FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Yano, EM Bair, MJ Carrasquillo, O Krein, SL Rubenstein, LV AF Yano, Elizabeth M. Bair, Matthew J. Carrasquillo, Olveen Krein, Sarah L. Rubenstein, Lisa V. TI Patient Aligned Care Teams (PACT): VA's Journey to Implement Patient-Centered Medical Homes SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Yano, Elizabeth M.; Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, Sepulveda, CA 91343 USA. [Yano, Elizabeth M.; Rubenstein, Lisa V.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Bair, Matthew J.] VA Ctr Hlth Informat & Commun, Roudebush VA Med Ctr, Indianapolis, IN USA. [Bair, Matthew J.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Carrasquillo, Olveen] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Krein, Sarah L.] VA Ann Arbor Hlth Care Syst, Ann Arbor, MI USA. [Krein, Sarah L.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA QUERI Ctr Implementat Practice & Res Support, Sepulveda, CA USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] RAND Corp, RAND Hlth, Santa Monica, CA USA. RP Yano, EM (reprint author), VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, Sepulveda, CA 91343 USA. RI Krein, Sarah/E-2742-2014 OI Krein, Sarah/0000-0003-2111-8131 NR 0 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 547 EP 549 DI 10.1007/s11606-014-2835-8 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700001 ER PT J AU Farmer, MM Rose, DE Rubenstein, LV Canelo, IA Schectman, G Stark, R Yano, EM AF Farmer, Melissa M. Rose, Danielle E. Rubenstein, Lisa V. Canelo, Ismelda A. Schectman, Gordon Stark, Richard Yano, Elizabeth M. TI Challenges Facing Primary Care Practices Aiming to Implement Patient-Centered Medical Homes SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care; patient-centered medical home; Veterans; VA healthcare system; health care management ID HEALTH INFORMATION-TECHNOLOGY; COST SAVINGS; CHRONIC PAIN; QUALITY; TRANSFORMATION; INNOVATION; FUTURE; PROVIDERS; SYSTEM AB While the potential of patient-centered medical homes (PCMH) is promising, little is known empirically about the frontline challenges that primary care (PC) leaders face before making the decision to implement PCMH, let alone in making it a reality. Prior to the design and implementation of the Veterans Health Administration's (VA) national PCMH model-Patient Aligned Care Teams (PACT)-we identified the top challenges faced by PC directors and examined the organizational and area level factors that influenced those challenges. A national cross-sectional key informant organizational survey was fielded to the census of PC directors at VA medical centers and large community-based outpatient clinics (final sample n = 229 sites). PC directors were asked to rate the degree to which they faced 48 management challenges in eight PCMH-related domains (access, preventive care, chronic diseases requiring care in PC, challenging medical conditions, mental health/substance abuse, special populations, PC coordination of care, and clinical informatics). Responses were dichotomized as moderately-to-extremely challenging versus somewhat-slightly-not at all challenging. Items were rank ordered; chi square or regression techniques were used to examine variations in facility size, type, urban/rural location, and region. On average, VA PC directors reported 16 moderate-to-extreme challenges, and the top 20 challenges spanned all eight PCMH domains. Four of the top 20 challenges, including the top two challenges, were from the clinical informatics domain. Management of chronic non-malignant pain requiring opiate therapy was the third most reported challenge nationwide. Significant organizational and area level variations in reported challenges were found especially for care coordination. Better understanding of PC challenges ahead of PCMH implementation provides important context for strategic planning and redesign efforts. As a national healthcare system, the VA provides a unique opportunity to examine organizational and area determinants relevant to other PCMH models. C1 [Farmer, Melissa M.; Rose, Danielle E.; Rubenstein, Lisa V.; Canelo, Ismelda A.; Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, Sepulveda, CA 91343 USA. [Rubenstein, Lisa V.] David Geffen UCLA Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. [Rubenstein, Lisa V.] RAND Hlth, Santa Monica, CA USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, Ctr Implementat Practice & Res Support, Sepulveda, CA 91343 USA. [Schectman, Gordon] Vet Hlth Adm, Off Patient Care Serv, Washington, DC USA. [Stark, Richard] Vet Hlth Adm, Off Primary Care Clin Operat, Washington, DC USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90024 USA. RP Farmer, MM (reprint author), VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, Sepulveda Campus,Mailcode 152,16111 Plummer St, Sepulveda, CA 91343 USA. EM Melissa.Farmer@va.gov FU VA Office of Patient Care Services [XVA 65-011]; VA HSR&D project examining implementation and impact of VA patient-centered medical homes [IIR 09-082]; VA HSR&D Service through a Senior Research Career Scientist award [RCS 05-195] FX We would like to acknowledge funding from the VA Office of Patient Care Services for this operations project in support of VA primary care planning for patient-centered medical home implementation (Project # XVA 65-011). Additional analysis of these data was also supported by a VA HSR&D project examining implementation and impact of VA patient-centered medical homes (Project # IIR 09-082). Dr. Yano's effort was funded by VA HSR&D Service through a Senior Research Career Scientist award (Project # RCS 05-195). We would also like to acknowledge Britney Chow, MPH for administrative support. NR 39 TC 1 Z9 1 U1 1 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 555 EP 562 DI 10.1007/s11606-013-2691-y PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700004 ER PT J AU Luck, J Bowman, C York, L Midboe, A Taylor, T Gale, R Asch, S AF Luck, Jeff Bowman, Candice York, Laura Midboe, Amanda Taylor, Thomas Gale, Randall Asch, Steven TI Multimethod Evaluation of the VA's Peer-to-Peer Toolkit for Patient-Centered Medical Home Implementation SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care redesign; patient-centered care; evaluation; implementation research; quality improvement ID HEALTH AB Effective implementation of the patient-centered medical home (PCMH) in primary care practices requires training and other resources, such as online toolkits, to share strategies and materials. The Veterans Health Administration (VA) developed an online Toolkit of user-sourced tools to support teams implementing its Patient Aligned Care Team (PACT) medical home model. To present findings from an evaluation of the PACT Toolkit, including use, variation across facilities, effect of social marketing, and factors influencing use. The Toolkit is an online repository of ready-to-use tools created by VA clinic staff that physicians, nurses, and other team members may share, download, and adopt in order to more effectively implement PCMH principles and improve local performance on VA metrics. Multimethod evaluation using: (1) website usage analytics, (2) an online survey of the PACT community of practice's use of the Toolkit, and (3) key informant interviews. Survey respondents were PACT team members and coaches (n = 544) at 136 VA facilities. Interview respondents were Toolkit users and non-users (n = 32). For survey data, multivariable logistic models were used to predict Toolkit awareness and use. Interviews and open-text survey comments were coded using a "common themes" framework. The Consolidated Framework for Implementation Research (CFIR) guided data collection and analyses. The Toolkit was used by 6,745 staff in the first 19 months of availability. Among members of the target audience, 