela Jones. BOCS wishes to thank The Wellcome Trust Case Control Consortium (see the WTCCC website for a full list of contributing investigators). BSUCH wishes to thank Peter Bugert and Medical Faculty Mannheim. CGPS wishes to thank staff and participants of the Copenhagen General Population Study, and Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank and Dorthe Kjeldgard Hansenor for the excellent technical assistance. CNIO-BCS thanks Guillermo Pita, Charo Alonso, Daniel Herrero, Nuria Alvarez, Pilar Zamora, Primitiva Menendez and the Human Genotyping-CEGEN Unit (CNIO). The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, Eunjung Lee, and Fred Schumacher at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, and Hoda Anton-Culver, Argyrios Ziogas and Hannah Park at the University of California Irvine. DIETCOMPLY thanks the patients, nurses and clinical staff involved in the study.; The University of Westminster Against Breast Cancer Research Unit acknowledges funding from the charity Against Breast Cancer (Registered Charity Number 1121258). ESTHER thanks Hartwig Ziegler, Sonja Wolf and Volker Hermann. GC-HBOC thanks Heide Hellebrand, Stefanie Engert and GC-HBOC (Supported by Deutsche Krebshilfe). GENICA thanks Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany (HB, Wing-Yee Lo, Christina Justenhoven), German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) (HB), Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Yon-Dschun Ko, Christian Baisch), Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer), Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (Ute Hamann), Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany (TB, Beate Pesch, Sylvia Rabstein, Anne Lotz) and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth). GESBC thanks Ursula Eilber. HABCS wishes to thank Michael Bremer. HEBCS wishes to thank Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen and Irja Erkkila. HMBCS wishes to thank Peter Hillemanns, Hans Christiansen and Johann H. Karstens. KBCP wishes to thank Eija Myohanen and Helena Kemilainen. kConFab/AOCS wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the clinical follow up study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. LAABC thanks all the study participants and the entire data collection team, especially Annie Fung and June Yashiki. LMBC wishes to thank Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts. MARIE wishes to thank Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. MBCSG wishes to thank Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and the personnel of the Cogentech Cancer Genetic Test Laboratory. MSKCC thanks Marina Corines and Lauren Jacobs. MTLGEBCS would like to thank Martine Tranchant (CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital, McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. MYBRCA wishes to thank Phuah Sze Yee, Peter Kang, Kang In Nee, Kavitta Sivanandan, Shivaani Mariapun, Yoon Sook-Yee, Daphne Lee, Teh Yew Ching and Nur Aishah Mohd Taib for DNA extraction and patient recruitment. NBCS wishes to thank Dr. Kristine Kleivi, PhD (K.G. Jebsen Centre for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Department of Research, Vestre Viken, Drammen, Norway), Dr. Lars Ottestad, MD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Prof. Em.; Rolf Karesen, MD (Department of Oncology, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway), Dr. Anita Langerod, PhD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Ellen Schlichting, MD (Department for Breast and Endocrine Surgery, Oslo University Hospital Ullevaal, Oslo, Norway), Dr. Marit Muri Holmen, MD (Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway), Prof. Toril Sauer, MD (Department of Pathology at Akershus University hospital, Lorenskog, Norway), Dr. Vilde Haakensen, MD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Olav Engebraten, MD (Institute for Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Oncology, Oslo University Hospital, Oslo, Norway), Prof. Bjorn Naume, MD (Division of Cancer Medicine and Radiotherapy, Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Cecile E. Kiserud, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr. Kristin V. Reinertsen, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Assoc. Prof. Aslaug Helland, MD (Department of Genetics, Institute for Cancer Research and Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Margit Riis, MD (Dept of Breast- and Endocrine Surgery, Oslo University Hospital, Ulleval, Oslo, Norway), Dr. Ida Bukholm, MD (Department of Breast-Endocrine Surgery, Akershus University Hospital, Oslo, Norway and Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway), Prof. Per Eystein Lonning, MD (Section of Oncology, Institute of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital, Bergen, Norway), and Grethe I. Grenaker Alnaes, M.Sc. (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway). NBHS wishes to thank study participants and research staff for their contributions and commitment to this study. OBCS thanks Meeri Otsukka and Kari Mononen. OFBCR wishes to thank Teresa Selander and Nayana Weerasooriya. ORIGO wishes to thank E. Krol-Warmerdam and J. Blom for patient accrual, administering questionnaires and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J. Molenaar. PBCS wishes to thank Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. pKARMA wishes to thank the Swedish Medical Research Counsel. RBCS wishes to thank Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk and the Erasmus MC Family Cancer Clinic. SASBAC thanks the Swedish Medical Research Counsel. SBCGS wishes to thank the study participants and research staff for their contributions and commitment to this study. SBCS wishes to thank Sue Higham, Helen Cramp, Ian Brock, Sabapathy Balasubramanian and Dan Connley. SEARCH wishes to thank the SEARCH and EPIC teams. SGBCC wishes to thank the participants and research coordinator Kimberley Chua.; SKKDKFZS wishes to thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. TNBCC wishes to thank Robert Pilarski and Charles Shapiro who were instrumental in the formation of the OSU Breast Cancer Tissue Bank. We thank the Human Genetics Sample Bank for processing of samples and providing OSU Columbus area control samples. UCIBCS wishes to thank Irene Masunaka. UKBGS wishes to thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre.; CIMBA studies acknowledge the following. BCFR-AU wishes to thank Maggie Angelakos, Judi Maskiell, Gillian Dite and Helen Tsimiklis. BCFR-NY wishes to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON wishes to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT acknowledges Vilius Rudaitis, Laimonas Griskevicius, Ramunas Janavicius. BFBOCC-LV acknowledges Drs. Janis Eglitis, Anna Krilova and Aivars Stengrevics. BMBSA wishes to thank the families who contribute to the BMBSA study. BRICOH wishes to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. CNIO wishes to thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. The CONSIT TEAM wishes to thank Maria Grazia Tibiletti of the Ospedale di Circolo-Universitu dellInsubria,Varese, Italy, Giulietta Scuvera of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Gabriele Capone of the University of Florence, Florence, Italy, Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano, Italy, Aline Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy, Stefania Tommasi e Brunella Pilato of the Istituto Nazionale Tumori "Giovanni Paolo II", Bari, Italy, Liliana Varesco of the IRCCS, AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, Laura Cortesi of the University of Modena and Reggio Emilia, Modena, Italy and Laura Ottini of the University La Sapienza, Rome, Italy. FCCC thanks Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: National Cancer Genetics Network (UNICANCER Genetic Group), France. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon - Centre Leon Berard & Equipe, Genetique du cancer du sein, Centre de Recherche en Cancerologie de Lyon: Olga Sinilnikova dagger, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Melanie Leone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnes Collet, Virginie Moncoutier, Cedrick Lefol, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona, Sandrine Handallou. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Francois Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joelle Fournier, Francoise Revillion, Philippe Vennin dagger, Claude Adenis. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy.; Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Helene Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay. CHU Limoges: Laurence Venat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitie-Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besancon: Marie-Agnes Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. G-FAST wishes to thank the technical support of Ilse Coene en Brecht Crombez. GOG: this study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517), and the GOG Cancer Prevention and Control Committee (CA 101165). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI. HCSC was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. We acknowledge Alicia Tosar for her technical assistance. HCSC wishes to thank the technical support of Ilse Coene en Brecht Crombez. HEBCS would like to thank Dr. Kristiina Aittomaki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkila and Virpi Palola for their help with the HEBCS data and samples. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gomez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HRBCP wishes to thank Hong Kong Sanatoriuma and Hospital for their continual support.; HUNBOCS wishes to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos and Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH wishes to thank the Oncogenetics Group (VHIO), and the High Risk and Cancer Prevention Unit of the University Hospital Vall dHebron. ICO wishes to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. INHERIT would like to thank Dr. Martine Dumont, Martine Tranchant for sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (http://ccge.medschl.cam.ac.uk/research/consortia/icogs/) (BCAC and CIMBA). IPOBCS wishes to thank Drs. Ana Peixoto, Catarina Santos, Patricia Rocha and Pedro Pinto for their skillful contribution to the study. KCONFAB wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the clinical follow up study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. The Modifier Study of Quantitative Effects on Disease (MODSQUAD) acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic) and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). MSKCC wishes to thank Anne Lincoln and Lauren Jacobs. NICCC wishes to thank the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the laboratory team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev. NRG Oncology thanks the investigators of the Australia New Zealand NRG Oncology group. OCGN wishes to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. SEABASS would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL study respectively. The Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from the Cancer Research Initiatives Foundation. The SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study.; Swedish scientists participating as SWE-BRCA collaborators are: Ake Borg, Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller and Ulf Kristoffersson from Lund University and University Hospital; Anna Ofverholm, Margareta Nordling, Per Karlsson and Zakaria Einbeigi from Gothenburg Sahlgrenska University Hospital; Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza and Johanna Rantala from Stockholm and Karolinska University Hospital; Beatrice Melin, Christina Edwinsdotter Ardnor and Monica Emanuelsson from Umea University Hospital; Hans Ehrencrona, Maritta Hellstrom Pigg and Richard Rosenquist from Uppsala University; and Marie Stenmark-Askmalm and Sigrun Liedgren from Linkoping University Hospital. UCHICAGO wishes to thank Cecilia Zvocec, Qun Niu, the physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource and the many families who contribute to our program. UCLA thanks Joyce Seldon, MSGC and Lorna Kwan, MPH, for assembling the data for this study. UCSF would like to thank Dr. Robert Nussbaum and the following genetic counselors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad, and Ms. Salina Chan for data management. UKFOCR thanks Paul Pharoah, Simon Gayther, Susan Ramus, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. UPENN wishes to thank the Breast Cancer Research Foundation, Susan G. Komen Foundation for the cure and Basser Research Center for BRCA. VFCTG wishes to thank Geoffrey Lindeman, Marion Harris and Martin Delatycki of the Victorian Familial Cancer Trials Group. VFCTG also thanks Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing all DNA amplification. Funding was as follows: the work conducted for this project at Vanderbilt Epidemiology Center is supported in part by NIH grant R37CA070867 and endowment funds for the Ingram Professorship and Anne Potter Wilson Chair. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from the European Community Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA14811he GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR.; The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M.C.S. is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363); BBMRI-NL, which is a research infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The Australian Breast Cancer Tissue Bank is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guys & St. Thomas NHS Foundation Trust in partnership with Kings College London, UK. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372 and C8620/A8857), a US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204) and the Institute of Cancer Research (UK). C.T. is funded by a Medical Research Council (UK) Clinical Research Fellowship. BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES) and Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database created by and funded by Against Breast Cancer Registered Charity No. 1121258. The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).; The GC-HBOC was supported by Deutsche Krebshilfe (107 352). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, and the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, and Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by an intramural grant from Hannover Medical School. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry of Health, Labor and Welfare of Japan, by Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry Health, Labor and Welfare of Japan, National Cancer Center Research and Development Fund and Grant form Takeda Health Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and and Bert von Kantzows foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations and strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LAABC is supported by grants (1RB-0287, 3 PB-0102, 5 PB-0018, 10 PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403.; LMBC is supported by the Stichting tegen Kanker (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"). The MCBCS was supported by the NIH grants CA128978, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). The MEC was supported by NIH grants CA63464, CA54281, CA098758 and CA132839. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program, grant number CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade, grant number PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research, the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale) and the Norwegian Cancer Society (to A-L Borresen-Dale and V.N. Kristensen). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted using the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The NHS was funded by NIH grant CA87969.; The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667 and R37CA70867. Biological sample preparation was conducted using the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.; SEBCS was supported by the BRL (Basic Research Laboratory) programme through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund - ESF), and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH (CA58860, CA92044) and the Lon V Smith Foundation (LVS39420). The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centres, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. Support for CIMBA studies: BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names and commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-07/2012; BIDMC is supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg; SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. The CBCS was supported by the NEYE Foundation. CNIO was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493. City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J.; Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funds for CONSIT TEAM were from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects 5x1000) to SM and from FiorGen Foundation for Pharmacogenomics to LP. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. SH is supported by an NHMRC Program Grant to GCT. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. The DEMOKRITOS has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. The DKFZ study was supported by the DKFZ. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eelses is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC was supported by The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). The GEMO study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa). GEORGETOWN (CI) received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing For the Cure. Kim De Leeneer (the G-FAST study) is supported by GOA grant BOF10/GOA/019 (Ghent University) and spearhead financing of Ghent University Hospital. The HCSC was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation.; The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9. ICO: contract grant sponsor, Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" programme, the Canadian Breast Cancer Research Alliance-grant 019511 and the Ministry of Economic Development, Innovation and Export Trade - grant PSR-SIIRI-701. IOVHBOCS is supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant. The IPOBCS study was in part supported by Liga Portuguesa Contra o Cancro. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD was supported by NIH grant:1R01 CA149429-01. The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat Inc, Rockville, MD. NICCC is supported by Clalit Health Services in Israel.; Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO has been supported by the Russian Federation for Basic Research (grants 13-04-92613, 14-04-93959 and 15-04-01744). NRG Oncology was supported by National Cancer Institute grants to the NRG Oncology Administrative Office and Tissue Bank (CA 27469), the NRG Oncology Statistical and Data Center (CA 37517), and NRG Oncologys Cancer Prevention and Control Committee (CA 101165). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI. OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. PBCS was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013. SEABASS was supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited Breast Cancer Consortium. SWE-BRCA collaborators are supported by the Swedish Cancer Society. UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Womens Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor. UCLA was supported by the Jonsson Comprehensive Cancer Center Foundation, Breast Cancer Research Foundation. UCSF was supported by the UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR was supported by a project grant from CRUK to Paul Pharoah. UPENN was supported by National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. UPITT/MWH was supported by the Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program, Hackers for Hope Pittsburgh. Kate Lawrenson is funded by Ovarian Cancer Research Fund (OCRF) grant number 258807 and an Ann Schreiber Program of Excellence award from the Ovarian Cancer Research Fund (POE/USC/01.12). Janet Lee and Howard Shen are funded by National Institute of Health grant number 5 U19 CA148112-02. Tassja Spindler is funded by National Institute of Health grant number CA173531-01. Work was performed within the USC Norris Comprehensive Cancer Center which is supported by a Cancer Center Support Grant (award number P30 CA014089) from the National Cancer Institute. VFCTG was supported by the Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Dr. Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. NR 45 TC 1 Z9 1 U1 22 U2 31 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 21 PY 2016 VL 18 AR 64 DI 10.1186/s13058-016-0718-0 PG 21 WC Oncology SC Oncology GA DR9CE UT WOS:000380193900001 PM 27459855 ER PT J AU Nishino, M AF Nishino, Mizuki TI Immune-related response evaluations during immune-checkpoint inhibitor therapy: establishing a "common language" for the new arena of cancer treatment SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Editorial Material ID CELL LUNG-CANCER; GUIDELINE VERSION 1.1; SOLID TUMORS; RECIST PROGRESSION; CRITERIA; VARIABILITY; IMMUNOTHERAPY; RADIOLOGISTS; MEDICINE; SCANS AB The recent study by Hodi et al. published in the Journal of Clinical Oncology has evaluated unconventional response patterns during PD-1 inhibitor therapy using immune-related response criteria (irRC) in comparison with RECIST1.1, which constitutes an important step to further understand immune-related response phenomena. This commentary discusses the key observations in the study in terms of their implications and pitfalls, and describes unmet needs that remain to be addressed. The article also emphasizes the important role of tumor response criteria as a "common language" to describe the results of cancer treatment, and discusses future directions for further advances of the field of immuno-oncology. C1 [Nishino, Mizuki] Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. [Nishino, Mizuki] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Nishino, M (reprint author), Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA.; Nishino, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Mizuki_Nishino@DFCI.HARVARD.EDU NR 22 TC 2 Z9 2 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD JUN 21 PY 2016 VL 4 AR 30 DI 10.1186/s40425-016-0134-0 PG 4 WC Oncology SC Oncology GA DQ9RI UT WOS:000379546600001 PM 27330803 ER PT J AU Sridharan, V Margalit, DN Lynch, SA Severgnini, M Hodi, FS Haddad, RI Tishler, RB Schoenfeld, JD AF Sridharan, Vishwajith Margalit, Danielle N. Lynch, Stephanie A. Severgnini, Mariano Hodi, F. Stephen Haddad, Robert I. Tishler, Roy B. Schoenfeld, Jonathan D. TI Effects of definitive chemoradiation on circulating immunologic angiogenic cytokines in head and neck cancer patients SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Angiogenesis; Cytokines; Radiation; Head and neck cancer; VEGF; PLGF; Angiopoietins ID SQUAMOUS-CELL CARCINOMA; ENDOTHELIAL GROWTH-FACTOR; HUMAN-PAPILLOMAVIRUS; TUMOR ANGIOGENESIS; ORAL-CAVITY; VEGF; EXPRESSION; THERAPY; RADIATION; ANGIOPOIETIN-2 AB Background: Preclinical studies suggest a synergistic effect between radiation, immunotherapy and anti-angiogenic therapy, although the mechanisms are unclear. Angiogenic cytokines are known to affect the immune system, and their levels may be associated with response to immunotherapy. Here, we assess changes in circulating VEGF, as well as angiogenic cytokines angiopoietin-1 and -2 (Ang1, Ang2), and placental growth factor (PLGF) that occur during definitive chemo-radiotherapy in HNSCC patients. Methods: We prospectively collected blood samples from patients receiving definitive radiation with or without chemotherapy. Serum Ang1, Ang2, VEGF, and PLGF were measured via cytokine assays. Results: The majority of patients had advanced stage, node positive HPV-associated oropharyngeal cancer, and received radiation to a median dose of 70 Gy with concurrent cisplatin. Over the course of treatment, serum VEGF and Ang1 levels decreased in 20/ 24 (84 %, p < 0.0001) and 21/ 24 (88 %, p < 0.0001) patients, respectively, and Ang2 and PLGF levels increased in 20/ 24 (83 %, p < 0.0001) patients. Conclusions: We find significant changes in angiogenic cytokines in the majority of HNSCC patients over the course of chemoradiation. Decreases in VEGF caused by radiation may represent one mechanism of potential synergy with immunotherapy. Increases in Ang2 and PLGF are interesting given their link to tumor associated angiogenesis and poor prognosis. Additional studies are needed to explore synergies between anti-angiogenic treatments, immunotherapy, and chemoradiation in HNSCC. C1 [Sridharan, Vishwajith; Margalit, Danielle N.; Lynch, Stephanie A.; Tishler, Roy B.; Schoenfeld, Jonathan D.] Brigham & Womens Hosp, Dana Farber Canc Ctr, Dept Radiat Oncol, 450 Brookline Ave,L2-57, Boston, MA 02114 USA. [Sridharan, Vishwajith] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. [Severgnini, Mariano; Hodi, F. Stephen] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA USA. [Hodi, F. Stephen; Haddad, Robert I.] Brigham & Womens Hosp, Dana Farber Canc Ctr, Dept Med Oncol, Boston, MA USA. RP Schoenfeld, JD (reprint author), Brigham & Womens Hosp, Dana Farber Canc Ctr, Dept Radiat Oncol, 450 Brookline Ave,L2-57, Boston, MA 02114 USA. EM JDSCHOENFELD@PARTNERS.ORG NR 53 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 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD JUN 21 PY 2016 VL 4 AR 32 DI 10.1186/s40425-016-0138-9 PG 10 WC Oncology SC Oncology GA DQ9RI UT WOS:000379546600003 PM 27330805 ER PT J AU Brown, KA Jones, M Daneman, N Adler, FR Stevens, V Nechodom, KE Goetz, MB Samore, MH Mayer, J AF Brown, Kevin A. Jones, Makoto Daneman, Nick Adler, Frederick R. Stevens, Vanessa Nechodom, Kevin E. Goetz, Matthew B. Samore, Matthew H. Mayer, Jeanmarie TI Importation, Antibiotics, and Clostridium difficile Infection in Veteran Long-Term Care SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MEDICAL-CENTERS; RISK-FACTORS; FACILITIES; DIARRHEA; TRANSMISSION; METAANALYSIS AB Background: Although clinical factors affecting a person's susceptibility to Clostridium difficile infection are well-understood, little is known about what drives differences in incidence across long-term care settings. Objective: To obtain a comprehensive picture of individual and regional factors that affect C difficile incidence. Design: Multilevel longitudinal nested case-control study. Setting: Veterans Health Administration health care regions, from 2006 through 2012. Participants: Long-term care residents. Measurements: Individual-level risk factors included age, number of comorbid conditions, and antibiotic exposure. Regional risk factors included importation of cases of acute care C difficile infection per 10 000 resident-days and antibiotic use per 1000 resident-days. The outcome was defined as a positive result on a long-term care C difficile test without a positive result in the prior 8 weeks. Results: 6012 cases (incidence, 3.7 cases per 10 000 resident-days) were identified in 86 regions. Long-term care C difficile incidence (minimum, 0.6 case per 10 000 resident-days; maximum, 31.0 cases per 10 000 resident-days), antibiotic use (minimum, 61.0 days with therapy per 1000 resident-days; maximum, 370.2 days with therapy per 1000 resident-days), and importation (minimum, 2.9 cases per 10 000 resident-days; maximum, 341.3 cases per 10 000 resident-days) varied substantially across regions. Together, antibiotic use and importation accounted for 75% of the regional variation in C difficile incidence (R-2 = 0.75). Multilevel analyses showed that regional factors affected risk together with individual-level exposures (relative risk of regional antibiotic use, 1.36 per doubling [95% CI, 1.15 to 1.60]; relative risk of importation, 1.23 per doubling [CI, 1.14 to 1.33]). Limitations: Case identification was based on laboratory criteria. Admission of residents with recent C difficile infection from non-Veterans Health Administration acute care sources was not considered. Conclusion: Only 25% of the variation in regional C difficile incidence in long-term care remained unexplained after importation from acute care facilities and antibiotic use were accounted for, which suggests that improved infection control and antimicrobial stewardship may help reduce the incidence of C difficile in long-term care settings. C1 Univ Utah, Salt Lake City, UT USA. [Jones, Makoto] Vet Affairs Salt Lake City Hlth Care Syst, 500 Foothill Dr,Mailstop 182, Salt Lake City, UT 84148 USA. [Daneman, Nick] Sunnybrook Hlth Sci Ctr, 2075 Bayview Ave,G Wing Room 106, Toronto, ON M4N 3M5, Canada. [Goetz, Matthew B.] Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. [Brown, Kevin A.] Publ Hlth Ontario, 480 Univ Ave, Toronto, ON M5G1V2, Canada. [Adler, Frederick R.] Univ Utah, Dept Math, 155 South 1400 East, Salt Lake City, UT 84112 USA. [Stevens, Vanessa] Univ Utah, Coll Pharm, Dept Pharmacotherapy, 30 South 2000 East,Room 4410, Salt Lake City, UT 84112 USA. [Nechodom, Kevin E.; Samore, Matthew H.; Mayer, Jeanmarie] Univ Utah, Sch Med, Dept Internal Med, Div Epidemiol, 295 Chipeta Way, Salt Lake City, UT 84132 USA. RP Brown, KA (reprint author), Publ Hlth Ontario, 480 Univ Ave, Toronto, ON M5G1V2, Canada. EM kevin.brown@oahpp.ca OI Brown, Kevin Antoine/0000-0002-1483-2188 FU Centers for Disease Control and Prevention [11FED1106563]; Veterans Health Administration (Centers of Innovation) [13-414] FX By the Centers for Disease Control and Prevention (Intra-agency agreement 11FED1106563) and the Veterans Health Administration (Centers of Innovation grant 13-414; Advanced Fellowship in Informatics [Dr. Brown]). NR 31 TC 2 Z9 2 U1 0 U2 0 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 21 PY 2016 VL 164 IS 12 BP 787 EP U39 DI 10.7326/M15-1754 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DQ6VG UT WOS:000379343000012 PM 27088642 ER PT J AU Mills, JR Cornec, D Dasari, S Ladwig, PM Hummel, AM Cheu, M Murray, DL Willrich, MA Snyder, MR Hoffman, GS Kallenberg, CGM Langford, CA Merkel, PA Monach, PA Seo, P Spiera, RF St Cair, EW Stone, JH Specks, U Barnidge, DR AF Mills, John R. Cornec, Divi Dasari, Surendra Ladwig, Paula M. Hummel, Amber M. Cheu, Melissa Murray, David L. Willrich, Maria A. Snyder, Melissa R. Hoffman, Gary S. Kallenberg, Cees G. M. Langford, Carol A. Merkel, Peter A. Monach, Paul A. Seo, Philip Spiera, Robert F. St Cair, E. William Stone, John H. Specks, Ulrich Barnidge, David R. TI Using Mass Spectrometry to Quantify Rituximab and Perform Individualized Immunoglobulin Phenotyping in ANCA-Associated Vasculitis SO ANALYTICAL CHEMISTRY LA English DT Article ID LC-MS/MS; MONOCLONAL IMMUNOGLOBULINS; LIGHT-CHAINS; QUANTIFICATION; SERUM; PEPTIDES; ANTIBODY; INDUCTION; BIOMARKER; DISEASE AB Therapeutic monoclonal immunoglobulins (mAbs) are used to treat patients with a wide range of disorders including autoimmune diseases. As pharmaceutical companies bring more fully humanized therapeutic mAb drugs to the healthcare market analytical platforms that perform therapeutic drug monitoring (TDM) without relying on mAb specific reagents will be needed. In this study we demonstrate that liquid-chromatography mass spectrometry (LC-MS) can be used to perform TDM of mAbs in the same manner as smaller nonbiologic drugs. The assay uses commercially available reagents combined with heavy and light chain disulfide bond reduction followed by light chain analysis by microflow-LC electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-Q-TOF MS). Quantification is performed using the peak areas from multiply charged mAb light chain ions using an in-house developed software package developed for TDM of mAbs. The data presented here demonstrate the ability of an LC-MS assay to quantify a therapeutic mAb in a large cohort of patients in a clinical trial. The ability to quantify any mAb in serum via the reduced light chain without the need for reagents specific for each mAb demonstrates the unique capabilities of LC-MS. This fact, coupled with the ability to phenotype a patient's polydonal repertoire in the same analysis further shows the potential of this approach to mAb analysis. C1 [Mills, John R.; Ladwig, Paula M.; Murray, David L.; Willrich, Maria A.; Snyder, Melissa R.; Barnidge, David R.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Cornec, Divi; Hummel, Amber M.; Specks, Ulrich] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN 55905 USA. [Cornec, Divi] Brest Univ Hosp, Dept Rheumatol, F-29609 Brest, France. [Dasari, Surendra] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Cheu, Melissa] Genentech Inc, San Francisco, CA 94080 USA. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 GZ Groningen, Netherlands. [Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Monach, Paul A.] Boston Univ, Med Ctr, Boston, MA 02115 USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Spiera, Robert F.] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [St Cair, E. William] Duke Univ, Durham, NC 27710 USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Barnidge, DR (reprint author), Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. EM barnidge.david@mayo.edu FU National Institute of Allergy and Infectious Diseases [N01-AI-15416, ITN021AI]; Genentech, Inc.; Biogen IDEC, Inc.; European Union [668036]; French Society of Rheumatology FX The rituximab versus cyclophosphamide for ANCA-associated vasculitis (RAVE) trial, from which this data was obtained, was supported by a grant from the National Institute of Allergy and Infectious Diseases to the Immune Tolerance Network (Grant N01-AI-15416; Protocol No. ITN021AI). Genentech, Inc. and Biogen IDEC, Inc. provided the study medications and partial funding for the trial. Genentech, Inc. performed the rituximab concentration measurements by ELISA for the trial. This project also received funding from the European Union's Horizon 2020 Research and Innovation Program under Grant Agreement No. 668036 (RELENT). Divi Cornec received a fellowship grant from the French Society of Rheumatology. NR 21 TC 0 Z9 0 U1 4 U2 6 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 21 PY 2016 VL 88 IS 12 BP 6317 EP 6325 DI 10.1021/acs.analchem.6b00544 PG 9 WC Chemistry, Analytical SC Chemistry GA DP4MO UT WOS:000378470200034 PM 27228216 ER PT J AU Lu, XR Wood, DK Higgins, JM AF Lu, Xinran Wood, David K. Higgins, John M. TI Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension SO BIOPHYSICAL JOURNAL LA English DT Article ID RISK-FACTORS; DISEASE; HEMOGLOBIN; ANEMIA; VASOOCCLUSION; SATURATION; DEFORMABILITY; HEMATOLOGY; CHILDREN; RHEOLOGY AB The majority of morbidity and mortality in sickle cell disease is caused by vaso-occlusion: circulatory obstruction leading to tissue ischemia and infarction. The consequences of vaso-occlusion are seen clinically throughout the vascular tree, from the relatively high-oxygen and high-velocity cerebral arteries to the relatively low-oxygen and low-velocity postcapillary venules. Prevailing models of vaso-occlusion propose mechanisms that are relevant only to regions of low oxygen and low velocity, leaving a wide gap in our understanding of the most important pathologic process in sickle cell disease. Progress toward understanding vaso-occlusion is further challenged by the complexity of the multiple processes thought to be involved, including, but not limited to 1) deoxygenation-dependent hemoglobin polymerization leading to impaired rheology, 2) endothelial and leukocyte activation, and 3) altered cellular adhesion. Here, we chose to focus exclusively on deoxygenation-dependent rheologic processes in an effort to quantify their contribution independent of the other processes that are likely involved in vivo. We take advantage of an experimental system that, to our knowledge, uniquely enables the study of pressure-driven blood flow in physiologic-sized tubes at physiologic hematocrit under controlled oxygenation conditions, while excluding the effects of endothelium, leukocyte activation, adhesion, inflammation, and coagulation. We find that deoxygenation-dependent rheologic processes are sufficient to increase apparent viscosity significantly, slowing blood flow velocity at arterial oxygen tension even without additional contributions from inflammation, adhesion, and endothelial and leukocyte activation. We quantify the changes in apparent viscosity and define a set of functional regimes of sickle cell blood flow personalized for each patient that may be important in further dissecting mechanisms of in vivo vaso-occlusion as well as in assessing risk of patient complications, response to transfusion, and the optimization of experimental therapies in development. C1 [Lu, Xinran; Wood, David K.] Univ Minnesota, Dept Biomed Engn, Minneapolis, MN USA. [Higgins, John M.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Higgins, John M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Higgins, John M.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Wood, DK (reprint author), Univ Minnesota, Dept Biomed Engn, Minneapolis, MN USA.; Higgins, JM (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.; Higgins, JM (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Higgins, JM (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. EM dkwood@umn.edu; john_higgins@hms.harvard.edu FU National Heart, Lung, and Blood Institute (NHLBI) [R21HL130818]; NHLBI [HL114476]; National Institutes of Health (NIH) Director's New Innovator Award [DP2DK098087]; American Heart Association [13SDG6450000] FX This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R21HL130818. J.M.H. was also supported by NHLBI grant HL114476, and a National Institutes of Health (NIH) Director's New Innovator Award (DP2DK098087). D.K.W. was also supported by the American Heart Association under grant 13SDG6450000. NR 36 TC 1 Z9 1 U1 4 U2 5 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 21 PY 2016 VL 110 IS 12 BP 2751 EP 2758 DI 10.1016/j.bpj.2016.04.050 PG 8 WC Biophysics SC Biophysics GA DP3HG UT WOS:000378383300022 PM 27332133 ER PT J AU Toh, CXD Chan, JW Chong, ZS Wang, HF Guo, HC Satapathy, S Ma, DR Goh, GYL Khattar, E Yang, L Tergaonkar, V Chang, YT Collins, JJ Daley, GQ Wee, KB EL Farran, CA Li, H Lim, YP Bard, FA Loh, YH AF Toh, Cheng-Xu Delon Chan, Jun-Wei Chong, Zheng-Shan Wang, Hao Fei Guo, Hong Chao Satapathy, Sandeep Ma, Dongrui Goh, Germaine Yen Lin Khattar, Ekta Yang, Lin Tergaonkar, Vinay Chang, Young-Tae Collins, James J. Daley, George Q. Wee, Keng Boon EL Farran, Chadi A. Li, Hu Lim, Yoon-Pin Bard, Frederic A. Loh, Yuin-Han TI RNAi Reveals Phase-Specific Global Regulators of Human Somatic Cell Reprogramming SO CELL REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN IPSC GENERATION; HUMAN FIBROBLASTS; DEFINED FACTORS; GENOME; TRANSITION; PATHWAY AB Incomplete knowledge of the mechanisms at work continues to hamper efforts to maximize reprogramming efficiency. Here, we present a systematic genome-wide RNAi screen to determine the global regulators during the early stages of human reprogramming. Our screen identifies functional repressors and effectors that act to impede or promote the reprogramming process. Repressors and effectors form close interacting networks in pathways, including RNA processing, G protein signaling, protein ubiquitination, and chromatin modification. Combinatorial knockdown of five repressors (SMAD3, ZMYM2, SFRS11, SAE1, and ESET) synergistically resulted in similar to 85% TRA-1-60-positive cells. Removal of the novel splicing factor SFRS11 during reprogramming is accompanied by rapid acquisition of pluripotency-specific spliced forms. Mechanistically, SFRS11 regulates exon skipping and mutually exclusive splicing of transcripts in genes involved in cell differentiation, mRNA splicing, and chromatin modification. Our study provides insights into the reprogramming process, which comprises comprehensive and multi-layered transcriptional, splicing, and epigenetic machineries. C1 [Toh, Cheng-Xu Delon; Chan, Jun-Wei; Chong, Zheng-Shan; Wang, Hao Fei; Guo, Hong Chao; Satapathy, Sandeep; EL Farran, Chadi A.; Loh, Yuin-Han] A STAR Inst Mol & Cell Biol, Epigenet & Cell Fates Lab, 61 Biopolis Dr Proteos, Singapore 138673, Singapore. [Toh, Cheng-Xu Delon; Lim, Yoon-Pin; Loh, Yuin-Han] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, 28 Med Dr, Singapore 117456, Singapore. [Wang, Hao Fei; EL Farran, Chadi A.; Loh, Yuin-Han] Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore. [Guo, Hong Chao] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China. [Ma, Dongrui] Natl Heart Ctr Singapore, RDU, 5th Hosp Dr, Singapore 169609, Singapore. [Goh, Germaine Yen Lin; Bard, Frederic A.] A STAR Inst Mol & Cell Biol, Membrane Traff Lab, 61 Biopolis Dr Proteos, Singapore 138673, Singapore. [Khattar, Ekta; Tergaonkar, Vinay] A STAR Inst Mol & Cell Biol, Lab NF KB Signaling, Div Canc Genet & Therapeut, 61 Biopolis Dr Proteos, Singapore 138673, Singapore. [Yang, Lin] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Yang, Lin] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Yang, Lin; Collins, James J.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02114 USA. [Tergaonkar, Vinay; Lim, Yoon-Pin; Bard, Frederic A.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117545, Singapore. [Chang, Young-Tae] A STAR Singapore Bioimaging Consortium SBIC, Lab Bioimaging Probe Dev, 11 Biopolis Way Helios, Singapore 138673, Singapore. [Chang, Young-Tae] Natl Univ Singapore, Inst Life Sci, Dept Chem, 3 Sci Dr 3, Singapore 117543, Singapore. [Chang, Young-Tae] Natl Univ Singapore, Inst Life Sci, MedChem Program, 3 Sci Dr 3, Singapore 117543, Singapore. [Collins, James J.] MIT, Dept Biol Engn, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Collins, James J.] MIT, Synthet Biol Ctr, Cambridge, MA 02139 USA. [Collins, James J.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Collins, James J.] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Wee, Keng Boon] A STAR Inst High Performance Comp IHPC, Singapore 138632, Singapore. [Wee, Keng Boon; Lim, Yoon-Pin] A STAR Bioinformat Inst, Singapore 138671, Singapore. [Li, Hu] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Ctr Individualized Med, Rochester, MN 55905 USA. RP Loh, YH (reprint author), A STAR Inst Mol & Cell Biol, Epigenet & Cell Fates Lab, 61 Biopolis Dr Proteos, Singapore 138673, Singapore.; Lim, YP; Loh, YH (reprint author), Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, 28 Med Dr, Singapore 117456, Singapore.; Loh, YH (reprint author), Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore.; Lim, YP (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117545, Singapore.; Lim, YP (reprint author), A STAR Bioinformat Inst, Singapore 138671, Singapore.; Li, H (reprint author), Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Ctr Individualized Med, Rochester, MN 55905 USA. EM li.hu@mayo.edu; bchlyp@nus.edu.sg; yhloh@imcb.a-star.edu.sg RI Chang, Young-Tae/B-2780-2010 OI Chang, Young-Tae/0000-0002-1927-3688 FU National Institutes of Health [CA196631-01A1, 1U54GM114838-01]; A*Star Investigatorship [JCO R09138, JCO R09125]; Biomedical Research Council, Agency for Science, Technology and Research, Singapore FX We are grateful to Kenneth Zaret and Samantha Seah for helpful discussion. We thank Tan Yong-Si, Kin Xiao-Xuan, and Julien Maury for technical assistance. H.L. supported by grants from the National Institutes of Health (CA196631-01A1 and 1U54GM114838-01). Y.-H.L. is supported by the A*Star Investigatorship research award and grants JCO R09138 and JCO R09125. We are grateful to the Biomedical Research Council, Agency for Science, Technology and Research, Singapore for research funding. NR 29 TC 2 Z9 2 U1 3 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 21 PY 2016 VL 15 IS 12 BP 2597 EP 2607 DI 10.1016/j.celrep.2016.05.049 PG 11 WC Cell Biology SC Cell Biology GA DP1NE UT WOS:000378255900004 PM 27292646 ER PT J AU Spangle, JM Dreijerink, KM Groner, AC Cheng, HL Ohlson, CE Reyes, J Lin, CY Bradner, J Zhao, JJ Roberts, TM Brown, M AF Spangle, Jennifer M. Dreijerink, Koen M. Groner, Anna C. Cheng, Hailing Ohlson, Carolynn E. Reyes, Jaime Lin, Charles Y. Bradner, James Zhao, Jean J. Roberts, Thomas M. Brown, Myles TI PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer SO CELL REPORTS LA English DT Article ID HISTONE DEMETHYLASE RBP2; CELL-GROWTH; RNA-SEQ; PHOSPHORYLATION; DIFFERENTIATION; REVEALS; COMPLEX; TRIMETHYLATION; PROGRESSION; ACTIVATION AB Post-translational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show that H3K4me3 is increased in breast tumors driven by an activated PIK3CA allele and that inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy. Supporting a role for KDM5A in mediating PI3K/AKT transcriptional effects, the decreased expression in response to AKT inhibition of a subset of cell-cycle genes associated with poor clinical outcome is blunted by KDM5A silencing. Our data identify a mechanism by which PI3K/AKT signaling modulates the cancer epigenome through controlling H3K4 methylation and suggest that KDM5A subcellular localization and genome occupancy may be pharmacodynamic markers of the activity of PI3K/AKT inhibitors currently in clinical development. C1 [Spangle, Jennifer M.; Cheng, Hailing; Ohlson, Carolynn E.; Zhao, Jean J.; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. [Spangle, Jennifer M.; Zhao, Jean J.; Roberts, Thomas M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 44 Binney St, Boston, MA 02115 USA. [Dreijerink, Koen M.; Groner, Anna C.; Reyes, Jaime; Lin, Charles Y.; Bradner, James; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Dreijerink, Koen M.; Groner, Anna C.; Brown, Myles] Harvard Univ, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02115 USA. [Cheng, Hailing] Dalian Med Univ, Hosp 2, Inst Canc, Dalian 116044, Peoples R China. RP Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA.; Roberts, TM (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 44 Binney St, Boston, MA 02115 USA.; Brown, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA.; Brown, M (reprint author), Harvard Univ, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02115 USA. EM thomas_roberts@dfci.harvard.edu; myles_brown@dfci.harvard.edu FU NIH [5-P50-CA168504-03]; American Cancer Society [125303-PF-13-097-01-CCE]; Dutch Cancer Society [UU2012-5370] FX We thank Dr. W. Kaelin (DFCI) for generously providing the pBabeHA-FLAG-KDM5A plasmid and the KDM5A #1416 antibody, Drs. Y. Shi and A. Heilmann for project discussions, and I. Koutsopatriy for technical assistance. This study was supported in part by grants from the NIH (5-P50-CA168504-03 to T.M.R. and J.J.Z.), the American Cancer Society (125303-PF-13-097-01-CCE to J.M.S.), the Dutch Cancer Society (UU2012-5370 to K.M.D.), and Susan G. Komen (to M.B.). NR 47 TC 3 Z9 3 U1 4 U2 10 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 21 PY 2016 VL 15 IS 12 BP 2692 EP 2704 DI 10.1016/j.celrep.2016.05.046 PG 13 WC Cell Biology SC Cell Biology GA DP1NE UT WOS:000378255900012 PM 27292631 ER PT J AU Lv, CX Stewart, WJ Akanyeti, O Frederick, C Zhu, J Santos-Sacchi, J Sheets, L Liao, JC Zenisek, D AF Lv, Caixia Stewart, William J. Akanyeti, Otar Frederick, Courtney Zhu, Jie Santos-Sacchi, Joseph Sheets, Lavinia Liao, James C. Zenisek, David TI Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels SO CELL REPORTS LA English DT Article ID RETINAL BIPOLAR CELLS; SACCULAR HAIR-CELLS; ACTIVE ZONES; POSTSYNAPTIC CURRENTS; EXOCYTOSIS; ZEBRAFISH; VESICLES; RELEASE; TRANSMISSION; FREQUENCY AB Synaptic ribbons are structures made largely of the protein Ribeye that hold synaptic vesicles near release sites in non-spiking cells in some sensory systems. Here, we introduce frameshift mutations in the two zebrafish genes encoding for Ribeye and thus remove Ribeye protein from neuromast hair cells. Despite Ribeye depletion, vesicles collect around ribbon-like structures that lack electron density, which we term ``ghost ribbons.'' Ghost ribbons are smaller in size but possess a similar number of smaller vesicles and are poorly localized to synapses and calcium channels. These hair cells exhibit enhanced exocytosis, as measured by capacitance, and recordings from afferent neurons post-synaptic to hair cells show no significant difference in spike rates. Our results suggest that Ribeye makes up most of the synaptic ribbon density in neuromast hair cells and is necessary for proper localization of calcium channels and synaptic ribbons. C1 [Lv, Caixia; Frederick, Courtney; Zhu, Jie; Santos-Sacchi, Joseph; Zenisek, David] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, 333 Cedar St, New Haven, CT 06520 USA. [Zenisek, David] Yale Univ, Sch Med, Dept Opthalmol & Visual Sci, 333 Cedar St, New Haven, CT 06520 USA. [Santos-Sacchi, Joseph] Yale Univ, Sch Med, Dept Surg Otolaryngol, 333 Cedar St, New Haven, CT 06520 USA. [Santos-Sacchi, Joseph] Yale Univ, Sch Med, Dept Neurosci, 333 Cedar St, New Haven, CT 06520 USA. [Stewart, William J.; Akanyeti, Otar; Liao, James C.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. [Stewart, William J.; Akanyeti, Otar; Liao, James C.] Univ Florida, Dept Biol, St Augustine, FL 32080 USA. [Sheets, Lavinia] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Sheets, Lavinia] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02114 USA. RP Zenisek, D (reprint author), Yale Univ, Sch Med, Dept Cellular & Mol Physiol, 333 Cedar St, New Haven, CT 06520 USA.; Zenisek, D (reprint author), Yale Univ, Sch Med, Dept Opthalmol & Visual Sci, 333 Cedar St, New Haven, CT 06520 USA. EM david.zenisek@yale.edu OI Sheets, Lavinia/0000-0001-5231-2450 FU NIH [EY021195, DC008130, DC010809]; Amelia Peabody Charitable Fund; National Science Foundation [IOS1257150] FX This work was funded by NIH grants EY021195 (to D.Z.), DC008130 (to J.S.-S.), and DC010809 (to J.C.L.); the Amelia Peabody Charitable Fund (to L.S.); and National Science Foundation grant IOS1257150 (to J.C.L.). NR 48 TC 0 Z9 0 U1 2 U2 2 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 21 PY 2016 VL 15 IS 12 BP 2784 EP 2795 DI 10.1016/j.celrep.2016.05.045 PG 12 WC Cell Biology SC Cell Biology GA DP1NE UT WOS:000378255900019 PM 27292637 ER PT J AU van der Sijde, JN Karanasos, A Villiger, M Bouma, BE Regar, E AF van der Sijde, Johannes N. Karanasos, Antonios Villiger, Martin Bouma, Brett E. Regar, Evelyn TI First-in-man assessment of plaque rupture by polarization-sensitive optical frequency domain imaging in vivo SO EUROPEAN HEART JOURNAL LA English DT Editorial Material C1 [van der Sijde, Johannes N.; Karanasos, Antonios; Regar, Evelyn] Erasmus MC, Dept Intervent Cardiol, Thoraxctr, BA 585,Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands. [Villiger, Martin; Bouma, Brett E.] Harvard Univ, Sch Med, Boston, MA USA. [Villiger, Martin; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Regar, E (reprint author), Erasmus MC, Dept Intervent Cardiol, Thoraxctr, BA 585,Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands. EM e.regar@erasmusmc.nl NR 0 TC 2 Z9 2 U1 3 U2 5 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 2016 VL 37 IS 24 BP 1932 EP 1932 DI 10.1093/eurheartj/ehw179 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP5KF UT WOS:000378534300015 PM 27174288 ER PT J AU Ginsberg, JP AF Ginsberg, J. P. TI Editorial: Dysregulation of Autonomic Cardiac Control by Traumatic Stress and Anxiety SO FRONTIERS IN PSYCHOLOGY LA English DT Editorial Material DE autonomic nervous system; traumatic stress; heart rate variability; Hrv biofeedback; cardiac psychology C1 [Ginsberg, J. P.] US Dept Vet Affairs, Dorn VA Med Ctr, Dorn Res Inst, Columbia, SC USA. RP Ginsberg, JP (reprint author), US Dept Vet Affairs, Dorn VA Med Ctr, Dorn Res Inst, Columbia, SC USA. EM jay.ginsberg@va.gov NR 6 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUN 21 PY 2016 VL 7 AR 945 DI 10.3389/fpsyg.2016.00945 PG 2 WC Psychology, Multidisciplinary SC Psychology GA DP2CX UT WOS:000378296800001 PM 27445913 ER PT J AU Sun, RR Shen, J Gao, Y Zhou, YB Yu, ZJ Hornicek, F Kan, QC Duan, ZF AF Sun, Ranran Shen, Jacson Gao, Yan Zhou, Yubing Yu, Zujiang Hornicek, Francis Kan, Quancheng Duan, Zhenfeng TI Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential SO ONCOTARGET LA English DT Article DE osteosarcoma; EZH2; tissue microarray; proliferation; apoptosis ID AGGRESSIVE BREAST-CANCER; TUMOR-CELL PROLIFERATION; STEM-CELLS; PROSTATE-CANCER; HISTONE H3; GENE; PROGRESSION; EXPRESSION; INVASION; INHIBITOR AB Osteosarcoma is a primary malignant bone tumor that has a poor prognosis due to local recurrence, metastasis, and chemotherapy resistance. Therefore, there is an urgent need to develop novel potential therapeutic targets for osteosarcoma. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of proteins, which has important functions in epigenetic silencing and cell cycle regulation. Overexpression of EZH2 has been found in several malignancies, however, its expression and the role of EZH2 in osteosarcoma is largely unknown. In this study, we examined EZH2 expression by immunohistochemistry in a large series of osteosarcoma tissues in association with tumor characteristics and patient outcomes. EZH2 expression was also analyzed in a microarray dataset of osteosarcoma. Results showed that higher expression of EZH2 was significantly associated with more aggressive tumor behavior and poor patient outcomes of osteosarcoma. We subsequently investigated the functional and therapeutic relevance of EZH2 as a target in osteosarcoma. Immunohistochemical analysis indicated that EZH2 expression was significantly associated with more aggressive tumor behavior and poorer patient outcomes of osteosarcoma. EZH2 silencing by siRNA inhibited osteosarcoma cell growth, proliferation, migration, and invasion. Moreover, suppression of EZH2 attenuated cancer stem cell functions. Similar results were observed in osteosarcoma cells treated with EZH2 specific inhibitor 3-deazaneplanocin A (DZNep), which exhausted cellular levels of EZH2. These results suggest that EZH2 is critical for the growth and metastasis of osteosarcoma, and an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma. C1 [Sun, Ranran; Zhou, Yubing; Yu, Zujiang; Kan, Quancheng; Duan, Zhenfeng] Zhengzhou Univ, Affiliated Hosp 1, Dept Infect Dis, Zhengzhou 450052, Henan, Peoples R China. [Sun, Ranran; Shen, Jacson; Gao, Yan; Hornicek, Francis; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. RP Kan, QC; Duan, ZF (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Infect Dis, Zhengzhou 450052, Henan, Peoples R China.; Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. EM qckan19632012@163.com; zduan@mgh.harvard.edu FU Joint Research Fund devoted to clinical pharmacy and precision medicine; National Natural Science Foundation of China [81402266, 81372875]; Gattegno fund; Kenneth Stanton Fund; Wechsler fund; 5451 project of Health Science and Technology of Henan Province, China FX This work was supported by a Joint Research Fund devoted to clinical pharmacy and precision medicine (Z.D and Q.K). Support has also been provided by the National Natural Science Foundation of China (No.: 81402266 and 81372875), the Gattegno and Wechsler funds, and the Kenneth Stanton Fund. Dr. Sun is supported by the 5451 project of Health Science and Technology of Henan Province, China. NR 43 TC 2 Z9 2 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 21 PY 2016 VL 7 IS 25 BP 38333 EP 38346 DI 10.18632/oncotarget.9518 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DP1CW UT WOS:000378229100073 PM 27223261 ER PT J AU Dasgupta, P Dorsey, NJ Li, JQ Qi, XL Smith, EP Yamaji-Kegan, K Keegan, AD AF Dasgupta, Preeta Dorsey, Nicolas J. Li, Jiaqi Qi, Xiulan Smith, Elizabeth P. Yamaji-Kegan, Kazuyo Keegan, Achsah D. TI The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation SO SCIENCE SIGNALING LA English DT Article ID IL-4 RECEPTOR; SIGNAL TRANSDUCER; AIRWAY HYPERRESPONSIVENESS; MUCUS PRODUCTION; GENE-EXPRESSION; CELL-GROWTH; ALPHA-CHAIN; C/EBP-BETA; TH2 CELLS; IN-VIVO AB Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in response to the cytokines interleukin-4 (IL-4) and IL-13, which results in activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. IL-4 and IL-13 contribute to allergic lung inflammation. To examine the role of IRS2 in allergic disease, we evaluated the responses of IRS2-deficient (IRS2(-/-)) mice. Unexpectedly, loss of IRS2 resulted in a substantial increase in the expression of a subset of genes associated with the generation of alternatively activated macrophages (AAMs) in response to IL-4 or IL-13 in vitro. AAMs secrete factors that enhance allergic responses and promote airway remodeling. Moreover, compared to IRS2(+/+) mice, IRS2+/- and IRS2(-/-) mice developed enhanced pulmonary inflammation, accumulated eosinophils and AAMs, and exhibited airway and vascular remodeling upon allergen stimulation, responses that partially depended onmacrophage-intrinsic IRS2 signaling. Both in unstimulated and IL-4-stimulated macrophages, lack of IRS2 enhanced phosphorylation of Akt and ribosomal S6 protein. Thus, we identified a critical inhibitory loop downstream of IRS2, demonstrating an unanticipated and previously unrecognized role for IRS2 in suppressing allergic lung inflammation and remodeling. C1 [Dasgupta, Preeta; Li, Jiaqi; Qi, Xiulan; Smith, Elizabeth P.; Keegan, Achsah D.] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, 800 West Baltimore St, Baltimore, MD 21201 USA. [Dasgupta, Preeta; Keegan, Achsah D.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Dorsey, Nicolas J.] Univ Maryland, Sch Med, Med Scientist Training Program, Baltimore, MD 21201 USA. [Yamaji-Kegan, Kazuyo] Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, 720 Rutland Ave, Baltimore, MD 21205 USA. [Keegan, Achsah D.] Vet Affairs Maryland Hlth Care Syst, US Dept Vet Affairs, Res & Dev Serv, Baltimore, MD 21201 USA. RP Keegan, AD (reprint author), Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, 800 West Baltimore St, Baltimore, MD 21201 USA.; Keegan, AD (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA.; Keegan, AD (reprint author), Vet Affairs Maryland Hlth Care Syst, US Dept Vet Affairs, Res & Dev Serv, Baltimore, MD 21201 USA. EM akeegan@som.umaryland.edu FU U.S. Public Health Service (PHS) [AI038985, HL110111, T32HL06798, T32AI007540]; United Negro College Fund/Merck Science Initiative; VA-MERIT [I01 BX001850] FX This work was supported by U.S. Public Health Service (PHS) grants AI038985 and HL110111 and VA-MERIT I01 BX001850 to A.D.K., a Pulmonary Hypertension Association/American Thoracic Society/Pfizer Research Fellowship in Pulmonary Arterial Hypertension to K.Y.-K., and PHS grants T32HL06798 and T32AI007540 and a United Negro College Fund/Merck Science Initiative to N.J.D. NR 60 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUN 21 PY 2016 VL 9 IS 433 AR ra63 DI 10.1126/scisignal.aad6724 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DP2RU UT WOS:000378339500003 PM 27330190 ER PT J AU Lassen, KG McKenzie, CI Mari, M Murano, T Begun, J Baxt, LA Goel, G Villablanca, EJ Kuo, SY Huang, HL Macia, L Bhan, AK Batten, M Daly, MJ Reggiori, F Mackay, CR Xavier, RJ AF Lassen, Kara G. McKenzie, Craig I. Mari, Muriel Murano, Tatsuro Begun, Jakob Baxt, Leigh A. Goel, Gautam Villablanca, Eduardo J. Kuo, Szu-Yu Huang, Hailiang Macia, Laurence Bhan, Atul K. Batten, Marcel Daly, Mark J. Reggiori, Fulvio Mackay, Charles R. Xavier, Ramnik J. TI Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk SO IMMUNITY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; PEROXISOME BIOGENESIS; PANETH CELLS; AMINO-ACIDS; AUTOPHAGY; ATG16L1; INFECTION; IMMUNITY; MOUSE AB Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria- induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense. C1 [Lassen, Kara G.; Murano, Tatsuro; Villablanca, Eduardo J.; Kuo, Szu-Yu; Huang, Hailiang; Daly, Mark J.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Lassen, Kara G.; Murano, Tatsuro; Begun, Jakob; Baxt, Leigh A.; Goel, Gautam; Villablanca, Eduardo J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [McKenzie, Craig I.; Macia, Laurence; Mackay, Charles R.] Monash Univ, Monash Biomed Discovery Inst, Melbourne, Vic 3800, Australia. [McKenzie, Craig I.; Macia, Laurence; Mackay, Charles R.] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3800, Australia. [Mari, Muriel; Reggiori, Fulvio] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, NL-3713 AV Groningen, Netherlands. [Mari, Muriel; Reggiori, Fulvio] Univ Med Ctr Utrecht, Dept Cell Biol, NL-3564 CX Utrecht, Netherlands. [Begun, Jakob; Villablanca, Eduardo J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Begun, Jakob] Univ Queensland, Mater Res Inst, Brisbane, Qld 4101, Australia. [Begun, Jakob] Univ Queensland, Sch Med, Brisbane, Qld 4101, Australia. [Huang, Hailiang; Daly, Mark J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Bhan, Atul K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bhan, Atul K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bhan, Atul K.; Daly, Mark J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Batten, Marcel] Univ New S Wales, Garvan Inst Med Res, Sydney, NSW 2010, Australia. [Batten, Marcel] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW 2010, Australia. RP Lassen, KG; Xavier, RJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Lassen, KG; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. EM klassen@broadinstitute.org; xavier@molbio.mgh.harvard.edu RI Mackay, Charles/A-9673-2008; Begun, Jakob/J-6793-2014; OI Mackay, Charles/0000-0002-6338-7340; 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 [DK097485, AI109725]; ALW Open Program [822.02.014]; DFG-NWO cooperation [DN82-303]; SNF [CRSII3_154421]; ZonMW VICI [016.130.606] FX We thank Natalia Nedelsky for editorial assistance, Jenny Tam for help with the generation of DQ-BSA-conjugated beads, and Rushika C. Wirasinha for support with Gpr65-/- mice. We thank Skip Virgin and Beth Levine for comments. This work was supported by funding from The Leona M. and Harry B. Helmsley Charitable Trust, Crohn's and Colitis Foundation of America, and NIH grants DK097485 and AI109725 to R. J. X. F. R. is supported by ALW Open Program (822.02.014), DFG-NWO cooperation (DN82-303), SNF (CRSII3_154421), and ZonMW VICI (016.130.606) grants. NR 60 TC 1 Z9 1 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 21 PY 2016 VL 44 IS 6 BP 1392 EP 1405 DI 10.1016/j.immuni.2016.05.007 PG 14 WC Immunology SC Immunology GA DP2SE UT WOS:000378341200017 PM 27287411 ER PT J AU Khullar, D Chokshi, DA AF Khullar, Dhruv Chokshi, Dave A. TI Toward an Integrated Federal Health System SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Khullar, Dhruv] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chokshi, Dave A.] New York City Hlth Hosp, New York, NY USA. [Chokshi, Dave A.] NYU Langone Med Ctr, Dept Populat Hlth, 125 Worth St,Room 410, New York, NY 10013 USA. RP Chokshi, DA (reprint author), NYU Langone Med Ctr, New York City Hlth Hosp, 125 Worth St,Room 410, New York, NY 10013 USA. EM dave.chokshi@nychhc.org OI Chokshi, Dave/0000-0001-7467-4591 NR 2 TC 1 Z9 1 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 21 PY 2016 VL 315 IS 23 BP 2521 EP 2522 DI 10.1001/jama.2016.4641 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DP2GQ UT WOS:000378306700012 PM 27123569 ER PT J AU Sabatine, MS AF Sabatine, Marc S. TI Using Aptamer-Based Technology to Probe the Plasma Proteome for Cardiovascular Disease Prediction SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. EM msabatine@partners.org NR 11 TC 2 Z9 2 U1 3 U2 8 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 21 PY 2016 VL 315 IS 23 BP 2525 EP 2526 DI 10.1001/jama.2016.6110 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DP2GQ UT WOS:000378306700014 PM 27327798 ER PT J AU Bibbins-Domingo, K Grossman, DC Curry, SJ Davidson, KW Epling, JW Garcia, FAR Gillman, MW Harper, DM Kemper, AR Krist, AH Kurth, AE Landefeld, CS Mangione, CM Owens, DK Phillips, WR Phipps, MG Pignone, MP Siu, AL AF Bibbins-Domingo, Kirsten Grossman, David C. Curry, Susan J. Davidson, Karina W. Epling, John W., Jr. Garcia, Francisco A. R. Gillman, Matthew W. Harper, Diane M. Kemper, Alex R. Krist, Alex H. Kurth, Ann E. Landefeld, C. Seth Mangione, Carol M. Owens, Douglas K. Phillips, William R. Phipps, Maureen G. Pignone, Michael P. Siu, Albert L. CA US Preventive Serv Task Force TI Screening for Colorectal Cancer US Preventive Services Task Force Recommendation Statement SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID RANDOMIZED-CLINICAL-TRIAL; AMERICAN-COLLEGE; COLONOSCOPY; GUIDELINES; MORTALITY; PATTERNS; OUTCOMES AB IMPORTANCE Colorectal cancer is the second leading cause of cancer death in the United States. In 2016, an estimated 134 000 persons will be diagnosed with the disease, and about 49 000 will die from it. Colorectal cancer is most frequently diagnosed among adults aged 65 to 74 years; the median age at death from colorectal cancer is 68 years. OBJECTIVE To update the 2008 US Preventive Services Task Force (USPSTF) recommendation on screening for colorectal cancer. EVIDENCE REVIEW The USPSTF reviewed the evidence on the effectiveness of screening with colonoscopy, flexible sigmoidoscopy, computed tomography colonography, the guaiac-based fecal occult blood test, the fecal immunochemical test, the multitargeted stool DNA test, and the methylated SEPT9 DNA test in reducing the incidence of and mortality from colorectal cancer or all-cause mortality; the harms of these screening tests; and the test performance characteristics of these tests for detecting adenomatous polyps, advanced adenomas based on size, or both, as well as colorectal cancer. The USPSTF also commissioned a comparative modeling study to provide information on optimal starting and stopping ages and screening intervals across the different available screeningmethods. FINDINGS The USPSTF concludes with high certainty that screening for colorectal cancer in average-risk, asymptomatic adults aged 50 to 75 years is of substantial net benefit. Multiple screening strategies are available to choose from, with different levels of evidence to support their effectiveness, as well as unique advantages and limitations, although there are no empirical data to demonstrate that any of the reviewed strategies provide a greater net benefit. Screening for colorectal cancer is a substantially underused preventive health strategy in the United States. CONCLUSIONS AND RECOMMENDATIONS The USPSTF recommends screening for colorectal cancer starting at age 50 years and continuing until age 75 years (A recommendation). The decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient's overall health and prior screening history (C recommendation). C1 [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grossman, David C.] Grp Hlth Res Inst, Seattle, WA USA. [Curry, Susan J.] Univ Iowa, Iowa City, IA USA. [Davidson, Karina W.] Columbia Univ, New York, NY USA. [Epling, John W., Jr.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Garcia, Francisco A. R.] Pima Cty Dept Hlth, Tucson, AZ USA. [Gillman, Matthew W.] Harvard Univ, Sch Med, Boston, MA USA. [Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Harper, Diane M.] Univ Louisville, Louisville, KY 40292 USA. [Kemper, Alex R.] Duke Univ, Durham, NC USA. [Krist, Alex H.] Fairfax Family Practice Residency, Fairfax, VA USA. [Krist, Alex H.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Kurth, Ann E.] Yale Univ, New Haven, CT USA. [Landefeld, C. Seth] Univ Alabama Birmingham, Birmingham, AL USA. [Mangione, Carol M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Owens, Douglas K.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Owens, Douglas K.] Stanford Univ, Stanford, CA 94305 USA. Univ Washington, Seattle, WA 98195 USA. Brown Univ, Providence, RI 02912 USA. [Pignone, Michael P.] Univ N Carolina, Chapel Hill, NC USA. [Siu, Albert L.] Mt Sinai Sch Med, New York, NY USA. [Siu, Albert L.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Bibbins-Domingo, K (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM chair@uspstf.net OI Epling, John W/0000-0001-9445-8669; Phillips, William/0000-0003-2802-4349 FU Agency for Healthcare Research and Quality (AHRQ) FX The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF. NR 30 TC 41 Z9 41 U1 4 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 21 PY 2016 VL 315 IS 23 BP 2564 EP 2575 DI 10.1001/jama.2016.5989 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DP2GQ UT WOS:000378306700020 ER PT J AU Knudsen, AB Zauber, AG Rutter, CM Naber, SK Doria-Rose, VP Pabiniak, C Johanson, C Fischer, SE Lansdorp-Vogelaar, I Kuntz, KM AF Knudsen, Amy B. Zauber, Ann G. Rutter, Carolyn M. Naber, Steffie K. Doria-Rose, V. Paul Pabiniak, Chester Johanson, Colden Fischer, Sara E. Lansdorp-Vogelaar, Iris Kuntz, Karen M. TI Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies Modeling Study for the US Preventive Services Task Force SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED-TRIAL; COST-EFFECTIVENESS ANALYSIS; FLEXIBLE SIGMOIDOSCOPY; CT COLONOGRAPHY; LARGE-INTESTINE; LARGE-BOWEL; NEGATIVE COLONOSCOPY; POPULATION; MORTALITY AB IMPORTANCE The US Preventive Services Task Force (USPSTF) is updating its 2008 colorectal cancer (CRC) screening recommendations. OBJECTIVE To inform the USPSTF by modeling the benefits, burden, and harms of CRC screening strategies; estimating the optimal ages to begin and end screening; and identifying a set of model-recommendable strategies that provide similar life-years gained (LYG) and a comparable balance between LYG and screening burden. DESIGN, SETTING, AND PARTICIPANTS Comparative modeling with 3 microsimulation models of a hypothetical cohort of previously unscreened US 40-year-olds with no prior CRC diagnosis. EXPOSURES Screening with sensitive guaiac-based fecal occult blood testing, fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy with or without stool testing, computed tomographic colonography (CTC), or colonoscopy starting at age 45, 50, or 55 years and ending at age 75, 80, or 85 years. Screening intervals varied by modality. Full adherence for all strategies was assumed. MAIN OUTCOMES AND MEASURES Life-years gained compared with no screening (benefit), lifetime number of colonoscopies required (burden), lifetime number of colonoscopy complications (harms), and ratios of incremental burden and benefit (efficiency ratios) per 1000 40-year-olds. RESULTS The screening strategies provided LYG in the range of 152 to 313 per 1000 40-year-olds. Lifetime colonoscopy burden per 1000 persons ranged from fewer than 900 (FIT every 3 years from ages 55-75 years) to more than 7500 (colonoscopy screening every 5 years from ages 45-85 years). Harm from screening was at most 23 complications per 1000 persons screened. Strategies with screening beginning at age 50 years generally provided more LYG as well as more additional LYG per additional colonoscopy than strategies with screening beginning at age 55 years. There were limited empirical data to support a start age of 45 years. For persons adequately screened up to age 75 years, additional screening yielded small increases in LYG relative to the increase in colonoscopy burden. With screening from ages 50 to 75 years, 4 strategies yielded a comparable balance of screening burden and similar LYG (median LYG per 1000 across the models): colonoscopy every 10 years (270 LYG); sigmoidoscopy every 10 years with annual FIT (256 LYG); CTC every 5 years (248 LYG); and annual FIT (244 LYG). CONCLUSIONS AND RELEVANCE In this microsimulation modeling study of a previously unscreened population undergoing CRC screening that assumed 100% adherence, the strategies of colonoscopy every 10 years, annual FIT, sigmoidoscopy every 10 years with annual FIT, and CTC every 5 years performed from ages 50 through 75 years provided similar LYG and a comparable balance of benefit and screening burden. C1 [Zauber, Ann G.; Fischer, Sara E.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,Second Floor, New York, NY 10017 USA. [Knudsen, Amy B.; Johanson, Colden] Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Boston, MA USA. [Rutter, Carolyn M.] RAND Corp, Santa Monica, CA USA. [Naber, Steffie K.; Lansdorp-Vogelaar, Iris] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Doria-Rose, V. Paul] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Pabiniak, Chester] Grp Hlth Res Inst, Seattle, WA USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Dept Hlth Policy & Management, Minneapolis, MN USA. [Johanson, Colden] Optum, Boston, MA USA. RP Zauber, AG (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,Second Floor, New York, NY 10017 USA. EM zaubera@mskcc.org OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute (NCI) of the National Institutes of Health (NIH) [U01CA152959]; NCI Cancer Center Support Grant [P30CA008748] FX This analysis was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) (through a supplement from the Agency for Healthcare Research and Quality [AHRQ]) under award U01CA152959. Dr Zauber was also supported in part by a NCI Cancer Center Support Grant under award P30CA008748. NR 69 TC 15 Z9 15 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 21 PY 2016 VL 315 IS 23 BP 2595 EP 2609 DI 10.1001/jama.2016.6828 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DP2GQ UT WOS:000378306700022 PM 27305518 ER PT J AU Weinrauch, LA Segal, AR D'Elia, JA AF Weinrauch, Larry A. Segal, Alissa R. D'Elia, John A. TI Cardiovascular Risk Reduction and the Community Pharmacist SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE adherence; community pharmacy; diabetes; hypertension control; risk factors ID ADHERENCE; MEDICATIONS; TRIAL C1 [Weinrauch, Larry A.; Segal, Alissa R.; D'Elia, John A.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Kidney & Hypertens Sect, Boston, MA 02115 USA. [Segal, Alissa R.] MCPHS Univ, Dept Pharm Practice, Boston, MA USA. RP Weinrauch, LA (reprint author), Harvard Univ, Sch Med, 521 Mt Auburn St,Suite 204, Watertown, MA 02472 USA. EM lweinrauch@hms.harvard.edu NR 13 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 21 PY 2016 VL 67 IS 24 BP 2855 EP 2857 DI 10.1016/j.jacc.2016.04.018 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO8RU UT WOS:000378052100008 PM 27311524 ER PT J AU Chan, KE Giugliano, RP Patel, MR Abramson, S Jardine, M Zhao, S Perkovic, V Maddux, FW Piccini, JP AF Chan, Kevin E. Giugliano, Robert P. Patel, Manesh R. Abramson, Stuart Jardine, Meg Zhao, Sophia Perkovic, Vlado Maddux, Franklin W. Piccini, Jonathan P. TI Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE apixaban; dabigatran; edoxaban; renal dialysis; rivaroxaban; stroke ID NONVALVULAR ATRIAL-FIBRILLATION; STAGE RENAL-DISEASE; PROTHROMBIN COMPLEX CONCENTRATE; GLOMERULAR-FILTRATION-RATE; HEMODIALYSIS-PATIENTS; ORAL ANTICOAGULANTS; PLATELET-AGGREGATION; APPENDAGE CLOSURE; SERUM CREATININE; SINGLE-CENTER AB Nonvitamin K-dependent oral anticoagulant agents (NOACs) are currently recommended for patients with atrial fibrillation at risk for stroke. As a group, NOACs significantly reduce stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with warfarin. All NOACs are dependent on the kidney for elimination, such that patients with creatinine clearance < 25 ml/min were excluded from all the pivotal phase 3 NOAC trials. It therefore remains unclear how or if NOACs should be prescribed to patients with advanced chronic kidney disease and those on dialysis. The authors review the current pharmacokinetic, observational, and prospective data on NOACs in patients with advanced chronic kidney disease (creatinine clearance < 30 ml/min) and those on dialysis. The authors frame the evidence in terms of risk versus benefit to bring greater clarity to NOAC-related major bleeding and efficacy at preventing stroke specifically in patients with creatinine clearance < 30 ml/min. (C) 2016 by the American College of Cardiology Foundation. C1 [Chan, Kevin E.; Zhao, Sophia] Fresenius Med Care North Amer, Waltham, MA USA. [Chan, Kevin E.; Maddux, Franklin W.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Giugliano, Robert P.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Patel, Manesh R.; Piccini, Jonathan P.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Abramson, Stuart] Tufts Univ, Sch Med, Maine Med Ctr, Portland, ME USA. [Jardine, Meg; Perkovic, Vlado] Univ Sydney, George Inst Global Hlth, Sydney, NSW 2006, Australia. RP Chan, KE (reprint author), Fresenius Kidney Care, 920 Winter St, Waltham, MA 02451 USA. EM kevin.chan@fmc-na.com FU Bristol-Myers Squibb; ARCA Biopharma; Agency for Healthcare Research and Quality; Gilead; Johnson Johnson; St. Jude Medical; Daiichi-Sankyo; National Health and Medical Research Council of Australia; National Heart Foundation; Amgen; Roche; Boehringer Ingelheim; Gambro; Baxter; CSL; Eli Lilly; Merck; Janssen; AstraZeneca; Bayer; Procyrion; Jansen; National Heart, Lung, and Blood Institute FX Dr. Chan is a steering committee member of the RENAL-AF trial, which is funded by Bristol-Myers Squibb; and is an employee of Fresenius Medical Care. Dr. Piccini receives grants for clinical research from ARCA Biopharma, the Agency for Healthcare Research and Quality, Gilead, Johnson & Johnson, and St. Jude Medical; and serves as a consultant to Janssen Pharmaceuticals, Pfizer-BMS, and Medtronic. Dr. Giugliano was the principal investigator of the ENGAGE AF-TIMI 48 trial, which was supported by a research grant from Daiichi-Sankyo to the Brigham and Women's Hospital, where he is employed; and has received honoraria for consulting or continuing medical education activities from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, The American College of Cardiology, Pfizer, and Portola. Dr. Maddux is an employee of Fresenius Medical Care and has stock ownership. Dr. Jardine is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia and the National Heart Foundation; has received speaking fees from Amgen and Roche; has received advisory board funding from Boehringer Ingelheim; has received unrestricted research funding from Gambro, Baxter, CSL, Amgen, Eli Lilly and Merck; and has served on a steering committee for a trial funded by Janssen; all honoraria are contributed directly to clinical research programs. Dr. Patel is supported by research grants from AstraZeneca, Bayer, Procyrion, Jansen, and the National Heart, Lung, and Blood Institute; and is a consultant advisory board member to AstraZeneca, Jansen, Bayer, Genzyme, and Merck. Dr. Perkovic chairs the steering committee of a trial of an unrelated compound funded by Janssen; has consulted for Bristol-Myers Squibb in an unrelated area; and has a policy of honoraria going to his institution. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 64 TC 4 Z9 4 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 21 PY 2016 VL 67 IS 24 BP 2888 EP 2899 DI 10.1016/j.jacc.2016.02.082 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO8RU UT WOS:000378052100012 PM 27311528 ER PT J AU Stetler, RA Gao, YQ Leak, RK Weng, ZF Shi, YJ Zhang, LL Pu, HJ Zhang, F Hu, XM Hassan, S Ferguson, C Homanics, GE Cao, GD Bennett, MVL Chen, J AF Stetler, R. Anne Gao, Yanqin Leak, Rehana K. Weng, Zhongfang Shi, Yejie Zhang, Lili Pu, Hongjian Zhang, Feng Hu, Xiaoming Hassan, Sulaiman Ferguson, Carolyn Homanics, Gregg E. Cao, Guodong Bennett, Michael V. L. Chen, Jun TI APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ischemia; neurodegeneration; base excision repair; oxidative DNA; damage; white matter injury ID STRANDED DEOXYRIBONUCLEIC-ACID; TRANSIENT FOCAL ISCHEMIA; GLOBAL CEREBRAL-ISCHEMIA; BASE-EXCISION-REPAIR; OXIDATIVE DNA-DAMAGE; NEURONAL CELL-DEATH; APURINIC/APYRIMIDINIC ENDONUCLEASE; SIGNALING PATHWAY; HSP27 PROTECTS; APURINIC SITES AB A major hallmark of oxidative DNA damage after stroke is the induction of apurinic/apyrimidinic (AP) sites and strand breaks. To mitigate cell loss after oxidative DNA damage, ischemic cells rapidly engage the base excision-repair proteins, such as the AP site-repairing enzyme AP endonuclease-1 (APE1), also named redox effector factor-1 (Ref-1). Although forced overexpression of APE1 is known to protect against oxidative stress-induced neurodegeneration, there is no concrete evidence demonstrating a role for endogenous APE1 in the long-term recovery of gray and white matter following ischemic injury. To address this gap, we generated, to our knowledge, the first APE1 conditional knockout (cKO) mouse line under control of tatamoxifen-dependent Cre recombinase. Using a well-established model of transient focal cerebral ischemia (tFCI), we show that induced deletion of APE1 dramatically enlarged infarct volume and impaired the recovery of sensorimotor and cognitive deficits. APE1 cKO markedly increased postischemic neuronal and oligodendrocyte degeneration, demonstrating that endogenous APE1 preserves both gray and white matter after tFCI. Because white matter repair is instrumental in behavioral recovery after stroke, we also examined the impact of APE1 cKO on demyelination and axonal conduction and discovered that APE1 cKO aggravated myelin loss and impaired neuronal communication following tFCI. Furthermore, APE1 cKO increased AP sites and activated the prodeath signaling proteins, PUMA and PARP1, after tFCI in topographically distinct manners. Our findings provide evidence that endogenous APE1 protects against ischemic infarction in both gray and white matter and facilitates the functional recovery of the central nervous system after mild stroke injury. C1 [Stetler, R. Anne; Gao, Yanqin; Zhang, Feng; Hu, Xiaoming; Cao, Guodong; Bennett, Michael V. L.; Chen, Jun] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Stetler, R. Anne; Gao, Yanqin; Zhang, Feng; Hu, Xiaoming; Cao, Guodong; Bennett, Michael V. L.; Chen, Jun] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China. [Stetler, R. Anne; Gao, Yanqin; Weng, Zhongfang; Shi, Yejie; Zhang, Lili; Pu, Hongjian; Zhang, Feng; Hu, Xiaoming; Hassan, Sulaiman; Cao, Guodong; Chen, Jun] Univ Pittsburgh, Dept Neurol, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA. [Stetler, R. Anne; Weng, Zhongfang; Shi, Yejie; Zhang, Lili; Zhang, Feng; Hu, Xiaoming; Hassan, Sulaiman; Cao, Guodong; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. [Leak, Rehana K.] Duquesne Univ, Mylan Sch Pharm, Div Pharmaceut Sci, Pittsburgh, PA 15282 USA. [Ferguson, Carolyn; Homanics, Gregg E.