80 % had heard of the Toolkit, and of those, 70 % had visited the website. Tools had been implemented at 65 % of facilities. Qualitative findings revealed a range of user perspectives from enthusiastic support to lack of sufficient time to browse the Toolkit. An online Toolkit to support PCMH implementation was used at VA facilities nationwide. Other complex health care organizations may benefit from adopting similar online peer-to-peer resource libraries. C1 [Luck, Jeff] Oregon State Univ, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Luck, Jeff; Bowman, Candice; York, Laura] VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, Los Angeles, CA USA. [Midboe, Amanda; Taylor, Thomas; Gale, Randall; Asch, Steven] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA USA. [Asch, Steven] Stanford Univ, Div Gen Med Disciplines, Palo Alto, CA 94304 USA. RP Luck, J (reprint author), Oregon State Univ, Coll Publ Hlth & Human Sci, 401 Waldo Hall, Corvallis, OR 97331 USA. EM Jeff.luck@oregonstate.edu FU VA Office of Systems Redesign FX Funding: This study was funded by a grant from the VA Office of Systems Redesign with additional in-kind support from the VA Center for Applied Systems Engineering (VA-CASE). NR 23 TC 5 Z9 5 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 572 EP 578 DI 10.1007/s11606-013-2738-0 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700006 ER PT J AU Butler, A Canamucio, A Macpherson, D Skoko, J True, G AF Butler, Anneliese Canamucio, Anne Macpherson, David Skoko, Jennifer True, Gala TI Primary Care Staff Perspectives on a Virtual Learning Collaborative to Support Medical Home Implementation SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care redesign; medical education-computer/web-based learning; survey research; qualitative research; quality improvement; curriculum/program evaluation ID QUALITY IMPROVEMENT COLLABORATIVES; BLACK-BOX; LESSONS; TRANSFORMATION; INTERVENTIONS; PROJECT AB Many organizations rely on quality improvement collaboratives (QICs) to facilitate Patient-Centered Medical Home (PCMH) implementation, and there is a trend toward conducting QIC activities virtually to reduce costs and expand their reach. However, the evidence base for QICs is limited; questions remain about how QICs operate, why they succeed or fail, and how they are experienced by participants. We surveyed participants in an innovative Virtual Collaborative (VC) designed to support PCMH implementation within one Veterans Integrated Service Network, to understand why and for whom the VC was more/less effective and identify opportunities for improvement. This anonymous online survey was designed to assess participants' views on the VC's usefulness, impact, and acceptability, and to explore variations by role, practice setting, prior training, and overall engagement in VC activities. Respondents were 353 primary care staff, including providers, nurses, and support staff. The survey comprised 32 structured and three free-response items. Structured items assessed participation in and perceived usefulness of VC activities; perceived acceptability of the training format; overall perceived impact; and basic demographics. Responses were dichotomized and compared using Chi-square tests. Free-response items inviting constructive criticism of the VC were coded and summarized to identify themes and illustrative quotes. The VC most benefited respondents with prior PCMH training and those who fully participated in VC activities. Respondents especially valued the opportunity to share experiences with other teams. Non-providers and those new to PCMH felt learning content did not meet their needs. Reported barriers to full participation included staffing constraints, insufficient and/or unprotected time, and inadequate leadership support. Our study offers practical lessons for others considering a virtual collaborative model for PCMH spread. Findings contribute to the evidence base for QICs overall and virtual QICs in particular, highlighting the value of seeking input from "the trenches.". C1 [Butler, Anneliese; Canamucio, Anne; True, Gala] Philadelphia Vet Affairs Med Ctr, Ctr Evaluat Patient Aligned Care Teams CEPACT, Philadelphia, PA 19104 USA. [Macpherson, David; Skoko, Jennifer] 4th Vet Integrated Serv Network, Pittsburgh, PA USA. [Macpherson, David] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [True, Gala] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Butler, A (reprint author), Philadelphia Vet Affairs Med Ctr, Ctr Evaluat Patient Aligned Care Teams CEPACT, 3900 Woodland Ave,Bldg 4100, Philadelphia, PA 19104 USA. EM Anneliese.Butler@va.gov FU VA Office of Patient Care Services FX Funders: This work was undertaken as part of the Veterans Administration's PACT Demonstration Laboratory initiative, supporting and evaluating VA's transition to a patient-centered medical home. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services. NR 25 TC 5 Z9 5 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 579 EP 588 DI 10.1007/s11606-013-2668-x PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700007 ER PT J AU Rubenstein, LV Stockdale, SE Sapir, N Altman, L Dresselhaus, T Salem-Schatz, S Vivell, S Ovretveit, J Hamilton, AB Yano, EM AF Rubenstein, Lisa V. Stockdale, Susan E. Sapir, Negar Altman, Lisa Dresselhaus, Timothy Salem-Schatz, Susanne Vivell, Susan Ovretveit, John Hamilton, Alison B. Yano, Elizabeth M. TI A Patient-Centered Primary Care Practice Approach Using Evidence-Based Quality Improvement: Rationale, Methods, and Early Assessment of Implementation SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE quality improvement; primary care; patient-centered medical home; logic model; interdisciplinary leadership ID NATIONAL DEMONSTRATION PROJECT; MEDICAL HOME; COLLABORATIVE CARE; SERVICE ORGANIZATIONS; HEALTH; MODEL; DEPRESSION; LESSONS; SUCCESS; CONTEXT AB Healthcare systems and their primary care practices are redesigning to achieve goals identified in Patient-Centered Medical Home (PCMH) models such as Veterans Affairs (VA)'s Patient Aligned Care Teams (PACT). Implementation of these models, however, requires major transformation. Evidence-Based Quality Improvement (EBQI) is a multi-level approach for supporting organizational change and innovation spread. To describe EBQI as an approach for promoting VA's PACT and to assess initial implementation of planned EBQI elements. Descriptive. Regional and local interdisciplinary clinical leaders, patient representatives, Quality Council Coordinators, practicing primary care clinicians and staff, and researchers from six demonstration site practices in three local healthcare systems in one VA region. EBQI promotes bottom-up local innovation and spread within top-down organizational priorities. EBQI innovations are supported by a research-clinical partnership, use continuous quality improvement methods, and are developed in regional demonstration sites. We developed a logic model for EBQI for PACT (EBQI-PACT) with inputs, outputs, and expected outcomes. We describe implementation of logic model outputs over 18 months, using qualitative data from 84 key stakeholders (104 interviews from two waves) and review of study documents. Nearly all implementation elements of the EBQI-PACT logic model were fully or partially implemented. Elements not fully achieved included patient engagement in Quality Councils (4/6) and consistent local primary care practice interdisciplinary leadership (4/6). Fourteen of 15 regionally approved innovation projects have been completed, three have undergone initial spread, five are prepared to spread, and two have completed toolkits that have been pretested in two to three sites and are now ready for external spread. EBQI-PACT has been feasible to implement in three participating healthcare systems in one VA region. Further development of methods for engaging patients in care design and for promoting interdisciplinary leadership is needed. C1 [Rubenstein, Lisa V.; Stockdale, Susan E.; Sapir, Negar; Altman, Lisa; Vivell, Susan; Hamilton, Alison B.; Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, North Hills, CA USA. [Rubenstein, Lisa V.; Stockdale, Susan E.; Altman, Lisa; Hamilton, Alison B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] RAND Corp, Santa Monica, CA USA. [Rubenstein, Lisa V.; Altman, Lisa] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Dresselhaus, Timothy] VA San Diego Healthcare Syst, San Diego, CA USA. [Dresselhaus, Timothy] Univ Calif San Diego, Dept Med, San Diego, CA USA. [Salem-Schatz, Susanne] Hlth Care Qual Initiat, Newton, MA USA. [Ovretveit, John] Karolinska Inst, Stockholm, Sweden. [Rubenstein, Lisa V.; Yano, Elizabeth M.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Rubenstein, Lisa V.] VA QUERI Ctr Implementat Practice & Res Support, Los Angeles, CA USA. RP Rubenstein, LV (reprint author), VA Greater Los Angeles, VA HSR & D Ctr Study Healthcare Innovat Implement, VA Greater Los Angeles Healthcare Syst, 16111 Plummer St, North Hills, CA 91343 USA. EM lisa.rubenstein@va.gov FU VA Office of Patient Care Services [XVA 65-018]; VA HSR&D Senior Research Career Scientist award [05-195]; VA HSR&D Center for the Study of Healthcare Innovation, Implementation and Policy; VA HSR&D Center of Innovation; VA Quality Enhancement Research Initiative's Center for Implementation Practice and Research Support at the VA Greater Los Angeles Healthcare System FX Funders: This work was undertaken as part of the Veterans Affairs PACT Demonstration Laboratory initiative, supporting and evaluating VA's transition to a patient-centered medical home. Funding for the PACT Demonstration Laboratory (XVA 65-018) initiative is provided by the VA Office of Patient Care Services. Dr. Yano's time was supported by a VA HSR&D Senior Research Career Scientist award (Project #05-195). VAIL is also supported, in part, by the VA HSR&D Center for the Study of Healthcare Innovation, Implementation and Policy, a VA HSR&D Center of Innovation (formerly Center of Excellence), and the VA Quality Enhancement Research Initiative's Center for Implementation Practice and Research Support at the VA Greater Los Angeles Healthcare System. NR 52 TC 10 Z9 10 U1 2 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 589 EP 597 DI 10.1007/s11606-013-2703-y PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700008 ER PT J AU Tuepker, A Kansagara, D Skaperdas, E Nicolaidis, C Joos, S Alperin, M Hickam, D AF Tuepker, Anais Kansagara, Devan Skaperdas, Eleni Nicolaidis, Christina Joos, Sandra Alperin, Michael Hickam, David TI "We've Not Gotten Even Close to What We Want to Do": a Qualitative Study of Early Patient-Centered Medical Home Implementation SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care redesign; patient-centered medical home; team-based care; Veterans; health services research; qualitative research ID SAFETY NET CLINICS; PRIMARY-CARE; PRACTICE TRANSFORMATION; LESSONS; FEATURES; TEAMS AB The Veterans Health Administration (VA) Patient Aligned Care Teams (PACT) initiative is designed to deliver a medical home model of care associated with better patient outcomes, but success will depend in part on the model's acceptability and sustainability among clinic employees. We sought to identify key themes in the experience of primary care providers, nurse care managers, clerical and clinical associates, and clinic administrators implementing PACT, with the aim of informing recommendations for continued development of the model and its components. Observational qualitative study; data collection from 2010 to 2013, using role-stratified and team focus groups and semi-structured interviews. 241 of 337 (72 %) identified primary care clinic employees in PACT team or administrative roles, from 15 VA clinics in Oregon and Washington. Data coded and analyzed using conventional content analysis techniques. Overall, participants were enthusiastic about the PACT concept, but felt necessary resources for success were not yet in place. Well-functioning teams were perceived as key to successful implementation. Development of such teams depended on adequate staffing, training, and dedicated time for team development. Changes within the broader VA system were also seen as necessary, including devolving greater control to the clinic level and improving system alignment with the PACT model. PACT advocates from among clinic and institutional level leadership were identified as a final key ingredient for success. These themes were consistent despite differences in clinic settings and characteristics. PACT implementation faced significant challenges in its early years. Realizing PACT's transformative potential will require acting on the needs identified by clinic workers in this study: ensuring adequate staffing in all team roles, devoting resources to in-depth training for all employees in communication and other skills needed to maximize team success, and aligning the broader VA hospital system with PACT's decentralized, team-based approach. C1 [Tuepker, Anais; Kansagara, Devan; Skaperdas, Eleni; Joos, Sandra; Alperin, Michael; Hickam, David] Vet Hlth Adm, Portland VA Med Ctr, Hlth Serv Res Dev VISN PACT Demonstrat Lab 20, Portland, OR 97239 USA. [Tuepker, Anais; Kansagara, Devan; Nicolaidis, Christina; Joos, Sandra; Hickam, David] Oregon Hlth & Sci Univ, Sch Med, Div Gen Internal Med & Geriatr, Portland, OR 97201 USA. [Nicolaidis, Christina] Portland State Univ, Sch Social Work, Portland, OR 97207 USA. [Nicolaidis, Christina] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Hickam, David] Patient Ctr Outcomes Res Inst PCORI, Washington, DC USA. RP Tuepker, A (reprint author), Vet Hlth Adm, Portland VA Med Ctr, Hlth Serv Res Dev VISN PACT Demonstrat Lab 20, Mail Code RD63,POB 1034, Portland, OR 97239 USA. EM anais.tuepker@va.gov FU VA Office of Patient Care Services FX We gratefully acknowledge the contribution of all members of the VISN 20 PACT Demonstration Lab, as well as the employees in participating clinics, who generously shared their experiences. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services. Dr. Tuepker is a Health Science Specialist at the Portland VA Medical Center. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 27 TC 8 Z9 8 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 614 EP 622 DI 10.1007/s11606-013-2690-z PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700011 ER PT J AU Rodriguez, HP Giannitrapani, KF Stockdale, S Hamilton, AB Yano, EM Rubenstein, LV AF Rodriguez, Hector P. Giannitrapani, Karleen F. Stockdale, Susan Hamilton, Alison B. Yano, Elizabeth M. Rubenstein, Lisa V. TI Teamlet Structure and Early Experiences of Medical Home Implementation for Veterans SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE team structure; patient-centered medical home; practice redesign; primary care teams; veterans ID PRIMARY-CARE; RELATIONAL COORDINATION; QUALITY; IMPACT; SATISFACTION; PROVIDERS; JOB AB High functioning interdisciplinary primary care teams are a critical component of the patient-centered medical home. In 2010, the Veterans Administration (VA) implemented a medical home model termed the Patient Aligned Care Teams (PACT), with reorganization of staff into small teams ("teamlets") as a core feature. To examine the early experiences of primary care personnel as they assumed new roles through reorganization into teamlets. Convergent mixed methods study design involving semi-structured interviews and a survey; data were collected in 2011 and 2012. We interviewed 41 frontline teamlet members (i.e., primary care physicians and staff) from three practices that were part of a PACT demonstration laboratory and examined