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Ferguson, Carolyn; Homanics, Gregg E.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Bennett, Michael V. L.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. RP Bennett, MVL; Chen, J (reprint author), Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China.; Bennett, MVL; Chen, J (reprint author), Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China.; Chen, J (reprint author), Univ Pittsburgh, Dept Neurol, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA.; Chen, J (reprint author), Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA.; Bennett, MVL (reprint author), Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. EM michael.bennett@einstein.yu.edu; chenj2@upmc.edu OI Shi, Yejie/0000-0001-7502-9201 FU National Institutes of Health [NS036736, NS045048, NS089534, NS45287, AA10422]; US Department of Veterans Affairs Senior Research Career Scientist Award; Chinese Natural Science Foundation [81020108021, 81171149, 81371306, 81228008]; State Administration of Foreign Experts Affairs of China [GDW20133100069] FX We thank Ed Mallick for technical assistance in generating the apurinic/apyrimidinic endonuclease-1 conditional knockout mouse line. This research was supported by National Institutes of Health Grants NS036736, NS045048, and NS089534 (to J.C.), NS45287 (to M.V.L.B.), and AA10422 (to G.E.H); a US Department of Veterans Affairs Senior Research Career Scientist Award (to J.C.); Chinese Natural Science Foundation Grants 81020108021, 81171149, and 81371306 (to Y.G.), and 81228008 (to J.C.); and the High-end Distinguished Professorship GDW20133100069 from the State Administration of Foreign Experts Affairs of China (to M.V.L.B.). NR 47 TC 1 Z9 1 U1 2 U2 4 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 21 PY 2016 VL 113 IS 25 BP E3558 EP E3567 DI 10.1073/pnas.1606226113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP1TN UT WOS:000378272400015 PM 27274063 ER PT J AU Perko, Z van der Voort, SR van de Water, S Hartman, CMH Hoogeman, M Lathouwers, D AF Perko, Zoltan van der Voort, Sebastian R. van de Water, Steven Hartman, Charlotte M. H. Hoogeman, Mischa Lathouwers, Danny TI Fast and accurate sensitivity analysis of IMPT treatment plans using Polynomial Chaos Expansion SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton therapy; uncertainty; sensitivity; setup error; range error; robust optimization; Polynomial Chaos ID MODULATED PROTON THERAPY; VOLUME HISTOGRAM COMPUTATION; RANGE UNCERTAINTIES; ROBUST OPTIMIZATION; OROPHARYNGEAL CANCER; DOSE UNCERTAINTIES; SETUP ERRORS; MARGINS; RADIOTHERAPY; MODELS AB The highly conformal planned dose distribution achievable in intensity modulated proton therapy (IMPT) can severely be compromised by uncertainties in patient setup and proton range. While several robust optimization approaches have been presented to address this issue, appropriate methods to accurately estimate the robustness of treatment plans are still lacking. To fill this gap we present Polynomial Chaos Expansion (PCE) techniques which are easily applicable and create a meta-model of the dose engine by approximating the dose in every voxel with multidimensional polynomials. This Polynomial Chaos (PC) model can be built in an automated fashion relatively cheaply and subsequently it can be used to perform comprehensive robustness analysis. We adapted PC to provide among others the expected dose, the dose variance, accurate probability distribution of dose-volume histogram (DVH) metrics (e.g. minimum tumor or maximum organ dose), exact bandwidths of DVHs, and to separate the effects of random and systematic errors. We present the outcome of our verification experiments based on 6 head-and-neck (HN) patients, and exemplify the usefulness of PCE by comparing a robust and a non-robust treatment plan for a selected HN case. The results suggest that PCE is highly valuable for both research and clinical applications. C1 [Perko, Zoltan; van der Voort, Sebastian R.; Hartman, Charlotte M. H.; Lathouwers, Danny] Delft Univ Technol, Dept Radiat Sci & Technol, Sect Nucl Energy & Radiat Applicat, Mekelweg 15, Delft, Netherlands. [van der Voort, Sebastian R.; van de Water, Steven; Hartman, Charlotte M. H.; Hoogeman, Mischa] Erasmus MC Canc Inst, Dept Radiat Oncol, Rotterdam, Netherlands. [Perko, Zoltan] Massachusetts Gen Hosp, Dept Radiat Oncol, Phys Res Grp, Boston, MA 02114 USA. RP Perko, Z (reprint author), Delft Univ Technol, Dept Radiat Sci & Technol, Sect Nucl Energy & Radiat Applicat, Mekelweg 15, Delft, Netherlands.; Perko, Z (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Phys Res Grp, Boston, MA 02114 USA. EM zperko@mgh.harvard.edu; S.vanderVoort@erasmusmc.nl; S.vandeWater@erasmusmc.nl; M.Hoogeman@erasmusmc.nl; D.Lathouwers@tudelft.nl NR 37 TC 0 Z9 0 U1 1 U2 1 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 2016 VL 61 IS 12 BP 4646 EP 4664 DI 10.1088/0031-9155/61/12/4646 PG 19 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DO0AG UT WOS:000377441200024 PM 27227661 ER PT J AU Lin, YT Kooy, H Craft, D Depauw, N Flanz, J Clasie, B AF Lin, Yuting Kooy, Hanne Craft, David Depauw, Nicolas Flanz, Jacob Clasie, Benjamin TI A Greedy reassignment algorithm for the PBS minimum monitor unit constraint SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE pencil beam scanning; proton therapy; radiation therapy; treatment delivery; treatment planning ID DOSE DISTRIBUTIONS; ASSIGNMENT PROBLEM; PROTON; OPTIMIZATION; DELIVERY; BEAMS AB Proton pencil beam scanning (PBS) treatment plans are made of numerous unique spots of different weights. These weights are optimized by the treatment planning systems, and sometimes fall below the deliverable threshold set by the treatment delivery system. The purpose of this work is to investigate a Greedy reassignment algorithm to mitigate the effects of these low weight pencil beams. The algorithm is applied during post-processing to the optimized plan to generate deliverable plans for the treatment delivery system. The Greedy reassignment method developed in this work deletes the smallest weight spot in the entire field and reassigns its weight to its nearest neighbor(s) and repeats until all spots are above the minimum monitor unit (MU) constraint. Its performance was evaluated using plans collected from 190 patients (496 fields) treated at our facility. The Greedy reassignment method was compared against two other post-processing methods. The evaluation criteria was the gamma-index pass rate that compares the pre-processed and post-processed dose distributions. A planning metric was developed to predict the impact of post-processing on treatment plans for various treatment planning, machine, and dose tolerance parameters. For fields with a pass rate of 90 +/- 1% the planning metric has a standard deviation equal to 18% of the centroid value showing that the planning metric and gamma-index pass rate are correlated for the Greedy reassignment algorithm. Using a 3rd order polynomial fit to the data, the Greedy reassignment method has 1.8 times better planning metric at 90% pass rate compared to other post-processing methods. As the planning metric and pass rate are correlated, the planning metric could provide an aid for implementing parameters during treatment planning, or even during facility design, in order to yield acceptable pass rates. More facilities are starting to implement PBS and some have spot sizes (one standard deviation) smaller than 5 mm, hence would require small spot spacing. While this is not the only parameter that affects the optimized plan, the perturbation due to the minimum MU constraint increases with decreasing spot spacing. This work could help to design the minimum MU threshold with the goal to keep the gamma-index pass rate above an acceptable value. C1 [Clasie, Benjamin] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Clasie, B (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM bclasie@partners.org FU Federal Share of program by Massachusetts General Hospital, Proton Therapy Research and Treatment Center [C06 CA059267] FX The authors thank Clemens Grassherger for providing the small spot size beam models. We thank the Medical Physics Residency Program at Harvard Medical School for generous support to Y Lin. The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 26 TC 1 Z9 1 U1 1 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUN 21 PY 2016 VL 61 IS 12 BP 4665 EP 4678 DI 10.1088/0031-9155/61/12/4665 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DO0AG UT WOS:000377441200025 PM 27245098 ER PT J AU Ramos, AD Attenello, FJ Lim, DA AF Ramos, Alexander D. Attenello, Frank J. Lim, Daniel A. TI Uncovering the roles of long noncoding RNAs in neural development and glioma progression SO NEUROSCIENCE LETTERS LA English DT Review DE Long noncoding RNA; IncRNA; Chromatin; Epigenetics; Neural stem; Cell; Neurogenesis; Brain development; Brain tumor; Glioma ID ADULT MAMMALIAN BRAIN; STEM-CELLS; SUBVENTRICULAR ZONE; BINDING-PROTEINS; MOUSE-BRAIN; IN-VIVO; NEURONAL DIFFERENTIATION; EPIGENETIC REGULATION; EXPRESSION PROFILES; RETINAL DEVELOPMENT AB In the past decade, thousands of long noncoding RNA5 (lncRNAs) have been identified, and emerging data indicate that IncRNAs can have important biological functions and roles in human diseases including cancer. Many IncRNAs appear to be expressed specifically in the brain, and the roles of IncRNAs in neural stem cells (NSCs) and brain development are now beginning to be discovered. Here we review recent advances in understanding the diversity of IncRNA structure and functions in NSCs and brain development. NSCs in the adult mouse ventricular-subventricular zone (V-SVZ) generate new neurons throughout life, and we discuss how key elements of this adult neurogenic system have facilitated the discovery and functional characterization of known and novel IncRNAs. A review of lncRNAs described in other NSC systems reveals a variety of molecular mechanisms, including binding and recruitment of transcription factors, epigenetic modifiers, and RNA-splicing factors. Finally, we review emerging evidence indicating that specific IncRNAs can be key drivers of glial tumors, and discuss next steps towards an in vivo understanding of IncRNA function in development and disease. Published by Elsevier Ireland Ltd. C1 [Ramos, Alexander D.; Attenello, Frank J.; Lim, Daniel A.] Dept Neurol Surg, San Francisco, CA 94121 USA. [Ramos, Alexander D.; Attenello, Frank J.; Lim, Daniel A.] Ctr Regenerat Med & Stem Cell Res, Eli & Edythe Broad, San Francisco, CA 94121 USA. [Lim, Daniel A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Attenello, Frank J.] Univ Southern Calif, Keck Sch Med, Dept Neurosurg, Los Angeles, CA 90033 USA. RP Lim, DA (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 35 Med Ctr Way,RMB 1037, San Francisco, CA 94143 USA. EM daniel.lim@ucsf.edu FU American Brain Tumor Association; Sontag Foundation; Shurl and Kay Curci Foundation; NCI-SPORE DRP; Hana Jabsheh Initiative; [VA 5I01 BX000252-06] FX This work was supported by VA 5I01 BX000252-06, American Brain Tumor Association, Sontag Foundation, Shurl and Kay Curci Foundation, NCI-SPORE DRP, and the Hana Jabsheh Initiative. NR 100 TC 4 Z9 6 U1 6 U2 8 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 20 PY 2016 VL 625 BP 70 EP 79 DI 10.1016/j.neulet.2015.12.025 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DQ7GC UT WOS:000379373900012 PM 26733304 ER PT J AU Halilovic, A Schmedt, T Benischke, AS Hamill, C Chen, YM Santos, JH Jurkunas, UV AF Halilovic, Adna Schmedt, Thore Benischke, Anne-Sophie Hamill, Cecily Chen, Yuming Santos, Janine Hertzog Jurkunas, Ula V. TI Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID INDUCED OXIDATIVE STRESS; CELL-DEATH; INDUCED APOPTOSIS; MORPHOLOGY; EXPRESSION; PROTECTS; FUSION; CLUSTERIN; DIVISION; DYNAMICS AB Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in Delta Psi m and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. C1 [Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily; Chen, Yuming; Jurkunas, Ula V.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. [Santos, Janine Hertzog] Rutgers State Univ, New Jersey Med Sch Rutgers, Dept Physiol & Pharmacol, Piscataway, NJ 08855 USA. [Santos, Janine Hertzog] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Jurkunas, UV (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM ula_jurkunas@meei.harvard.edu FU NEI/NIH [R01 EY020581] FX This work was supported by NEI/NIH R01 EY020581. NR 47 TC 2 Z9 2 U1 4 U2 7 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 2016 VL 24 IS 18 BP 1072 EP 1083 DI 10.1089/ars.2015.6532 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DP2RE UT WOS:000378336900004 PM 26935406 ER PT J AU Nou, E Lo, J Grinspoon, SK AF Nou, Eric Lo, Janet Grinspoon, Steven K. TI Inflammation, immune activation, and cardiovascular disease in HIV SO AIDS LA English DT Review DE atherosclerosis; cardiovascular disease; HIV; immune activation; inflammation ID T-CELL-ACTIVATION; INTIMA-MEDIA THICKNESS; CORONARY-HEART-DISEASE; IMMUNODEFICIENCY-VIRUS TYPE-1; RECEIVING ANTIRETROVIRAL THERAPY; ACUTE MYOCARDIAL-INFARCTION; PLACEBO-CONTROLLED TRIAL; HUMAN ENDOTHELIAL-CELLS; PROTEASE INHIBITOR RITONAVIR; MULTICENTER AIDS COHORT AB Cardiovascular disease is one of the leading causes of morbidity and mortality in people living with HIV. Several epidemiological studies have shown an increased risk of myocardial infarction and stroke compared to uninfected controls. Although traditional risk factors contribute to this increased risk of cardiovascular disease, HIV-specific mechanisms likely also play a role. Systemic inflammation has been linked to cardiovascular disease in several populations suffering from chronic inflammation, including people living with HIV. Although antiretroviral therapy reduces immune activation, levels of inflammatory markers remain elevated compared to uninfected controls. The causes of this sustained immune response are likely multifactorial and incompletely understood. In this review, we summarize the evidence describing the relationship between inflammation and cardiovascular disease and discuss potential anti-inflammatory treatment options for cardiometabolic disease in people living with HIV. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Nou, Eric; Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, LON 207,55 Fruit St, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU National Institutes of Health [5T32DK007028-40, R01HL123351, U01HL123336, P30 DK040561] FX This work was supported by the National Institutes of Health (5T32DK007028-40 to E.N., R01HL123351 to J.L, and U01HL123336 and P30 DK040561 to S.K.G.). Funding sources had no role in the writing of the manuscript. NR 194 TC 4 Z9 4 U1 3 U2 10 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 2016 VL 30 IS 10 BP 1495 EP 1509 DI 10.1097/QAD.0000000000001109 PG 15 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DN9SD UT WOS:000377419500001 PM 27058351 ER PT J AU Mathew, ST Pakala, AV Thadani, U AF Mathew, Sunil T. Pakala, Aneesh V. Thadani, Udho TI Invasive strategy in acute coronary syndrome SO LANCET LA English DT Letter C1 [Mathew, Sunil T.] Univ Oklahoma, Hlth Sci Ctr, Cardiovasc Sect, Oklahoma City, OK 73104 USA. US Dept Vet Affairs, Med Ctr, Oklahoma City, OK 73104 USA. RP Mathew, ST (reprint author), Univ Oklahoma, Hlth Sci Ctr, Cardiovasc Sect, Oklahoma City, OK 73104 USA. EM stmathew@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 18 PY 2016 VL 387 IS 10037 BP 2503 EP 2504 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DO7FG UT WOS:000377947200021 PM 27353678 ER PT J AU Anthenelli, RM Benowitz, NL West, R St Aubin, L McRae, T Lawrence, D Ascher, J Russ, C Krishen, A Evins, AE AF Anthenelli, Robert M. Benowitz, Neal L. West, Robert St Aubin, Lisa McRae, Thomas Lawrence, David Ascher, John Russ, Cristina Krishen, Alok Evins, A. Eden TI Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial SO LANCET LA English DT Article ID SMOKING-CESSATION; ADVERSE EVENTS; DEPRESSION; RISK; COHORT; SCHIZOPHRENIA; ABSTINENCE; SUICIDE; ADULTS; SCALE AB Background Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. Methods We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1: 1: 1: 1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. Findings 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1.3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2.2%) of 989 in the bupropion group, 25 (2.5%) of 1006 in the nicotine patch group, and 24 (2.4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1.28 (95% CI -2.40 to -0.15) and -0.08 (-1.37 to 1.21), respectively; the RDs for comparisons with nicotine patch were -1.07 (-2.21 to 0.08) and 0.13 (-1.19 to 1.45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6.5%) of 1026 participants in the varenicline group, 68 (6.7%) of 1017 in the bupropion group, 53 (5.2%) of 1016 in the nicotine patch group, and 50 (4.9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1.59 (95% CI -0.42 to 3.59) and 1.78 (-0.24 to 3.81), respectively; the RDs versus nicotine patch were 1.22 (-0.81 to 3.25) and 1.42 (-0.63 to 3.46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3.61, 95% CI 3.07 to 4.24), nicotine patch (1.68, 1.46 to 1.93), and bupropion (1.75, 1.52 to 2.01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2.07 [1.75 to 2.45] and 2.15 [1.82 to 2.54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. Interpretation The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. C1 [Anthenelli, Robert M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Benowitz, Neal L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [West, Robert] UCL, London, England. [St Aubin, Lisa; McRae, Thomas; Lawrence, David; Russ, Cristina] Pfizer, New York, NY USA. [Ascher, John] GSK, Res Triangle Pk, NC USA. [Krishen, Alok] GSK, PAREXEL Int, Res Triangle Pk, NC USA. [Evins, A. Eden] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Evins, A. Eden] Harvard Univ, Sch Med, Boston, MA USA. RP Anthenelli, RM (reprint author), Univ Calif San Diego, Dept Psychiat, Hlth Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM ranthenelli@ucsd.edu FU Pfizer FX We thank the investigators and study site personnel involved in the study. They or their institutions were compensated for their contributions by Pfizer and GlaxoSmithKline. Editorial support (in the form of creating tables and figures, formatting references, collating review comments, and proofing and formatting for submission) was provided by Anne Jakobsen and Abegale Templar (Engage Scientific, Horsham, UK) and funded by Pfizer. NR 30 TC 19 Z9 20 U1 7 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 18 PY 2016 VL 387 IS 10037 BP 2507 EP 2520 DI 10.1016/S0140-6736(16)30272-0 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA DO7FG UT WOS:000377947200028 PM 27116918 ER PT J AU Lettre, G Bauer, DE AF Lettre, Guillaume Bauer, Daniel E. TI Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies SO LANCET LA English DT Article ID QUANTITATIVE-TRAIT LOCUS; GAMMA-GLOBIN GENE; GENOME-WIDE ASSOCIATION; ADULT ERYTHROID-CELLS; FACTOR KLF1 CAUSES; RISK-FACTORS; BETA-THALASSEMIA; CHROMOSOME 6Q23; DNA METHYLATION; LYMPHOID DEVELOPMENT AB Sickle-cell disease affects millions of individuals worldwide, but the global incidence is concentrated in Africa. The burden of sickle-cell disease is expected to continue to rise over the coming decades, adding to stress on the health infrastructures of many countries. Although the molecular cause of sickle-cell disease has been known for more than half a century, treatment options remain greatly limited. Allogeneic haemopoietic stem-cell transplantation is the only existing cure but is limited to specialised clinical centres and remains inaccessible for most patients. Induction of fetal haemoglobin production is a promising strategy for the treatment of sickle-cell disease. In this Series paper, we review scientific breakthroughs in epidemiology, genetics, and molecular biology that have brought reactivation of fetal haemoglobin to the forefront of sickle-cell disease research. Improved knowledge of the regulation of fetal haemoglobin production in human beings and the development of genome editing technology now support the design of innovative therapies for sickle-cell disease that are based on fetal haemoglobin. C1 [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Montreal, PQ H1T 1C8, Canada. [Bauer, Daniel E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, 44 Binney St, Boston, MA 02115 USA. [Bauer, Daniel E.] Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.; Lettre, G (reprint author), Univ Montreal, Montreal, PQ H1T 1C8, Canada.; Bauer, DE (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, 44 Binney St, Boston, MA 02115 USA.; Bauer, DE (reprint author), Harvard Stem Cell Inst, Boston, MA 02115 USA. EM guillaume.lettre@umontreal.ca; daniel.bauer@childrens.harvard.edu FU Canadian Institute of Health Research (MOP) [123382]; Canada Research Chair Program, National Institute of Diabetes and Digestive and Kidney Diseases [K08DK093705]; Doris Duke Charitable Foundation; Charles H Hood Foundation; Cooley's Anemia Foundation; Biogen FX We thank Carlo Brugnara (Boston Children's Hospital, Harvard Medical School, Boston, MA, USA) and Frederic Galacteros (Red Cell Genetic Disease Unit, Hopital Henri-Mondor, Creteil, France) for providing access to the GENMOD data used in figure 2, and H Franklin Bunn (Brigham and Women's Hospital, Harvard Medical School, Boston), William A Eaton (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MA, USA), Russell E Ware (Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA), and Stuart H Orkin (Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Howard Hughes Medical Institute, Boston) for providing comments and suggestions on an earlier version of this paper. Diane D Chen (Boston Children's Hospital) helped with figure preparation. This work is supported by grants from the Canadian Institute of Health Research (MOP #123382), the Canada Research Chair Program, National Institute of Diabetes and Digestive and Kidney Diseases (K08DK093705), the Doris Duke Charitable Foundation, the Charles H Hood Foundation, Biogen, and the Cooley's Anemia Foundation. NR 122 TC 1 Z9 1 U1 10 U2 15 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 18 PY 2016 VL 387 IS 10037 BP 2554 EP 2564 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DO7FG UT WOS:000377947200032 PM 27353686 ER PT J AU Winter, L Moriarty, H Robinson, KM Newhart, B AF Winter, Laraine Moriarty, Helene Robinson, Keith M. Newhart, Brian TI Rating competency in everyday activities in patients with TBI: clinical insights from a close look at patient-family differences SO DISABILITY AND REHABILITATION LA English DT Article DE traumatic brain injury; family; Caregivers; competence in activities; veterans ID TRAUMATIC BRAIN-INJURY; COMMUNITY REINTEGRATION; SELF; CAREGIVER; SYMPTOMS; REHABILITATION; PERSPECTIVE; MECHANISMS; DEPRESSION; VETERANS AB Purpose: Families of patients with traumatic brain injury (TBI) often perceive patients' functional capabilities differently from patients themselves. Research documents inconsistent findings regarding direction of differences. Differences have implications for family support and are germane to clinicians' treatment planning during rehabilitation. We compared two analytic approaches to patient-family differences in ratings of 30 functional tasks: (a) comparing patients' and families' mean scores in domains derived from factor analysis versus (b) examining differences on a task-by-task basis. Method: In-home interviews were conducted with 83 outpatients with TBI at a Veteran Affairs polytrauma clinic and for each a family member, using the Patient Competency Rating Scale with both. Results: Principal components analysis identified three functional domains - cognitive, interpersonal/emotional and physical - with significant patient-family differences in the cognitive domain only (family competency ratings were higher). By contrast, task-by-task examination showed significant veteran-family differences in 12 items, mostly in interpersonal/emotional functioning, with mixed directions of differences. The task-by-task approach thus revealed a different picture of patient-family differences than examination by functional domains. Conclusions: Grouping tasks by domains may obscure important differences in functional ratings. Examination of patient-family differences by task has clinical applications for helping patients and families to manage TBI symptoms and for treatment planning. Implications for Rehabilitation Differences in functional capacity ratings by patients with TBI and their family members are not well understood, with past research demonstrating inconsistencies in direction of difference. Differences in ratings may affect family relationships and may inform clinicians' treatment plans. The study showed that different approaches to analyzing the same data yield two distinct pictures of patient-family differences. Examining patient-family differences by specific tasks is clinically meaningful. The Competency Rating Scale could be used as a clinical tool with patients and families. Its use may improve family understanding of the patient's strengths and struggles and also guide treatment planning. C1 [Winter, Laraine; Moriarty, Helene] Dept Vet Affairs Med Ctr, Nursing Serv, Philadelphia, PA 19104 USA. [Winter, Laraine] Philadelphia Res & Educ Fdn, Dept Vet Affairs Med Ctr, Philadelphia, PA USA. [Moriarty, Helene] Villanova Univ, Coll Nursing, Villanova, PA 19085 USA. [Robinson, Keith M.; Newhart, Brian] Polytrauma Network Site Vet Integrated Serv Netwo, Rehabil Med Serv, Philadelphia, PA USA. [Robinson, Keith M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Winter, L (reprint author), Philadelphia Vet Affairs Med Ctr, Univ & Woodland Ave, Philadelphia, PA 19104 USA. EM laraine.winter@gmail.com NR 49 TC 0 Z9 0 U1 3 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0963-8288 EI 1464-5165 J9 DISABIL REHABIL JI Disabil. Rehabil. PD JUN 18 PY 2016 VL 38 IS 13 BP 1280 EP 1290 DI 10.3109/09638288.2015.1077531 PG 11 WC Rehabilitation SC Rehabilitation GA DH5OL UT WOS:000372839500006 PM 26314877 ER PT J AU Jung, JH Iwabuchi, K Yang, ZH Loeken, MR AF Jung, Jin Hyuk Iwabuchi, Kumiko Yang, Zhihong Loeken, Mary R. TI Embryonic Stem Cell Proliferation Stimulated By Altered Anabolic Metabolism From Glucose Transporter 2-Transported Glucosamine SO SCIENTIFIC REPORTS LA English DT Article ID NEURAL-TUBE DEFECTS; PRIMORDIAL GERM-CELLS; VISCERAL YOLK-SAC; O-GLCNAC; GENE-EXPRESSION; MOUSE EMBRYOS; PHYSIOLOGICAL-GLUCOSE; DIABETIC PREGNANCY; PERIOD; RAT AB The hexose transporter, GLUT2 (SLC2A2), which is expressed by mouse embryos, is important for survival before embryonic day 10.5, but its function in embryos is unknown. GLUT2 can transport the amino sugar glucosamine (GlcN), which could increase substrate for the hexosamine biosynthetic pathway (HBSP) that produces UDP-N-acetylglucosamine for O-linked N-acetylglucosamine modification (O-GlcNAcylation) of proteins. To understand this, we employed a novel murine embryonic stem cell (ESC) line that, like mouse embryos, expresses functional GLUT2 transporters. GlcN stimulated ESC proliferation in a GLUT2-dependent fashion but did not regulate pluripotency. Stimulation of proliferation was not due to increased O-GlcNAcylation. Instead, GlcN decreased dependence of the HBSP on fructose-6-PO4 and glutamine. Consequently, glycolytic-and glutaminederived intermediates that are needed for anabolic metabolism were increased. Thus, maternally obtained GlcN may increase substrates for biomass accumulation by embryos, as exogenous GlcN does for GLUT2-expressing ESC, and may explain the need for GLUT2 expression by embryos. C1 [Jung, Jin Hyuk; Iwabuchi, Kumiko; Yang, Zhihong; Loeken, Mary R.] Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. [Jung, Jin Hyuk; Iwabuchi, Kumiko; Loeken, Mary R.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Yang, Zhihong] Harvard Med Sch, Sect Vasc Cell Biol, Boston, MA 02115 USA. RP Loeken, MR (reprint author), Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA.; Loeken, MR (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM mary.loeken@joslin.harvard.edu OI Loeken, Mary/0000-0002-8056-9816 FU NIH [R01DK052865, R01DK058300, R01DK104649, P30DK036836] FX We thank Dr. Thomas Becker (Duke University) for kindly providing pSuper Glut2 shRNA plasmid. We are grateful to Dr. Andre Kleinridders for assistance with use of the Seahorse XF Analyzer. The flow cytometry core of the Joslin Diabetes Center assisted with FACS analyses. The global metabolic profiling and data analyses were performed by Drs. Lauren Bell and Edward Karoly of Metabolon, Inc. Kaitlyn Sanders provided technical assistance. We are very grateful to Drs. Aldo Rossini, Scott Fraser, and Keith Blackwell for helpful discussions and critical reading of the manuscript. This work was funded by NIH R01DK052865 (to M.R.L.), NIH R01DK058300 (to M.R.L.), NIH R01DK104649 (to M.R.L.), and NIH P30DK036836 (to the Joslin Diabetes Center). NR 45 TC 0 Z9 0 U1 0 U2 0 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 17 PY 2016 VL 6 AR 28452 DI 10.1038/srep28452 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9FN UT WOS:000392077200001 PM 27311888 ER PT J AU Mahato, B Otero, TMN Holland, CA Giguere, PT Bajwa, EK Camargo, CA Quraishi, SA AF Mahato, Bisundev Otero, Tiffany M. N. Holland, Carrie A. Giguere, Patrick T. Bajwa, Ednan K. Camargo, Carlos A., Jr. Quraishi, Sadeq A. TI Addition of 25-hydroxyvitamin D levels to the Deyo-Charlson Comorbidity Index improves 90-day mortality prediction in critically ill patients SO JOURNAL OF INTENSIVE CARE LA English DT Article DE Vitamin D; 25-hydroxyvitamin D; Mortality; ICU ID VITAMIN-D STATUS; LOCALLY WEIGHTED REGRESSION; TANDEM MASS-SPECTROMETRY; INTENSIVE-CARE-UNIT; ADMINISTRATIVE DATA; D DEFICIENCY; ANTIMICROBIAL PEPTIDES; SCORING SYSTEMS; APACHE-II; HOSPITAL MORTALITY AB Background: The Deyo-Charlson Comorbidity Index (DCCI) has low predictive value in the intensive care unit (ICU). Our goal was to determine whether addition of 25-hydroxyvitamin D (25OHD) levels to the DCCI improved 90-day mortality prediction in critically ill patients. Methods: Plasma 25OHD levels, DCCI, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were assessed within 24 h of admission in 310 ICU patients. Receiver operating characteristic curves of the prediction scores, without and with the addition of 25OHD levels, for 90-day mortality were constructed and the areas under the curve (AUC) were compared for equality. Results: Mean (standard deviation) plasma 25OHD levels, DCCI, and APACHE II score were 19 (SD 8) ng/mL, 4 (SD 3), and 17 (SD 9), respectively. Overall 90-day mortality was 19 %. AUC for DCCI vs. DCCI + 25OHD was 0.68 (95 % CI 0.58-0.77) vs. 0.75 (95 % CI 0.67-0.83); p < 0.001. AUC for APACHE II vs. APACHE II + 25OHD was 0.81 (95 % CI 0.73-0.88) vs. 0.82 (95 % CI 0.75-0.89); p < 0.001. There was a significant difference between the AUC for DCCI + 25OHD and APACHE II + 25OHD (p = 0.04) but not between the AUC for DCCI + 25OHD and APACHE II (p = 0.12). Conclusions: In our cohort of ICU patients, the addition of 25OHD levels to the DCCI improved 90-day mortality prediction compared to the DCCI alone. Moreover, the predictive capability of DCCI + 25OHD was comparable to that of APACHE II. Future prospective studies are needed to validate our findings and to determine whether the use of DCCI + 25OHD can influence clinical decision-making. C1 [Mahato, Bisundev; Otero, Tiffany M. N.; Giguere, Patrick T.; Quraishi, Sadeq A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 402, Boston, MA 02114 USA. [Mahato, Bisundev] Harvard Med Sch, Boston, MA USA. [Mahato, Bisundev] Univ Calif Irvine, Dept Anesthesiol & Perioperat Care, Orange, CA 92668 USA. [Otero, Tiffany M. N.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Holland, Carrie A.; Bajwa, Ednan K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Bajwa, Ednan K.; Camargo, Carlos A., Jr.] Harvard Med Sch, Dept Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Quraishi, Sadeq A.] Harvard Med Sch, Dept Anaesthesia, Boston, MA 02115 USA. RP Quraishi, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 402, Boston, MA 02114 USA.; Quraishi, SA (reprint author), Harvard Med Sch, Dept Anaesthesia, Boston, MA 02115 USA. EM squraishi@mgh.harvard.edu FU NCATS NIH HHS [TL1 TR001062, L30 TR001257]; NCRR NIH HHS [UL1 RR025758]; NIAID NIH HHS [U01 AI087881, R01 AI093723]; NIGMS NIH HHS [L30 GM102903, T32 GM007592] NR 66 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2052-0492 J9 J INTENSIVE CARE JI J. Intensive Care PD JUN 17 PY 2016 VL 4 AR 40 DI 10.1186/s40560-016-0165-0 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA DR6JN UT WOS:000380008300001 PM 27330812 ER PT J AU Gatera, M Bhatt, S Ngabo, F Utamuliza, M Sibomana, H Karema, C Mugeni, C Nutt, CT Nsanzimana, S Wagner, CM Binagwaho, A AF Gatera, Maurice Bhatt, Sunil Ngabo, Fidele Utamuliza, Mathilde Sibomana, Hassan Karema, Corine Mugeni, Cathy Nutt, Cameron T. Nsanzimana, Sabin Wagner, Claire M. Binagwaho, Agnes TI Successive introduction of four new vaccines in Rwanda: High coverage and rapid scale up of Rwanda's expanded immunization program from 2009 to 2013 SO VACCINE LA English DT Article DE Immunization; Rwanda; Sub-Saharan Africa; Implementation science ID HEALTH SYSTEMS; WORLD AB As the pace of vaccine uptake accelerates globally, there is a need to document low-income country experiences with vaccine introductions. Over the course of five years, the government of Rwanda rolled out vaccines against pneumococcus, human papillomavirus, rotavirus, and measles & rubella, achieving over 90% coverage for each. To carry out these rollouts, Rwanda's Ministry of Health engaged in careful review of disease burden information and extensive, cross-sectoral planning at least one year before introducing each vaccine. Rwanda's local leaders, development partners, civil society organizations and widespread community health worker network were mobilized to support communication efforts. Community health workers were also used to confirm target population size. Support from Gavi, UNICEF and WHO was used in combination with government funds to promote country ownership and collaboration. Vaccination was also combined with additional community-based health interventions. Other countries considering rapid consecutive or simultaneous rollouts of new vaccines may consider lessons from Rwanda's experience while tailoring the strategies used to local context. (C) 2016 Published by Elsevier Ltd. C1 [Gatera, Maurice; Utamuliza, Mathilde; Sibomana, Hassan; Karema, Corine; Nsanzimana, Sabin] Rwanda Biomed Ctr, Kigali, Rwanda. [Bhatt, Sunil; Binagwaho, Agnes] Geisel Sch Med Dartmouth, 1 Rope Ferry Rd, Hanover, NH 03755 USA. [Ngabo, Fidele; Mugeni, Cathy; Binagwaho, Agnes] Govt Rwanda, Minist Hlth, POB 84, Kigali, Rwanda. [Wagner, Claire M.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Nutt, Cameron T.] Partners Hlth, 3rd Floor,888 Commonwealth Ave, Boston, MA 02215 USA. [Binagwaho, Agnes] Harvard Univ, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. [Karema, Corine] Univ Basel, Swiss Trop & Publ Hlth Inst, Socinstr 57,POB, CH-4002 Basel, Switzerland. RP Gatera, M (reprint author), Rwanda Biomed Ctr, Kigali, Rwanda. EM gamaurice2003@gmail.com NR 40 TC 1 Z9 1 U1 3 U2 5 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 17 PY 2016 VL 34 IS 29 BP 3420 EP 3426 DI 10.1016/j.vaccine.2015.11.076 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DP7GU UT WOS:000378668000013 PM 26704259 ER PT J AU Garg, S Sharp, PA AF Garg, Salil Sharp, Phillip A. TI GENE EXPRESSION Single-cell variability guided by microRNAs SO SCIENCE LA English DT Editorial Material ID STEM-CELLS; PLURIPOTENCY C1 [Garg, Salil] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Garg, Salil; Sharp, Phillip A.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Sharp, PA (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM sharppa@mit.edu FU NCI NIH HHS [P01 CA042063, R01 CA133404] NR 6 TC 0 Z9 0 U1 3 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 17 PY 2016 VL 352 IS 6292 BP 1390 EP 1391 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO7PV UT WOS:000377975400019 PM 27313022 ER PT J AU Bezzerides, VJ Platt, C Lerchenmuller, C Paruchuri, K Oh, NL Xiao, CY Cao, YS Mann, N Spiegelman, BM Rosenzweig, A AF Bezzerides, Vassilios J. Platt, Colin Lerchenmuller, Carolin Paruchuri, Kaavya Oh, Nul Loren Xiao, Chunyang Cao, Yunshan Mann, Nina Spiegelman, Bruce M. Rosenzweig, Anthony TI CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury SO JCI INSIGHT LA English DT Article ID INDUCED CARDIAC GROWTH; REPERFUSION INJURY; ISCHEMIA/REPERFUSION INJURY; MYOCARDIAL-INFARCTION; MAMMALIAN TARGET; VENTRICULAR MASS; MOUSE HEART; EXERCISE; AUTOPHAGY; RAPAMYCIN AB The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury. C1 [Bezzerides, Vassilios J.; Platt, Colin; Lerchenmuller, Carolin; Paruchuri, Kaavya; Oh, Nul Loren; Xiao, Chunyang; Cao, Yunshan; Mann, Nina; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. [Bezzerides, Vassilios J.; Platt, Colin; Lerchenmuller, Carolin; Paruchuri, Kaavya; Oh, Nul Loren; Xiao, Chunyang; Cao, Yunshan; Mann, Nina; Spiegelman, Bruce M.; Rosenzweig, Anthony] Harvard Med Sch, Boston, MA USA. [Spiegelman, Bruce M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Platt, Colin; Lerchenmuller, Carolin; Xiao, Chunyang; Cao, Yunshan; Rosenzweig, Anthony] Massachusetts Gen Hosp, Div Cardiovasc, GRB 810,55 Fruit St, Boston, MA 02114 USA. [Bezzerides, Vassilios J.] Boston Childrens Hosp, Div Cardiovasc, Boston, MA USA. RP Rosenzweig, A (reprint author), Massachusetts Gen Hosp, Div Cardiovasc, GRB 810,55 Fruit St, Boston, MA 02114 USA. EM arosenzweig@partners.org NR 43 TC 0 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUN 16 PY 2016 VL 1 IS 9 AR e85904 DI 10.1172/jci.insight.85904 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LG UT WOS:000387112700002 ER PT J AU Herter-Sprie, GS Koyama, S Korideck, H Hai, J Deng, JH Li, YY Buczkowski, KA Grant, AK Ullas, S Rhee, K Cavanaugh, JD Neupane, NP Christensen, CL Herter, JM Makrigiorgos, GM Hodi, FS Freeman, GJ Dranoff, G Hammerman, PS Kimmelman, AC Wong, KK AF Herter-Sprie, Grit S. Koyama, Shohei Korideck, Houari Hai, Josephine Deng, Jiehui Li, Yvonne Y. Buczkowski, Kevin A. Grant, Aaron K. Ullas, Soumya Rhee, Kevin Cavanaugh, Jillian D. Neupane, Neermala Poudel Christensen, Camilla L. Herter, Jan M. Makrigiorgos, G. Mike Hodi, F. Stephen Freeman, Gordon J. Dranoff, Glenn Hammerman, Peter S. Kimmelman, Alec C. Wong, Kwok-Kin TI Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer SO JCI INSIGHT LA English DT Article ID REGULATORY T-CELLS; RESPONSE CRITERIA; NEUTROPHIL RECRUITMENT; ANTITUMOR IMMUNITY; PROSTATE-CANCER; TUMOR RESPONSE; BREAST-CANCER; MOUSE MODELS; RADIATION; IMMUNOTHERAPY AB Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non-small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional Kras-driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (alpha PD-1). However, while alpha PD-1 therapy was beneficial when combined with RT in radiation-naive tumors, alpha PD-1 therapy had no antineoplastic efficacy in RT-relapsed tumors and further induced T cell inhibitory markers in this setting. Furthermore, there was differential efficacy of alpha PD-1 plus RT among Kras-driven GEMMs, with additional loss of the tumor suppressor serine/threonine kinase 11/liver kinase B1 (Stk11/Lkb1) resulting in no synergistic efficacy. Taken together, our data provide evidence for a close interaction among RT, T cells, and the PD-1/PD-L1 axis and underscore the rationale for clinical combinatorial therapy with immune modulators and radiotherapy. C1 [Herter-Sprie, Grit S.; Koyama, Shohei; Hai, Josephine; Deng, Jiehui; Li, Yvonne Y.; Buczkowski, Kevin A.; Rhee, Kevin; Cavanaugh, Jillian D.; Neupane, Neermala Poudel; Christensen, Camilla L.; Hodi, F. Stephen; Freeman, Gordon J.; Dranoff, Glenn; Hammerman, Peter S.; Wong, Kwok-Kin] Harvard Med Sch, Dept Med, Boston, MA USA. [Herter-Sprie, Grit S.; Koyama, Shohei; Hai, Josephine; Deng, Jiehui; Li, Yvonne Y.; Buczkowski, Kevin A.; Rhee, Kevin; Cavanaugh, Jillian D.; Neupane, Neermala Poudel; Christensen, Camilla L.; Hodi, F. Stephen; Freeman, Gordon J.; Dranoff, Glenn; Hammerman, Peter S.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Herter-Sprie, Grit S.; Hai, Josephine; Deng, Jiehui; Li, Yvonne Y.; Buczkowski, Kevin A.; Rhee, Kevin; Cavanaugh, Jillian D.; Neupane, Neermala Poudel; Christensen, Camilla L.; Hammerman, Peter S.] Harvard Med Sch, Lowe Ctr Thorac Oncol, Boston, MA USA. [Koyama, Shohei; Freeman, Gordon J.; Dranoff, Glenn; Wong, Kwok-Kin] Harvard Med Sch, Canc Vaccine Ctr, Boston, MA USA. [Korideck, Houari; Makrigiorgos, G. Mike] Harvard Med Sch, Div Med Phys & Biophys, Boston, MA USA. [Korideck, Houari; Makrigiorgos, G. Mike; Kimmelman, Alec C.; Wong, Kwok-Kin] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA USA. [Grant, Aaron K.] Harvard Med Sch, Dept Radiol, Div MRI Res, Boston, MA USA. [Ullas, Soumya] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Longwood Small Anim Imaging Facil, Boston, MA USA. [Herter, Jan M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Ctr Excellence Vasc Biol, Boston, MA USA. [Kimmelman, Alec C.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair, Boston, MA USA. Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, 450 Brookline Ave, Boston, MA 02115 USA. RP Wong, KK (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA.; Kimmelman, AC (reprint author), NYU, Langone Med Ctr, Dept Radiat Oncol, 560 First Ave,2nd FL, New York, NY 10016 USA. EM alec.kimmelman@nyumc.org; kwong1@partners.org FU NCI NIH HHS [R01 CA205150, R01 CA122794, R01 CA140594, R01 CA163896, R01 CA166480, R01 CA188048, R01 CA195740]; NIGMS NIH HHS [R01 GM095567] NR 71 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUN 16 PY 2016 VL 1 IS 9 AR e87415 DI 10.1172/jci.insight.87415 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LG UT WOS:000387112700012 PM 27699275 ER PT J AU Luskin, MR Gimotty, PA Smith, C Loren, AW Figueroa, ME Harrison, J Sun, ZX Tallman, MS Paietta, EM Litzow, MR Melnick, AM Levine, RL Fernandez, HF Luger, SM Carroll, M Master, SR Wertheim, GBW AF Luskin, Marlise R. Gimotty, Phyllis A. Smith, Catherine Loren, Alison W. Figueroa, Maria E. Harrison, Jenna Sun, Zhuoxin Tallman, Martin S. Paietta, Elisabeth M. Litzow, Mark R. Melnick, Ari M. Levine, Ross L. Fernandez, Hugo F. Luger, Selina M. Carroll, Martin Master, Stephen R. Wertheim, Gerald B. W. TI A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia SO JCI INSIGHT LA English DT Article ID INTENSIVE CHEMOTHERAPY; MUTATIONS RESULT; TET2 FUNCTION; HYPERMETHYLATION; EPIGENETICS; RESISTANCE; SURVIVAL; IMPACT; OLDER AB BACKGROUND. Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML. METHODS. We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy. The association of M-score with complete remission (CR) and overall survival (OS) was evaluated. The optimal M-score cut-point for identifying groups with differing survival was used to define a binary M-score classifier. This classifier was validated in an independent cohort of 383 patients from the Eastern Cooperative Oncology Group Trial 1900 (E1900; NCT00049517). RESULTS. A higher mean M-score was associated with death and failure to achieve CR. Multivariable analysis confirmed that a higher M-score was associated with death (P = 0.011) and failure to achieve CR (P = 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. The ability of the M-score to perform as a classifier was confirmed in patients <= 60 years with intermediate cytogenetics and patients who achieved CR, as well as in the E1900 validation cohort. CONCLUSION. The M-score represents a valid binary prognostic classifier for patients with de novo AML. The xMELP assay and associated M-score can be used for prognosis and should be further investigated for clinical decision making in AML patients. C1 [Luskin, Marlise R.; Loren, Alison W.; Luger, Selina M.; Carroll, Martin] Univ Penn UPENN, Abramson Canc Ctr, Div Hematol & Oncol, Philadelphia, PA USA. [Gimotty, Phyllis A.] Univ Penn UPENN, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA USA. [Smith, Catherine; Harrison, Jenna; Wertheim, Gerald B. W.] Childrens Hosp Philadelphia, Dept Pathol, 5199b Main Bldg,324 S 34th St, Philadelphia, PA 19104 USA. [Figueroa, Maria E.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Sun, Zhuoxin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tallman, Martin S.; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Paietta, Elisabeth M.] Montefiore Med Ctr, New York, NY USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Melnick, Ari M.] Weill Cornell Med Coll, Div Hematol & Oncol, 525 E 68th St,Suite F-715,Box 79, New York, NY 10065 USA. [Fernandez, Hugo F.] Moffit Canc Ctr, Tampa, FL USA. [Carroll, Martin] Philadelphia Vet Adm Med Ctr, Philadelphia, PA USA. [Master, Stephen R.] Weill Cornell Med Coll, Dept Pathol & Lab Med, 525 E 68th St,Suite F-715,Box 79, New York, NY 10065 USA. [Wertheim, Gerald B. W.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Master, SR (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, 525 E 68th St,Suite F-715,Box 79, New York, NY 10065 USA.; Wertheim, GBW (reprint author), Childrens Hosp Philadelphia, Dept Pathol & Lab Med, 5199b Main Bldg,324 S 34th St, Philadelphia, PA 19104 USA. EM srm9012@med.cornell.edu; wertheimg@email.chop.edu NR 29 TC 3 Z9 3 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUN 16 PY 2016 VL 1 IS 9 AR e87323 DI 10.1172/jci.insight.87323 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LG UT WOS:000387112700011 ER PT J AU Keene, CD Darvas, M Kraemer, B Liggitt, D Sigurdson, C Ladiges, W AF Keene, C. Dirk Darvas, Martin Kraemer, Brian Liggitt, Denny Sigurdson, Christina Ladiges, Warren TI Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines SO PATHOBIOLOGY OF AGING AND AGE-RELATED DISEASES LA English DT Editorial Material DE Alzheimer's disease; mouse models of Alzheimer's disease; neuropathological validation; NIA-AA guidelines ID AD AB Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Ab and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Ab and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Ab and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Ab deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards for models of AD and other neurodegenerative disorders. C1 [Keene, C. Dirk; Darvas, Martin; Ladiges, Warren] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Kraemer, Brian] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Kraemer, Brian] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Liggitt, Denny; Ladiges, Warren] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Sigurdson, Christina] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Sigurdson, Christina] Scripps Res Inst, La Jolla, CA 92037 USA. RP Ladiges, W (reprint author), Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. EM wladiges@u.washington.edu FU BLRD VA [I01 BX002619] NR 8 TC 0 Z9 0 U1 2 U2 2 PU CO-ACTION PUBLISHING PI JARFALLA PA RIPVAGEN 7, JARFALLA, SE-175 64, SWEDEN EI 2001-0001 J9 PATHOBIOL AGING AGE JI Pathobiol. Aging Age-relat. Dis. PD JUN 16 PY 2016 VL 6 AR 32397 DI 10.3402/pba.v6.32397 PG 4 WC Pathology SC Pathology GA DT4EY UT WOS:000381434100001 PM 27317189 ER PT J AU Bao, XR Ong, SE Goldberger, O Peng, J Sharma, R Thompson, DA Vafai, SB Cox, AG Marutani, E Ichinose, F Goessling, W Regev, A Carr, SA Clish, CB Mootha, VK AF Bao, Xiaoyan Robert Ong, Shao-En Goldberger, Olga Peng, Jun Sharma, Rohit Thompson, Dawn A. Vafai, Scott B. Cox, Andrew G. Marutani, Eizo Ichinose, Fumito Goessling, Wolfram Regev, Aviv Carr, Steven A. Clish, Clary B. Mootha, Vamsi K. TI Mitochondrial dysfunction remodels one - carbon metabolism in human cells SO ELIFE LA English DT Article ID SUPPORTING ASPARTATE BIOSYNTHESIS; INTEGRATED-STRESS-RESPONSE; UNFOLDED-PROTEIN RESPONSE; PYRUVATE-KINASE M2; RESPIRATORY-CHAIN; HYDROGEN-SULFIDE; FEEDBACK INHIBITION; GENE-EXPRESSION; REDOX STATE; RAT-LIVER AB Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mitochondrial DNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis. C1 [Bao, Xiaoyan Robert; Goldberger, Olga; Peng, Jun; Sharma, Rohit; Vafai, Scott B.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. [Bao, Xiaoyan Robert; Mootha, Vamsi K.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Bao, Xiaoyan Robert; Ong, Shao-En; Peng, Jun; Thompson, Dawn A.; Vafai, Scott B.; Goessling, Wolfram; Regev, Aviv; Carr, Steven A.; Clish, Clary B.; Mootha, Vamsi K.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Cox, Andrew G.; Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA. [Marutani, Eizo; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. [Bao, Xiaoyan Robert] Berkeley Lights Inc, Emeryville, CA USA. [Ong, Shao-En] Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA.; Mootha, VK (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Mootha, VK (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM vamsi@hms.harvard.edu FU Howard Hughes Medical Institute; National Institutes of Health [R01DK081457, 2R01CA119176, R01HL101930] FX Howard Hughes Medical Institute Xiaoyan Robert Bao Olga Goldberger Jun Peng Rohit Sharma Dawn A Thompson Scott B Vafai Aviv Regev Vamsi K Mootha; National Institutes of Health R01DK081457 Xiaoyan Robert Bao Vamsi K Mootha; National Institutes of Health 2R01CA119176 Aviv Regev; National Institutes of Health R01HL101930 Fumito Ichinose NR 79 TC 9 Z9 9 U1 9 U2 11 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 16 PY 2016 VL 5 AR e10575 DI 10.7554/eLife.10575 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DR1RK UT WOS:000379682400001 ER PT J AU Oscari, F Finetto, C Kautz, SA Rosati, G AF Oscari, Fabio Finetto, Christian Kautz, Steve A. Rosati, Giulio TI Changes in muscle coordination patterns induced by exposure to a viscous force field SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Motor adaptation; Learning; Motor modules; Viscous field; Dynamic perturbation; Robotics; Haptics ID UPPER-LIMB; STROKE REHABILITATION; ACTIVATION PATTERNS; REACHING MOVEMENTS; MOTOR ADAPTATION; MODULAR CONTROL; HUMAN WALKING; SYNERGIES; RECOVERY; ERROR AB Background: Robotic neurorehabilitation aims at promoting the recovery of lost function after neurological injury by leveraging strategies of motor learning. One important aspect of the rehabilitation process is the improvement of muscle coordination patterns, which can be drastically altered after stroke. However, it is not fully understood if and how robotic therapy can address these deficits. The aim of our study was to find how muscle coordination, analyzed from the perspective of motor modules, could change during motor adaptation to a dynamic environment generated by a haptic interface. Methods: In our experiment we employed the traditional paradigm of exposure to a viscous force field to subjects that grasped the handle of an actuated joystick during a reaching movement (participants moved directly forward and back by 30 cm). EMG signals of ten muscles of the tested arm were recorded. We extracted motor modules from the pooled EMG data of all subjects and analyzed the muscle coordination patterns. Results: We found that the participants reacted by using a coordination strategy that could be explained by a change in the activation of motor modules used during free motion and by two complementary modules. These complementary modules aggregated changes in muscle coordination, and evolved throughout the experiment eventually maintaining a comparable structure until the late phase of re-adaptation. Conclusions: This result suggests that motor adaptation induced by the interaction with a robotic device can lead to changes in the muscle coordination patterns of the subject. C1 [Oscari, Fabio; Rosati, Giulio] Univ Padua, Dept Management & Engn, Via Venezia 1, I-35135 Padua, Italy. [Finetto, Christian; Kautz, Steve A.] Med Univ S Carolina, Dept Hlth Sci & Res, 77 President St,MSC 700, Charleston, SC 29425 USA. [Kautz, Steve A.] Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Oscari, F (reprint author), Univ Padua, Dept Management & Engn, Via Venezia 1, I-35135 Padua, Italy. EM fabio.oscari@unipd.it FU Institutional Development Award (IDeA) from National Institute of General Medical Sciences of the National Institutes of Health [P20GM109040]; Rehabilitation Research and Development Service of the Department of Veterans Affairs FX The authors would like to thank Dr. Stefano Masiero for providing the EMG system used for the experiment. Furthermore, we would like to acknowledge the contribution of Alice Marcato to the organization and execution of all data collections. Dr. Kautz is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM109040 and by the Rehabilitation Research and Development Service of the Department of Veterans Affairs. NR 49 TC 0 Z9 0 U1 11 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD JUN 16 PY 2016 VL 13 AR 58 DI 10.1186/s12984-016-0164-3 PG 16 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA DQ1XM UT WOS:000378994100002 PM 27305944 ER PT J AU Sonneveld, P Avet-Loiseau, H Lonial, S Usmani, S Siegel, D Anderson, KC Chng, WJ Moreau, P Attal, M Kyle, RA Caers, J Hillengass, J Miguel, JS van de Donk, NWCJ Einsele, H Blade, J Durie, BGM Goldschmidt, H Mateos, MV Palumbo, A Orlowski, R AF Sonneveld, Pieter Avet-Loiseau, Herve Lonial, Sagar Usmani, Saad Siegel, David Anderson, Kenneth C. Chng, Wee-Joo Moreau, Philippe Attal, Michel Kyle, Robert A. Caers, Jo Hillengass, Jens San Miguel, Jesus van de Donk, Niels W. C. J. Einsele, Hermann Blade, Joan Durie, Brian G. M. Goldschmidt, Hartmut Mateos, Maria-Victoria Palumbo, Antonio Orlowski, Robert TI Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; TOTAL THERAPY 3; LENALIDOMIDE PLUS DEXAMETHASONE; INDEPENDENT PROGNOSTIC-FACTOR; LOW-DOSE DEXAMETHASONE; GENE-EXPRESSION; INTERGROUPE FRANCOPHONE; AUTOLOGOUS TRANSPLANTATION; RANDOMIZED PHASE-3; STAGING SYSTEM AB The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4; 14), del(17/17p), t(14; 16), t(14; 20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4; 14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4; 14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification. C1 [Sonneveld, Pieter] Erasmus MC Canc Inst, Dept Hematol, Rotterdam, Netherlands. [Avet-Loiseau, Herve] Univ Canc Ctr Toulouse, Lab Genom Myeloma, Toulouse, France. [Lonial, Sagar] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA USA. [Usmani, Saad] Carolinas Healthcare Syst, Levine Canc Inst, Charlotte, NC USA. [Siegel, David] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Chng, Wee-Joo] Natl Univ Canc Inst, Div Hematol, Singapore, Singapore. [Moreau, Philippe] Univ Hosp, Dept Hematol, Nantes, France. [Attal, Michel] Purpan Univ Hosp, Dept Hematol, Toulouse, France. [Kyle, Robert A.] Mayo Clin, Dept Lab Med & Pathol, Minneapolis, MN USA. [Caers, Jo] Univ Liege, Ctr Hosp, Dept Hematol, Liege, Belgium. [Hillengass, Jens] Heidelberg Univ, Sect Multiple Myeloma, Med Clin 5, Heidelberg, Germany. [San Miguel, Jesus] Univ Navarra Clin, Ctr Invest Med Aplicada, Pamplona, Spain. [van de Donk, Niels W. C. J.] Free Univ Amsterdam, Med Ctr Amsterdam, Dept Hematol, Amsterdam, Netherlands. [Einsele, Hermann] Univ Klin Wurzburg, Med Clin 2, Wurzburg, Germany. [Blade, Joan] Univ Hosp Clin, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Durie, Brian G. M.] Int Myeloma Fdn, North Hollywood, CA USA. [Goldschmidt, Hartmut] Univ Heidelberg Hosp, Heidelberg, Germany. [Goldschmidt, Hartmut] Natl Ctr Tumor Dis Heidelberg, Heidelberg, Germany. [Mateos, Maria-Victoria] Univ Hosp Salamanca, Dept Hematol, Salamanca, Spain. [Palumbo, Antonio] Univ Turin, Myeloma Unit, Turin, Italy. [Orlowski, Robert] Univ Texas Houston, MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Div Canc Med, 1515 Holcombe Blvd, Houston, TX 77030 USA. RP Sonneveld, P (reprint author), Erasmus MC, Erasmus MC Canc Inst, Dept Hematol, Rm Na822,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM p.sonneveld@erasmusmc.nl RI richard, chrystelle/K-8595-2015 FU Amgen/Onyx; Celgene; Janssen; Karyopharm; SkylineDx FX This study was supported by Amgen/Onyx, Celgene, Janssen, Karyopharm, and SkylineDx, and by honoraria from Amgen/Onyx, Celgene, Janssen, and Karyopharm. NR 104 TC 16 Z9 17 U1 2 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 16 PY 2016 VL 127 IS 24 BP 2955 EP 2962 DI 10.1182/blood-2016-01-631200 PG 8 WC Hematology SC Hematology GA DP2RG UT WOS:000378337100009 PM 27002115 ER PT J AU Kariminia, A Holtan, SG Ivison, S Rozmus, J Hebert, MJ Martin, PJ Lee, SJ Wolff, D Subrt, P Abdossamadi, S Sung, S Storek, J Levings, M Aljurf, M Arora, M Cutler, C Gallagher, G Kuruvilla, J Lipton, J Nevill, TJ Newell, LF Panzarella, T Pidala, J Popradi, G Szwajcer, D Tay, J Toze, CL Walker, I Couban, S Storer, BE Schultz, KR AF Kariminia, Amina Holtan, Shernan G. Ivison, Sabine Rozmus, Jacob Hebert, Marie-Josee Martin, Paul J. Lee, Stephanie J. Wolff, Daniel Subrt, Peter Abdossamadi, Sayeh Sung, Susanna Storek, Jan Levings, Megan Aljurf, Mahmoud Arora, Mukta Cutler, Corey Gallagher, Genevieve Kuruvilla, John Lipton, Jeff Nevill, Thomas J. Newell, Laura F. Panzarella, Tony Pidala, Joseph Popradi, Gizelle Szwajcer, David Tay, Jason Toze, Cynthia L. Walker, Irwin Couban, Stephen Storer, Barry E. Schultz, Kirk R. TI Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3(+) NK cells SO BLOOD LA English DT Article ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CHRONIC GVHD; T-CELLS; CLINICAL-TRIALS; TRANSPLANTATION; IMPACT; PATHOGENESIS; DIAGNOSIS; SURVIVAL AB Chronic graft-versus-host disease(cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases <= 1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3(+)CD56(bright) natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates. C1 [Kariminia, Amina; Ivison, Sabine; Rozmus, Jacob; Subrt, Peter; Abdossamadi, Sayeh; Sung, Susanna; Levings, Megan; Schultz, Kirk R.] Univ British Columbia, British Columbia Childrens Hosp, Michael Cuccione Childhood Canc Res Program, Vancouver, BC V5Z 1M9, Canada. [Holtan, Shernan G.; Arora, Mukta] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Hebert, Marie-Josee] Univ Montreal, Hop Notre Dame, Ctr Hosp, Ctr Rech, Montreal, PQ, Canada. [Martin, Paul J.; Lee, Stephanie J.; Storer, Barry E.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Martin, Paul J.; Lee, Stephanie J.; Storer, Barry E.] Univ Washington, Seattle, WA 98195 USA. [Wolff, Daniel] Univ Hosp Regensburg, Dept Internal Med 3, Regensburg, Germany. [Storek, Jan] Univ Calgary, Calgary, AB, Canada. [Aljurf, Mahmoud] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. [Cutler, Corey] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Gallagher, Genevieve] Univ Quebec, Hop Enfant Jesus, Ctr Hosp, Quebec City, PQ, Canada. [Kuruvilla, John; Lipton, Jeff; Panzarella, Tony] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Nevill, Thomas J.; Toze, Cynthia L.] British Columbia Canc Agcy, Vancouver Gen Hosp, Leukemia Bone Marrow Transplant Program British C, Vancouver, BC V5Z 4E6, Canada. [Nevill, Thomas J.; Toze, Cynthia L.