clinician and staff survey data from 22 practices. Semi-structured interview guide and clinician and staff survey questions covering the following domains: teamlet formation and structure, within-teamlet communication, cross-coverage, role changes, teamlet training, impact on Veterans, and leadership facilitation and support. Respondents had limited input into teamlet structure and indicated limited training on the PACT initiative. Guidelines delineating each teamlet member's roles and responsibilities were emphasized as important needs. Chronic understaffing also contributed to implementation challenges and territorial attitudes surfaced when cross-coverage was not clear. In addition, several core features of VA's medical home transformation were not fully implemented by teamlet members. Most also reported limited guidance and feedback from leadership. Despite these challenges, teamlet-based care was perceived to have a positive impact on Veterans' experiences of primary care and also resulted in improved communication among staff. The PACT teamlet model holds much promise for improving primary care at the VA. However, more comprehensive training, improving the stability of teamlets, developing clear cross-coverage policies, and better defined teamlet member responsibilities are important areas in need of attention by VA leadership. C1 [Rodriguez, Hector P.; Giannitrapani, Karleen F.; Yano, Elizabeth M.; Rubenstein, Lisa V.] Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Rodriguez, Hector P.; Giannitrapani, Karleen F.; Stockdale, Susan; Hamilton, Alison B.; Yano, Elizabeth M.; Rubenstein, Lisa V.] VA Greater Los Angeles Hlth Care Syst, HSR & D Ctr Study Healthcare Innovat Implementat, Los Angeles, CA USA. [Stockdale, Susan; Hamilton, Alison B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] RAND Hlth, Santa Monica, CA USA. RP Rodriguez, HP (reprint author), Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, 650 Charles E Young Dr South, Los Angeles, CA 90095 USA. EM hrod@berkeley.edu FU VA Office of Patient Care Services; VA HSR&D Service Senior Research Career Scientist award [05-195] FX Funders: This work was undertaken as part of the Veterans Health Administration's PACT Demonstration Laboratory initiative, supporting and evaluating VA's transition to a patient-centered medical home. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services. Dr. Yano's effort was funded by a VA HSR&D Service Senior Research Career Scientist award (Project #05-195). The views expressed within are solely those of the authors, and do not necessarily represent the views of the Department of Veterans Affairs or the United States government. NR 20 TC 10 Z9 10 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 623 EP 631 DI 10.1007/s11606-013-2680-1 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700012 ER PT J AU True, G Stewart, GL Lampman, M Pelak, M Solimeo, SL AF True, Gala Stewart, Greg L. Lampman, Michelle Pelak, Mary Solimeo, Samantha L. TI Teamwork and Delegation in Medical Homes: Primary Care Staff Perspectives in the Veterans Health Administration SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered medical home; teams; implementation; Veteran's health; qualitative evaluation; primary care; Department of Veterans Affairs ID PRACTICE TRANSFORMATION; LESSONS; TEAMS; CULTURE; QUALITY; PILOT AB The patient-centered medical home (PCMH) relies on a team approach to patient care. For organizations engaged in transitioning to a PCMH model, identifying and providing the resources needed to promote team functioning is essential. To describe team-level resources required to support PCMH team functioning within the Veterans Health Administration (VHA), and provide insight into how the presence or absence of these resources facilitates or impedes within-team delegation. Semi-structured interviews with members of pilot teams engaged in PCMH implementation in 77 primary care clinics serving over 300,000 patients across two VHA regions covering the Mid-Atlantic and Midwest United States. A purposive sample of 101 core members of pilot teams, including 32 primary care providers, 42 registered nurse care managers, 15 clinical associates, and 12 clerical associates. Investigators from two evaluation sites interviewed frontline primary care staff separately, and then collaborated on joint analysis of parallel data to develop a broad, comprehensive understanding of global themes impacting team functioning and within-team delegation. We describe four themes key to understanding how resources at the team level supported ability of primary care staff to work as effective, engaged teams. Team-based task delegation was facilitated by demarcated boundaries and collective identity; shared goals and sense of purpose; mature and open communication characterized by psychological safety; and ongoing, intentional role negotiation. Our findings provide a framework for organizations to identify assets already in place to support team functioning, as well as areas in need of improvement. For teams struggling to make practice changes, our results indicate key areas where they may benefit from future support. In addition, this research sheds light on how variation in medical home implementation and outcomes may be associated with variation in team-based task delegation. C1 [True, Gala; Pelak, Mary] Philadelphia Vet Affairs Med Ctr, VISN Ctr Evaluat Patient Aligned Care Teams CEPAC, Philadelphia, PA 19104 USA. [True, Gala] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Stewart, Greg L.; Lampman, Michelle; Solimeo, Samantha L.] Iowa City VA Hlth Care Syst, Dept Vet Affairs, Patient Aligned Care Team Demonstrat Lab VISN23, Iowa City, IA USA. [Stewart, Greg L.] Univ Iowa, Tippie Coll Business, Iowa City, IA USA. [Lampman, Michelle; Solimeo, Samantha L.] Iowa City VA Hlth Care Syst, Dept Vet Affairs, Ctr Comprehens Access & Delivery Res & Evaluat CA, Iowa City, IA USA. RP True, G (reprint author), Philadelphia Vet Affairs Med Ctr, VISN Ctr Evaluat Patient Aligned Care Teams CEPAC, Bldg 4100,Univ & Woodland Aves, Philadelphia, PA 19104 USA. EM Jennifer.True2@va.gov FU VA Office of Patient Care Services FX Funders: The VISN 4 and VISN 23 Demonstration Laboratories are funded by the VA Office of Patient Care Services. NR 36 TC 6 Z9 6 U1 5 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 632 EP 639 DI 10.1007/s11606-013-2666-z PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700013 ER PT J AU Wang, ES Conde, MV Simon, B Leykum, LK AF Wang, Emily S. Conde, Michelle V. Simon, Bret Leykum, Luci K. TI Exploring End-of-Residency Transitions in a VA Patient Aligned Care Team SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE veterans; patient-centered care; transitions of care; medical education; complexity theory ID CONTINUITY PRACTICE; SIGN-OUT; SATISFACTION; PROGRAM; TRIAL AB End-of-residency transitions create disruptions in primary care continuity. The national implementation of Patient Aligned Care Teams (PACT) in Veterans Health Administration (VA) primary care clinics creates an opportunity to mitigate this discontinuity through the provision of team-based care. To identify team-based solutions to end-of-residency transitions in a resident PACT continuity clinic by assessing the knowledge, attitudes, and perceptions of non-physician PACT members and resident PACT physicians. Cross-sectional survey of 27 resident physicians and 24 non-physician PACT members in the Internal Medicine Clinic at the Audie L. Murphy VA Hospital in the South Texas Veterans Health Care System. Twenty-seven residents and 24 non-physician PACT members completed the survey, with response rates of 90 % and 100 %, respectively. All residents and 96 % of non-physician PACT members agreed or strongly agreed that the residents were responsible for informing patients about end-of-residency transitions. Only 38 % of non-physician PACT members versus 52 % of residents indicated that non-physician PACT members should be responsible for this transition. Approximately 80 % of resident physicians and non-physician PACT members agreed there should be a formalized approach to these transitions; 67 % of non-physician PACT members were willing to support this transition. Potential barriers to team-based care transitions were identified. Major themes of write-in suggestions for improving the transition focused on communication and relationships between the patient and PACT and among the PACT members. PACT implementation changes the roles and relationship structures among all team members. While end-of-residency transitions create a disruption in the relationship system, the remainder of the PACT may bridge this transition. Our results demonstrate the importance of a team-based solution that engages all PACT members by improving communication and fostering effective team relationships. C1 [Wang, Emily S.; Conde, Michelle V.; Leykum, Luci K.] South Texas Vet Hlth Care Syst, Audie L Murphy Hosp Div, San Antonio, TX 78229 USA. [Wang, Emily S.; Conde, Michelle V.; Simon, Bret; Leykum, Luci K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. RP Wang, ES (reprint author), South Texas Vet Hlth Care Syst, Audie L Murphy Hosp Div, Med Serv, 7400 Merton Minter,Mail Code 111, San Antonio, TX 78229 USA. EM wange@uthscsa.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [REA 05-129, CDA 07-022]; South Texas Veterans Health Care System FX The research supported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (#REA 05-129, #CDA 07-022). Author salary support is through this funding and through the South Texas Veterans Health Care System. The views expressed in this article are those of the authors and do not necessarily reflect the position of policy of the Department of Veterans Affairs. NR 22 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 649 EP 658 DI 10.1007/s11606-013-2726-4 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700015 ER PT J AU Helfrich, CD Dolan, ED Simonetti, J Reid, RJ Joos, S Wakefield, BJ Schectman, G Stark, R Fihn, SD Harvey, HB Nelson, K AF Helfrich, Christian D. Dolan, Emily D. Simonetti, Joseph Reid, Robert J. Joos, Sandra Wakefield, Bonnie J. Schectman, Gordon Stark, Richard Fihn, Stephan D. Harvey, Henry B. Nelson, Karin TI Elements of Team-Based Care in a Patient-Centered Medical Home Are Associated with Lower Burnout Among VA Primary Care Employees SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered medical home; burnout; team-based care; organizational change ID PHYSICIAN BURNOUT; SAFETY OUTCOMES; NURSE BURNOUT; STAFF MORALE; HEALTH; SATISFACTION; DISSATISFACTION; SURGEONS; QUALITY; ERRORS AB A high proportion of the US primary care workforce reports burnout, which is associated with negative consequences for clinicians and patients. Many protective factors from burnout are characteristics of patient-centered medical home (PCMH) models, though even positive organizational transformation is often stressful. The existing literature on the effects of PCMH on burnout is limited, with most findings based on small-scale demonstration projects with data collected only among physicians, and the results are mixed. To determine if components of PCMH related to team-based care were associated with lower burnout among primary care team members participating in a national medical home transformation, the VA Patient Aligned Care Team (PACT). Web-based, cross-sectional survey and administrative data from May 2012. A total of 4,539 VA primary care personnel from 588 VA primary care clinics. The dependent variable was burnout, and the independent variables were measures of team-based care: team functioning, time spent in huddles, team staffing, delegation of clinical responsibilities, working to top of competency, and collective self-efficacy. We also included administrative measures of workload and patient comorbidity. Overall, 39 % of respondents reported burnout. Participatory decision making (OR 0.65, 95 % CI 0.57, 0.74) and having a fully staffed PACT (OR 0.79, 95 % CI 0.68, 0.93) were associated with lower burnout, while being assigned to a PACT (OR 1.46, 95 % CI 1.11, 1.93), spending time on work someone with less training could do (OR 1.29, 95 % CI 1.07, 1.57) and a stressful, fast-moving work environment (OR 4.33, 95 % CI 3.78, 4.96) were associated with higher burnout. Longer tenure and occupation were also correlated with burnout. Lower burnout may be achieved by medical home models that are appropriately staffed, emphasize participatory decision making, and increase the proportion of time team members spend working to the top of their competency level. C1 [Helfrich, Christian D.; Dolan, Emily D.; Simonetti, Joseph; Nelson, Karin] US Dept Vet Affairs, VA Puget Sound Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. [Helfrich, Christian D.; Simonetti, Joseph] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Reid, Robert J.] Grp Hlth Res Inst, Seattle, WA USA. [Joos, Sandra] US Dept Vet Affairs, Portland VA Med Ctr, VISN PACT Demonstrat Lab 20, Seattle, WA USA. [Wakefield, Bonnie J.] VA Iowa City Hlth Serv Res & Dev, Ctr Comprehens Access & Delivery Res & Evaluat, Iowa City, IA USA. [Schectman, Gordon] VA Off Patient Care Serv, Washington, DC USA. [Schectman, Gordon] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Stark, Richard] VA Off Clin Operat, Washington, DC USA. [Fihn, Stephan D.; Harvey, Henry B.] US Dept Vet Affairs, Off Analyt & Business Intelligence, Seattle, WA USA. [Fihn, Stephan D.; Nelson, Karin] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Helfrich, CD (reprint author), US Dept Vet Affairs, VA Puget Sound Hlth Serv Res Dev Ctr Excellence, Seattle, WA 98174 USA. EM christian.helfrich@va.gov RI Helfrich, Christian/D-2382-2016 OI simonetti, joseph/0000-0002-1092-160X; Helfrich, Christian/0000-0002-9827-4768 FU VA Office of Patient Care Services FX This work was undertaken as part of the VA's PACT Demonstration Laboratory initiative, supporting and evaluating VA's transition to a patient-centered medical home. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services. 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. NR 51 TC 20 Z9 20 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 659 EP 666 DI 10.1007/s11606-013-2702-z PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700016 ER PT J AU Fix, GM Asch, SM Saifu, HN Fletcher, MD Gifford, AL Bokhour, BG AF Fix, Gemmae M. Asch, Steven M. Saifu, Hemen N. Fletcher, Michael D. Gifford, Allen L. Bokhour, Barbara G. TI Delivering PACT-Principled Care: Are Specialty Care Patients Being Left Behind? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered medical home; specialty care; HIV; qualitative research ID CENTERED MEDICAL HOME; NATIONAL DEMONSTRATION PROJECT; HUMAN-IMMUNODEFICIENCY-VIRUS; PHYSICIAN PRACTICES; AGING POPULATION; HEALTH-CARE; RYAN WHITE; HIV; MANAGEMENT; INFECTION AB With the reorganization of primary care into Patient Aligned Care Teams (PACT) teams, the Veteran Affairs Health System (VA) aims to ensure all patients receive care based on patient-centered medical home (PCMH) principles. However, some patients receive the preponderance of care from specialty rather than primary care clinics because of the special nature of their clinical conditions. We examined seven VA (HIV) clinics as a model to test the extent to which such patients receive PCMH-principled care. To examine the extent to which HIV specialty care in VA conforms to PCMH principles. Qualitative study. Forty-one HIV providers from seven HIV clinics and 20 patients from four of these clinics. We conducted semi-structured interviews with HIV clinic providers and patients about care practices and adherence to PCMH principles. Using an iterative approach, data was analyzed using both a content analysis and an a priori, PCMH-principled coding strategy. Patients with HIV receive varying levels of PCMH-principled care across a range of VA HIV clinic structures. The more PCMH-principled HIV clinics largely functioned as PCMHs; patients received integrated, coordinated, comprehensive primary care within a dedicated HIV clinic. In contrast, some clinics were unable to meet the criteria of being a patient's medical home, and instead functioned primarily as a place to receive HIV-related services with limited care coordination. Patients from the less PCMH-principled clinics reported less satisfaction with their care. Even in a large, integrated healthcare system, there is wide variation in patients' receipt of PCMH-principled care in specialty care settings. In order to meet the goal of having all patients receiving PCMH-principled care, there needs to be careful consideration of where primary and specialty care services are delivered and coordinated. The best mechanisms for ensuring that patients with complex medical conditions receive PCMH-principled care may need to be tailored to different specialty care contexts. C1 [Fix, Gemmae M.; Gifford, Allen L.; Bokhour, Barbara G.] ENRM Vet Hosp, Ctr Healthcare Org & Implementat Res CHOIR 152, Bedford, MA 01730 USA. [Fix, Gemmae M.; Gifford, Allen L.; Bokhour, Barbara G.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Fix, Gemmae M.; Asch, Steven M.; Saifu, Hemen N.; Fletcher, Michael D.; Gifford, Allen L.; Bokhour, Barbara G.] Vet Affairs VA Qual Enhancement Res Initiat HIV &, Bedford, MA USA. [Asch, Steven M.] Ctr Innovat Implementat Ci2i, VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Saifu, Hemen N.; Fletcher, Michael D.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Asch, Steven M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Fix, GM (reprint author), ENRM Vet Hosp, Ctr Healthcare Org & Implementat Res CHOIR 152, 200 Springs Rd, Bedford, MA 01730 USA. EM gemmae.fix@va.gov OI Fix, Gemmae/0000-0001-6055-4177 FU Department of Veteran Affairs, Health Services Research and Development, HIV/Hepatitis QUERI; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX Funders: This study was funded by the Department of Veteran Affairs, Health Services Research and Development, HIV/Hepatitis QUERI. This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 41 TC 2 Z9 2 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 695 EP 702 DI 10.1007/s11606-013-2677-9 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700021 ER PT J AU Yano, EM Haskell, S Hayes, P AF Yano, Elizabeth M. Haskell, Sally Hayes, Patricia TI Delivery of Gender-Sensitive Comprehensive Primary Care to Women Veterans: Implications for VA Patient Aligned Care Teams SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care; women's health; veterans ID HEALTH-CARE; MEDICAL HOME; QUALITY; CLINICS; SATISFACTION; TRANSFORMATION; IMPROVEMENT; ACCESS; SYSTEM; NEED AB The Veterans Health Administration (VA) has undertaken a major initiative to transform primary care delivery through implementation of Patient Aligned Care Teams (PACTs). Based on the patient-centered medical home concept, PACTs aim to improve access, continuity, coordination, and comprehensiveness using team-based care that is patient driven and patient centered. However, how PACT principles should be applied to meet the needs of special populations, including women veterans, is not entirely clear. While historical differences in military participation meant women veterans were rarely seen in VA healthcare settings, they now represent the fastest growing segment of new VA users. They also have complex healthcare needs, adding gender-specific services and other needs to the spectrum of services that the VA must deliver. These trends are changing the VA landscape, introducing challenges to how VA care is organized, how VA providers need to be trained, and how VA considers implementation of new initiatives, such as PACT. We briefly describe the evolution of VA primary care delivery for women veterans, review VA policy for delivering gender-sensitive comprehensive primary care for women, and discuss the challenges that women veterans' needs pose in the context of PACT implementation. We conclude with recommendations for addressing some of these challenges moving forward. C1 [Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, Sepulveda, CA 91343 USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Haskell, Sally; Hayes, Patricia] Vet Hlth Adm, Off Patient Care Serv, Womens Hlth Serv, Washington, DC USA. [Haskell, Sally] VA Connecticut Hlth Syst, West Haven, CT USA. [Haskell, Sally] Yale Univ, Sch Med, New Haven, CT USA. RP Yano, EM (reprint author), VA Greater Los Angeles Healthcare Syst, VA HSR & D Ctr Study Healthcare Innovat Implement, Sepulveda Campus,16111 Plummer St,Mail Code 152, Sepulveda, CA 91343 USA. EM Elizabeth.yano@va.gov FU Women's Health Services in the VHA Office of Patient Care Services; VA HSR&D Service (Women's Health CREATE) [CRE 12-026, IAE 07-170]; VA HSR&D Senior Research Career Scientist Award [05-195] FX Funders: This article was supported by funding from Women's Health Services in the VHA Office of Patient Care Services and VA HSR&D Service (Women's Health CREATE Project no. CRE 12-026 and Project no. IAE 07-170). Dr. Yano's effort was funded through a VA HSR&D Senior Research Career Scientist Award (project no. 05-195). NR 40 TC 13 Z9 13 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 SU 2 BP 703 EP 707 DI 10.1007/s11606-013-2699-3 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700022 ER PT J AU Gopalan, A Tahirovic, E Moss, H Troxel, AB Zhu, JS Loewenstein, G Volpp, KG AF Gopalan, Anjali Tahirovic, Emin Moss, Haley Troxel, Andrea B. Zhu, Jingsan Loewenstein, George Volpp, Kevin G. TI Translating the Hemoglobin A1C with More Easily Understood Feedback: A Randomized Controlled Trial SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE diabetes; hemoglobin A1C; communication; health literacy; diabetes education ID GLYCEMIC CONTROL; FINANCIAL INCENTIVES; ASSOCIATION; NUMERACY; MANAGEMENT; OUTCOMES; CARE AB Previous work has indicated that for patients with diabetes, there is value in understanding glycemic control. Despite these findings, patient understanding of the hemoglobin A1C value (A1C) is notably poor. In this study, we test the effect of two alternative communication formats of the A1C on improving glycemic control among patients with poorly controlled diabetes. 177 patients with poorly controlled diabetes were randomized to one of three study arms that varied in the information they received: (1) a "diabetes report card" containing individualized information about glycemic control for each participant with letter grades ranging from A to F; (2) a "report card" containing a face whose emotion reflected current glycemic control; or (3) a "report card" with glycemic control expressed with the A1C value (standard arm). The primary study outcome was change in A1C at 6 months. Secondary outcomes included changes in participant perceptions of their glycemic control. The average A1C for enrolled participants was 9.9 % (S.D. 1.7) and did not differ significantly among study arms. We noted no significant differences in change in A1C at 6 months between the standard and experimental arms. Using multiple imputation to account for missing A1C values, the changes in A1C for the letter grade, face, and standard arms were -0.55 % (-1.15, 0.05), -0.89 % (-1.49, -0.29), and -0.74 % (-1.51, 0.029), respectively (p = 0.67 for control vs. grade, p = 0.76 for control vs. face). Feedback to patients with poorly controlled diabetes in the form of letter grades and faces did not differentially impact glycemic control at 6 months or participant perceptions of current control. These efforts to improve communication and patient understanding of disease management targets need further refinement to significantly impact diabetes outcomes. NCT01143870. C1 [Gopalan, Anjali; Volpp, Kevin G.