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Newell, Laura F.] Oregon Hlth & Sci Univ, Knight Canc Inst, Ctr Hematol Malignancies, Portland, OR 97201 USA. [Pidala, Joseph] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Popradi, Gizelle] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Szwajcer, David] CancerCare Manitoba, Winnipeg, MB, Canada. [Tay, Jason] Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Walker, Irwin] Hamilton Hlth Sci, Hamilton, ON, Canada. [Walker, Irwin] McMaster Univ, Hamilton, ON, Canada. [Couban, Stephen] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. RP Schultz, KR (reprint author), Univ British Columbia, British Columbia Childrens Hosp, Michael Cuccione Childhood Canc Res Program, Vancouver, BC V5Z 1M9, Canada.; Schultz, KR (reprint author), Univ British Columbia, British Columbia Childrens Hosp, 4480 Oak St,Room A119, Vancouver, BC V6H 3V4, Canada. EM kschultz@mail.ubc.ca OI , Jacob/0000-0003-4036-2105 FU Canadian Institutes of Health; CIHR/Wyeth Clinical Research Chair in Transplantation; Canadian National Transplant Research Program - CIHR; Office of Research in Women's Health; National Institute of Child Health and Human Development, Oregon Building Interdisciplinary Research Careers in Women's Health Award [2K12HD043488]; Medical Foundation of Oregon; Deutsche Jose Carreras Leukamie-Stiftung; Center for Advancing Translational Sciences; National Cancer Institute (NCI) [U54CA163438]; NCI [CA118953]; National Institutes of Health/NCI [CBMTG 0601, 1R01CA108752-01A2]; CIHR [CBMTG 0801] FX This work was supported by a Canadian Institutes of Health Operating Grant; by the CIHR/Wyeth Clinical Research Chair in Transplantation (K.R.S.); by the Canadian National Transplant Research Program (funded by the CIHR); by the Office of Research in Women's Health and the National Institute of Child Health and Human Development, Oregon Building Interdisciplinary Research Careers in Women's Health Award No. 2K12HD043488 (S.G.H.); by the Medical Foundation of Oregon (S.G.H.); and by the Deutsche Jose Carreras Leukamie-Stiftung (D.W.). The Chronic GVHD Consortium is funded via collaboration between the Center for Advancing Translational Sciences and the National Cancer Institute (NCI) (U54CA163438). Support for the discovery samples was provided by grant CA118953 from NCI. The Canadian Bone Marrow Transplant Group Clinical Trials Network provided samples from CBMTG 0601 (funded by National Institutes of Health/NCI 1R01CA108752-01A2) and samples from CBMTG 0801 (funded by CIHR). NR 29 TC 6 Z9 6 U1 0 U2 0 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 16 PY 2016 VL 127 IS 24 BP 3082 EP 3091 DI 10.1182/blood-2015-09-668251 PG 10 WC Hematology SC Hematology GA DP2RG UT WOS:000378337100022 PM 27020088 ER PT J AU Lehmann, BD Jovanovic, B Chen, X Estrada, MV Johnson, KN Shyr, Y Moses, HL Sanders, ME Pietenpol, JA AF Lehmann, Brian D. Jovanovic, Bojana Chen, Xi Estrada, Monica V. Johnson, Kimberly N. Shyr, Yu Moses, Harold L. Sanders, Melinda E. Pietenpol, Jennifer A. TI Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection SO PLOS ONE LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; PATHOLOGICAL COMPLETE RESPONSE; PROGNOSTIC VALUE; SURVIVAL; IDENTIFICATION; IXABEPILONE; EXPRESSION; PACLITAXEL; WOMEN; RATES AB Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes. C1 [Lehmann, Brian D.; Johnson, Kimberly N.; Pietenpol, Jennifer A.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Jovanovic, Bojana] Harvard Univ, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Chen, Xi] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Div Biostat, Miami, FL 33136 USA. [Chen, Xi] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Estrada, Monica V.] Vanderbilt Univ, Breast Canc Res Program, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Shyr, Yu] Vanderbilt Univ, Dept Biostat, Div Canc Biostat, Ctr Quantitat Sci, 221 Kirkland Hall, Nashville, TN 37235 USA. [Moses, Harold L.; Pietenpol, Jennifer A.] Vanderbilt Univ, Dept Canc Biol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Sanders, Melinda E.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Lehmann, BD; Pietenpol, JA (reprint author), Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA.; Pietenpol, JA (reprint author), Vanderbilt Univ, Dept Canc Biol, 221 Kirkland Hall, Nashville, TN 37235 USA. EM brian.d.lehmann@vanderbilt.edu; j.pietenpol@vanderbilt.edu OI lehmann, brian/0000-0003-0407-5248 FU NCI/NCI grants [CA105436, CA068485, CA085492, CA102162]; Komen for the Cure Foundation grants [SAC110030, CCR13262005]; Vanderbilt-Ingram Cancer Center [P30 CA068485]; Vanderbilt Vision Center [P30 EY08126]; NIH/NCRR [G20 RR030956]; Specialized Program of Research Excellence in Breast Cancer [CA098131] FX This research was supported by: NCI/NCI grants CA105436 (JAP), CA068485 (JAP), CA085492 (HLM) and CA102162 (HLM); and Komen for the Cure Foundation grants SAC110030 (JAP) and CCR13262005 (BDL). The authors would like to thank Vanderbilt Technologies for Advanced Genomics (VANTAGE) and the Translational Pathology Shared Resources supported by the Vanderbilt-Ingram Cancer Center (P30 CA068485), the Vanderbilt Vision Center (P30 EY08126) and NIH/NCRR (G20 RR030956). Grant support for the histopathological analyses was provided by CA098131 (Specialized Program of Research Excellence in Breast Cancer).; We thank members of the Pietenpol lab and Robert Seitz for critical review of the manuscript. This research was supported by: NCI/NCI grants CA105436 (JAP), CA068485 (JAP), CA085492 (HLM) and CA102162 (HLM); and Komen for the Cure Foundation grants SAC110030 (JAP) and CCR13262005 (BDL). We would like to thank Vanderbilt Technologies for Advanced Genomics (VANTAGE) and the Translational Pathology Shared Resources supported by the Vanderbilt-Ingram Cancer Center (P30 CA068485), the Vanderbilt Vision Center (P30 EY08126) and NIH/NCRR (G20 RR030956). Grant support for the histopathological analyses was provided by CA098131 (Specialized Program of Research Excellence in Breast Cancer). NR 35 TC 10 Z9 10 U1 5 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 16 PY 2016 VL 11 IS 6 AR e0157368 DI 10.1371/journal.pone.0157368 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8JO UT WOS:000378029800062 PM 27310713 ER PT J AU Zhang, Y Walter, R Ng, P Luong, PN Dutt, S Heuer, H Rojas-Rodriguez, JC Tsai, R Litvan, I Dickerson, BC Tartaglia, MC Rabinovici, G Miller, BL Rosen, HJ Schuff, N Boxer, AL AF Zhang, Yu Walter, Rudolph Ng, Peter Luong, Phi N. Dutt, Shubir Heuer, Hilary Rojas-Rodriguez, Julio C. Tsai, Richard Litvan, Irene Dickerson, Bradford C. Tartaglia, Maria Carmela Rabinovici, Gil Miller, Bruce L. Rosen, Howard J. Schuff, Norbert Boxer, Adam L. TI Progression of Microstructural Degeneration in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Longitudinal Diffusion Tensor Imaging Study SO PLOS ONE LA English DT Article ID WHITE-MATTER; NEUROPATHOLOGIC CRITERIA; CEREBELLAR PEDUNCLE; CLINICAL-DIAGNOSIS; ALZHEIMERS-DISEASE; TASK-FORCE; MRI; ATROPHY; DISORDERS; RATES AB Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are both 4 microtubule binding repeat tauopathy related disorders. Clinical trials need new biomarkers to assess the effectiveness of tau-directed therapies. This study investigated the regional distribution of longitudinal diffusion tensor imaging changes, measured by fractional anisotropy, radial and axial diffusivity over 6 months median interval, in 23 normal control subjects, 35 patients with PSP, and 25 patients with CBS. A mixed-effects framework was used to test longitudinal changes within and between groups. Correlations between changes in diffusion variables and clinical progression were also tested. The study found that over a 6 month period and compared to controls, the most prominent changes in PSP were up to 3 +/- 1% higher rates of FA reduction predominantly in superior cerebellar peduncles, and up to 18 +/- 6% higher rates of diffusivity increases in caudate nuclei. The most prominent changes in CBS compared to controls were up to 4 +/- 1% higher rates of anisotropy reduction and 18 +/- 6% higher rates of diffusivity increase in basal ganglia and widespread white matter regions. Compared to PSP, CBS was mainly associated with up to 3 +/- 1% greater rates of anisotropy reduction around the central sulci, and 11 +/- 3% greater rates of diffusivity increase in superior fronto-occipital fascicules. Rates of diffusivity increases in the superior cerebellar peduncle correlated with rates of ocular motor decline in PSP patients. This study demonstrated that longitudinal diffusion tensor imaging measurement is a promising surrogate marker of disease progression in PSP and CBS over a relatively short period. C1 [Zhang, Yu; Walter, Rudolph; Ng, Peter; Schuff, Norbert] VA Med Ctr San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Zhang, Yu; Walter, Rudolph; Ng, Peter; Schuff, Norbert] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Luong, Phi N.; Dutt, Shubir; Heuer, Hilary; Rojas-Rodriguez, Julio C.; Tsai, Richard; Tartaglia, Maria Carmela; Rabinovici, Gil; Miller, Bruce L.; Rosen, Howard J.; Boxer, Adam L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Litvan, Irene] Univ Calif San Diego, Movement Disorder Ctr, Dept Neurosci, San Diego, CA 92103 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Tartaglia, Maria Carmela] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Tartaglia, Maria Carmela] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. RP Zhang, Y (reprint author), VA Med Ctr San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA.; Zhang, Y (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. EM Yu.Zhang@ucsf.edu OI Litvan, Irene/0000-0002-3485-3445 FU National Institutes of Health [R01AG038791, R01AG032306]; Frontotemporal Lobar Degeneration Clinical Research Consortium [U54NS092089]; Tau Consortium; Veterans Affairs Medical Center, San Francisco, California FX This study was supported in part by the National Institutes of Health grants (R01AG038791, R01AG032306); The Frontotemporal Lobar Degeneration Clinical Research Consortium (U54NS092089); Tau Consortium; and with resources of the Veterans Affairs Medical Center, San Francisco, California. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2016 VL 11 IS 6 AR e0157218 DI 10.1371/journal.pone.0157218 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO8JO UT WOS:000378029800045 PM 27310132 ER PT J AU Zhang, JF Xu, K Liu, PD Geng, Y Wang, B Gan, WJ Guo, JP Wu, F Chin, YR Berrios, C Lien, EC Toker, A DeCaprio, JA Sicinski, P Wei, WY AF Zhang, Jinfang Xu, Kai Liu, Pengda Geng, Yan Wang, Bin Gan, Wenjian Guo, Jianping Wu, Fei Chin, Y. Rebecca Berrios, Christian Lien, Evan C. Toker, Alex DeCaprio, James A. Sicinski, Piotr Wei, Wenyi TI Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt SO MOLECULAR CELL LA English DT Article ID RETINOBLASTOMA TUMOR-SUPPRESSOR; CELL-CYCLE; PROTEIN-PHOSPHORYLATION; TERMINAL DOMAIN; BREAST-CANCER; RAG GTPASES; MTOR; COMPLEX; GROWTH; GENE AB The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper-phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer. C1 [Xu, Kai] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Otolaryngol Head & Neck Surg, Tongji Med Coll, Wuhan 430030, Peoples R China. [Zhang, Jinfang; Xu, Kai; Liu, Pengda; Wang, Bin; Gan, Wenjian; Guo, Jianping; Wu, Fei; Chin, Y. Rebecca; Lien, Evan C.; Toker, Alex; Wei, Wenyi] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Geng, Yan; Sicinski, Piotr] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. [Geng, Yan; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wang, Bin] Third Mil Med Univ, Inst Surg Res, Daping Hosp, Dept Gastroenterol, Chongqing 400042, Peoples R China. [Berrios, Christian; DeCaprio, James A.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Berrios, Christian; DeCaprio, James A.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Wu, Fei] Fudan Univ, Huashan Hosp, Dept Urol, Shanghai 200040, Peoples R China. RP Wei, WY (reprint author), Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. EM wwei2@bidmc.harvard.edu OI Lien, Evan/0000-0001-7866-4761; CHIN, Yuet Ming Rebecca/0000-0001-8976-3466 FU NIH [R01CA177910, R01GM094777, R01CA083688, R01CA132740-08]; [1K99CA181342]; [5T32HL007893-17] FX We thank B. North, H. Inuzuka, X. Dai, and the other members of the W.W. lab for critical reading of the manuscript and Julien Sage, David Goodrich, and Nicolas Dyson for providing valuable reagents. W.W. is an ACS scholar. P.L. is supported by Grant 1K99CA181342. J.G. is an NRSA T32 trainee and supported by Grant 5T32HL007893-17. This work was supported in part by NIH Grants R01CA177910 and R01GM094777 (to W.W.) and R01CA083688 and R01CA132740-08 (to P.S.). NR 54 TC 0 Z9 0 U1 10 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 16 PY 2016 VL 62 IS 6 BP 929 EP 942 DI 10.1016/j.molcel.2016.04.023 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DP1BI UT WOS:000378224900013 PM 27237051 ER PT J AU Di Stefano, B Hochedlinger, K AF Di Stefano, Bruno Hochedlinger, Konrad TI CELL REPROGRAMMING Brain versus brawn SO NATURE LA English DT Editorial Material ID FIBROBLASTS; CONVERSION C1 [Di Stefano, Bruno; Hochedlinger, Konrad] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Di Stefano, Bruno; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Di Stefano, Bruno; Hochedlinger, Konrad] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Di Stefano, Bruno; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Hochedlinger, K (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Hochedlinger, K (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA.; Hochedlinger, K (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM khochedlinger@mgh.harvard.edu NR 13 TC 0 Z9 0 U1 1 U2 1 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 16 PY 2016 VL 534 IS 7607 BP 332 EP 333 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5XQ UT WOS:000377856800024 PM 27281201 ER PT J AU Eumann, CNN Hooker, JM Ritter, T AF Eumann, Constanze N. N. Hooker, Jacob M. Ritter, Tobias TI Concerted nucleophilic aromatic substitution with F-19(-) and F-18(-) SO NATURE LA English DT Article ID OXIDATIVE FLUORINATION; MECHANISMS; DEOXYFLUORINATION; FLUORIDE; PHENOLS; CARBON; SALTS; IONS; PET AB Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain F-18 for use in positron-emission tomography (PET) imaging(1). A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales(2). During SNAr, attack of a nucleophile at a carbon atom bearing a 'leaving group' leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong p-acceptors in the ortho and/or para position(s)(3.) Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant F-18-deoxyfluorination reaction of phenols, which can be used to synthesize F-18-PET probes. Selective F-18 introduction, without the need for the common, but cumbersome, azeotropic drying of F-18, can now be accomplished from phenols as starting materials, and provides access to F-18-labelled compounds not accessible through conventional chemistry. C1 [Eumann, Constanze N. N.; Ritter, Tobias] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Hooker, Jacob M.; Ritter, Tobias] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hooker, Jacob M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ritter, Tobias] Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany. RP Ritter, T (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.; Ritter, T (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA.; Ritter, T (reprint author), Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany. EM ritter@mpi-muelheim.mpg.de FU Patty and Michael Phelps Foundation; National Institutes of Health (NIH) National Institute of General Medical Sciences [GM088237]; NIH [1S10RR017208] FX We thank the Patty and Michael Phelps Foundation and the National Institutes of Health (NIH) National Institute of General Medical Sciences (GM088237) for funding. Radioisotope production and use were enabled by a shared instrument grant from the NIH (1S10RR017208). We thank S. Arlow and C. Kleinlein for preliminary mechanistic work and H. Lee for assistance with X-ray crystallography. We thank N. A. Stephenson for a synthetic precursor for S6 as well as the 19F-standard for this substrate. NR 30 TC 0 Z9 0 U1 34 U2 48 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 16 PY 2016 VL 534 IS 7607 BP 369 EP 373 DI 10.1038/nature17667 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5XQ UT WOS:000377856800032 ER PT J AU Gordon, DJ Motwani, M Pellman, D AF Gordon, D. J. Motwani, M. Pellman, D. TI Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells SO ONCOGENE LA English DT Article ID TRANSCRIPTION FACTOR; ENRICHMENT ANALYSIS; GENOMIC LANDSCAPE; DRUG-SENSITIVITY; IN-VITRO; CANCER; TUMORS; GENE; EXPRESSION; GROWTH AB Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. However, despite the well-established role of EWS-FLI1 in tumor initiation, the development of models of Ewing sarcoma in human cells with defined genetic elements has been challenging. Here, we report a novel approach to model the initiation of Ewing sarcoma tumorigenesis that exploits the developmental and pluripotent potential of human embryonic stem cells. The inducible expression of EWS-FLI1 in embryoid bodies, or collections of differentiating stem cells, generates cells with properties of Ewing sarcoma tumors, including characteristics of transformation. These cell lines exhibit anchorage-independent growth, a lack of contact inhibition and a strong Ewing sarcoma gene expression signature. Furthermore, these cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth, which is a hallmark of Ewing sarcoma tumors. C1 [Gordon, D. J.; Motwani, M.; Pellman, D.] Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Pellman, D.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Pellman, D.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Gordon, D. J.] Univ Iowa, Div Pediat Hematol Oncol, Dept Pediat, 25S Grand Ave, Iowa City, IA 52242 USA. [Motwani, M.] Univ Massachusetts, Sch Med, Grad Sch Biomed Sci, Worcester, MA 01655 USA. RP Pellman, D (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02115 USA.; Gordon, DJ (reprint author), Univ Iowa, Div Pediat Hematol Oncol, Dept Pediat, 25S Grand Ave, Iowa City, IA 52242 USA. EM david-j-gordon@uiowa.edu; david_pellman@dfci.harvard.edu FU NCI K08 award [5K08 CA160346-03]; CureSearch Award; Sarcoma Foundation of America Award; NIH [GM083299] FX We thank Hubo Li for helpful discussions and Kelli Goss for assistance with the drug dose-response experiments. DJG is supported by a NCI K08 award (5K08 CA160346-03), a CureSearch Award and a Sarcoma Foundation of America Award. DP is a HHMI investigator and supported by NIH grant GM083299. NR 59 TC 1 Z9 1 U1 4 U2 4 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 16 PY 2016 VL 35 IS 24 BP 3092 EP 3102 DI 10.1038/onc.2015.368 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DO9GI UT WOS:000378092700002 PM 26455317 ER PT J AU Ray, A Masch, WR Saukkonen, K Harrison, BT AF Ray, Alaka Masch, William R. Saukkonen, Kai Harrison, Beth T. TI Case 18-2016: A 52-Year-Old Woman with a Pleural Effusion SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OVARIAN-CANCER; DIAGNOSIS; FIBROMA; ADULTS; TUMORS C1 [Ray, Alaka; Saukkonen, Kai] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Masch, William R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Harrison, Beth T.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ray, Alaka; Saukkonen, Kai] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Masch, William R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Harrison, Beth T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Ray, A (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Ray, A (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA. NR 18 TC 0 Z9 0 U1 1 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 16 PY 2016 VL 374 IS 24 BP 2378 EP 2387 DI 10.1056/NEJMcpc1600612 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DO5WW UT WOS:000377854600013 PM 27305196 ER EF