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Gopalan, Anjali] Univ Penn, Robert Wood Johnson Clin Scholars Program, Philadelphia, PA 19104 USA. [Gopalan, Anjali; Tahirovic, Emin; Troxel, Andrea B.; Zhu, Jingsan; Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Moss, Haley] NYU, Sch Med, New York, NY USA. [Loewenstein, George] Carnegie Mellon Univ, Dietrich Coll Social & Decis Sci, Pittsburgh, PA 15213 USA. RP Gopalan, A (reprint author), Philadelphia VA Med Ctr, 423 Guardian Dr,Blockley Hall,Suite 1303, Philadelphia, PA 19104 USA. EM agopalan@upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU Penn CMU Roybal P30 Center [P30AG034546] FX Penn CMU Roybal P30 Center Grant P30AG034546. The funder was not involved in any part of the study design, conducting of the study or the analysis of the results. NR 20 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 996 EP 1003 DI 10.1007/s11606-014-2810-4 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100009 PM 24567202 ER PT J AU Chang, ET Magnabosco, JL Chaney, E Lanto, A Simon, B Yano, EM Rubenstein, LV AF Chang, Evelyn T. Magnabosco, Jennifer L. Chaney, Edmund Lanto, Andrew Simon, Barbara Yano, Elizabeth M. Rubenstein, Lisa V. TI Predictors of Primary Care Management of Depression in the Veterans Affairs Healthcare System SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care; mental health; depression; care management ID LATE-LIFE DEPRESSION; COMORBIDITY SURVEY REPLICATION; INTEGRATING MENTAL-HEALTH; COLLABORATIVE CARE; QUALITY IMPROVEMENT; UNITED-STATES; TREATMENT PREFERENCES; RANDOMIZED-TRIAL; MEDICAL HOME; DISORDERS AB Primary care providers (PCPs) vary in skills to effectively treat depression. Key features of evidence-based collaborative care models (CCMs) include the availability of depression care managers (DCMs) and mental health specialists (MHSs) in primary care. Little is known, however, about the relationships between PCP characteristics, CCM features, and PCP depression care. To assess relationships between various CCM features, PCP characteristics, and PCP depression management. Cross-sectional analysis of a provider survey. 180 PCPs in eight VA sites nationwide. Independent variables included scales measuring comfort and difficulty with depression care; collaboration with a MHS; self-reported depression caseload; availability of a collocated MHS, and co-management with a DCM or MHS. Covariates included provider type and gender. For outcomes, we assessed PCP self-reported performance of key depression management behaviors in primary care in the past 6 months. Response rate was 52 % overall, with 47 % attending physicians, 34 % residents, and 19 % nurse practitioners and physician assistants. Half (52 %) reported greater than eight veterans with depression in their panels and a MHS collocated in primary care (50 %). Seven of the eight clinics had a DCM. In multivariable analysis, significant predictors for PCP depression management included comfort, difficulty, co-management with MHSs and numbers of veterans with depression in their panels. PCPs who felt greater ease and comfort in managing depression, co-managed with MHSs, and reported higher depression caseloads, were more likely to report performing depression management behaviors. Neither a collocated MHS, collaborating with a MHS, nor co-managing with a DCM independently predicted PCP depression management. Because the success of collaborative care for depression depends on the ability and willingness of PCPs to engage in managing depression themselves, along with other providers, more research is necessary to understand how to engage PCPs in depression management. C1 [Chang, Evelyn T.; Rubenstein, Lisa V.] Vet Affairs VA Los Greater Angeles Healthcare Sys, Dept Gen Internal Med, Los Angeles, CA USA. [Chang, Evelyn T.; Lanto, Andrew; Simon, Barbara; Yano, Elizabeth M.; Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA Ctr Study Healthcare Innovat Implementat & Pol, Sepulveda, CA USA. [Magnabosco, Jennifer L.; Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, Ctr Implementat Practice & Res Support, Sepulveda, CA USA. [Magnabosco, Jennifer L.] Yo San Univ Tradit Chinese Med, Los Angeles, CA USA. [Chaney, Edmund] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Chaney, Edmund] Vet Affairs Puget Sound Healthcare Syst, Hlth Serv Res & Dev Northwest Ctr Excellence, Seattle, WA USA. [Yano, Elizabeth M.; Rubenstein, Lisa V.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Rubenstein, Lisa V.] RAND Corp, Santa Monica, CA USA. RP Chang, ET (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Gen Internal Med 111G, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Evelyn.chang@va.gov FU VA HSRD [MNT 03-215]; VA Mental Health Quality Enhancement Research Initiative; VA Office of Academic Affiliations, through the Health Services Research Fellowship Training Program [TMP 65-020]; VA HSR&D Service through a Senior Research Career Scientist Award [RCS 05-195] FX The ReTIDES project "Expanding and Testing VA Collaborative Care Models for Depression" was supported by VA HSR&D (Project #MNT 03-215, PIs Lisa Rubenstein, MD MSHS, and Edmund Chaney, PhD) and VA Mental Health Quality Enhancement Research Initiative. Funding support for preparation of this paper was provided by VA Office of Academic Affiliations, through the Health Services Research Fellowship Training Program (TMP 65-020). Dr. Yano's time was funded by the VA HSR&D Service through a Senior Research Career Scientist Award (Project #RCS 05-195). NR 65 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 1017 EP 1025 DI 10.1007/s11606-014-2807-z PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100012 PM 24567200 ER PT J AU Simon, SR AF Simon, Steven R. TI Capsule Commentary on Grant, et al., Exercise as a Vital Sign: A Quasi-Experimental Analysis of a Health System Intervention to Collect Patient-Reported Exercise Levels SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Simon, Steven R.] VA Boston Healthcare Syst, Boston, MA USA. RP Simon, SR (reprint author), Boston Healthcare Syst, Boston, MA 02130 USA. EM Steven.simon2@va.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 1059 EP 1059 DI 10.1007/s11606-013-2762-0 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100021 PM 24449034 ER PT J AU Jena, AB Sun, EC Prasad, V AF Jena, Anupam B. Sun, Eric C. Prasad, Vinay TI Does the Declining Lethality of Gunshot Injuries Mask a Rising Epidemic of Gun Violence in the United States? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID TRAUMA SYSTEM-DEVELOPMENT; FIREARM; DECADE; RATES AB Recent mass shootings in the U.S. have reignited the important public health debate concerning measures to decrease the epidemic of gun violence. Editorialists and gun lobbyists have criticized the recent focus on gun violence, arguing that gun-related homicide rates have been stable in the last decade. While true, data from the U.S. Centers for Disease Control and Prevention also demonstrate that although gun-related homicide rates were stable between 2002 and 2011, rates of violent gunshot injuries increased. These seemingly paradoxical trends may reflect the declining lethality of gunshot injuries brought about by surgical advances in the care of the patient with penetrating trauma. Focusing on gun-related homicide rates as a summary statistic of gun violence, rather than total violent gunshot injuries, can therefore misrepresent the rising epidemic of gun violence in the U.S. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Cambridge, MA USA. [Jena, Anupam B.] NBER, Cambridge, MA 02138 USA. [Sun, Eric C.] Stanford Univ Hosp, Dept Anesthesia, Stanford, CA 94305 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu; esun1@stanford.edu; vinayak.prasad@nih.gov FU Office of the Director, National Institutes of Health [1DP5OD017897-01] FX Dr. Jena had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Support was provided by the Office of the Director, National Institutes of Health (1DP5OD017897-01, Dr. Jena). NR 23 TC 9 Z9 9 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 1065 EP 1069 DI 10.1007/s11606-014-2779-z PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100023 PM 24452421 ER PT J AU Jones, B Brzezinski, WA Estrada, CA Rodriguez, M Kraemer, RR AF Jones, Benjamin Brzezinski, Walter A. Estrada, Carlos A. Rodriguez, Martin Kraemer, Ryan R. TI A 22-Year-Old Woman with Abdominal Pain SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE clinical reasoning; illness script; expert clinician; acute intermittent porphyria; abdominal pain ID PORPHYRIAS C1 [Jones, Benjamin] Univ Alabama Birmingham, Tinsley Harrison Internal Med Residency Program, Birmingham, AL 35294 USA. [Brzezinski, Walter A.] Med Univ S Carolina, Charleston, SC 29425 USA. [Estrada, Carlos A.; Kraemer, Ryan R.] Univ Alabama Birmingham, Div Gen Internal Med, Birmingham, AL 35294 USA. [Estrada, Carlos A.; Kraemer, Ryan R.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Estrada, Carlos A.] Vet Affairs Natl Qual Scholars Program, Birmingham, AL USA. [Rodriguez, Martin] Univ Alabama Birmingham, Birmingham, AL 35294 USA. RP Kraemer, RR (reprint author), Univ Alabama Birmingham, Tinsley Harrison Internal Med Residency Program, Div Gen Internal Med, 720 Fac Off Tower 510 20th St South, Birmingham, AL 35294 USA. EM rkraemer@uab.edu NR 10 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 1074 EP 1078 DI 10.1007/s11606-013-2747-z PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100026 PM 24420866 ER PT J AU Chiovaro, J AF Chiovaro, Joseph TI The Forgotten War SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 Portland VA Med Ctr, Dept Med, Div Hosp Med, Portland, OR 97239 USA. RP Chiovaro, J (reprint author), Portland VA Med Ctr, Dept Med, Div Hosp Med, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM jchiovaro@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 1079 EP 1080 DI 10.1007/s11606-013-2720-x PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100027 PM 24395099 ER PT J AU Hage, FG AF Hage, F. G. TI C-reactive protein and hypertension SO JOURNAL OF HUMAN HYPERTENSION LA English DT Review DE C-reactive protein; cardiovascular; biomarker; vascular stiffness; genetic variation ID CHRONIC KIDNEY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; ISCHEMIC-STROKE; BLOOD-PRESSURE; NEOINTIMA FORMATION; GENE POLYMORPHISMS; TRANSGENIC MICE; HAN CHINESE; CRP LEVELS AB C-reactive protein (CRP), the prototypical acute-phase reactant, is one of the most widely known biomarkers of cardiovascular disease. Circulating levels of CRP are clinically used to predict the occurrence of cardiovascular events and to aide in the selection of therapies based on more accurate risk assessment in individuals who are at intermediate risk. This paper reviews the role of CRP in hypertension. In hypertensive individuals, CRP levels associate with vascular stiffness, atherosclerosis and the development of end-organ damage and cardiovascular events. Data suggest that some anti-hypertensive medications may lower CRP levels in a manner independent of their effect on blood pressure. In individuals who are normotensive at baseline, CRP levels have been shown in multiple cohorts to foretell the development of hypertension on follow-up. Whether genetic variability that influences circulating levels of CRP independent of environmental and behavioral factors can also be used in a similar manner to predict the change in blood pressure and development of hypertension is controversial. In addition to its role as a biomarker, experimental studies have unraveled an active direct participation of CRP in the development of endothelial dysfunction, vascular stiffness and elevated blood pressure. CRP has also been implicated as a mediator of vascular remodeling in response to injury and cardiac remodeling in response to pressure overload. Emerging data may reveal novel vascular inflammatory pathways and identify new targets for treatment of vascular pathology. C1 [Hage, F. G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, F. G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Zeigler Res Bldg 1024,703 19th St South, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 FU Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award; American Heart Association NCRP Scientist Development [0930098N]; Novartis Pharmaceuticals FX This work was supported, in part, by a Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award and an American Heart Association NCRP Scientist Development Grant 0930098N. Grant support from Novartis Pharmaceuticals. NR 60 TC 17 Z9 19 U1 4 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 EI 1476-5527 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD JUL PY 2014 VL 28 IS 7 BP 410 EP 415 DI 10.1038/jhh.2013.111 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK3UQ UT WOS:000338350600002 PM 24226100 ER PT J AU Hou, YZ Lin, HJ Zhu, LN Liu, ZT Hu, FL Shi, JF Yang, T Shi, XY Guo, HF Tan, XT Zhang, LF Wang, Q Li, ZG Zhao, Y AF Hou, Yuzhu Lin, Haijiang Zhu, Linnan Liu, Zhaoting Hu, Fanlei Shi, Jianfeng Yang, Tao Shi, Xiaoyun Guo, Huifang Tan, Xiaotian Zhang, Lianfeng Wang, Qiang Li, Zhanguo Zhao, Yong TI The Inhibitory Effect of IFN-gamma on Protease HTRA1 Expression in Rheumatoid Arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; SERINE-PROTEASE; DEFICIENT MICE; LONG-TERM; CARTILAGE; GENE; MACROPHAGES; LPS; SUSCEPTIBILITY; DEGENERATION AB The high temperature requirement A1 (HTRA1) is a potent protease involved in many diseases, including rheumatoid arthritis (RA). However, the regulatory mechanisms that control HTRA1 expression need to be determined. In this study, we demonstrated that IFN-gamma significantly inhibited the basal and LPS-induced HTRA1 expression in fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the inhibitory effect of IFN-gamma on HTRA1 expression was evidenced in collagen-induced arthritis (CIA) mouse models and in human RA synovial cells. In parallel with the enhanced CIA incidence and pathological changes in IFN-gamma-deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-gamma deficiency increased the incidence of CIA and the pathological severity in mice. Neutralization of HTRA1 by Ab significantly reversed the enhanced CIA frequency and severity in IFN-gamma-deficient mice. Mechanistically, IFN-gamma negatively controls HTRA1 expression through activation of p38 MAPK/STAT1 pathway. Dual luciferase reporter assay and chromatin immunoprecipitation analysis showed that STAT1 could directly bind to HTRA1 promoter after IFN-gamma stimulation. This study offers new insights into the molecular regulation of HTRA1 expression and its role in RA pathogenesis, which may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer. C1 [Hou, Yuzhu; Zhu, Linnan; Liu, Zhaoting; Shi, Jianfeng; Yang, Tao; Shi, Xiaoyun; Tan, Xiaotian; Wang, Qiang; Zhao, Yong] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100101, Peoples R China. [Hou, Yuzhu; Zhu, Linnan; Shi, Jianfeng; Yang, Tao; Zhao, Yong] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. [Lin, Haijiang] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Hu, Fanlei; Li, Zhanguo] Peking Univ, Peoples Hosp, Clin Immunol Ctr, Dept Rheumatol & Immunol, Beijing 100044, Peoples R China. [Shi, Xiaoyun] Chinese Peoples Armed Police Forces, Gen Hosp, Beijing 100039, Peoples R China. [Guo, Huifang] Hebei Med Univ, Hosp 2, Dept Rheumatol, Shijiazhuang 050000, Peoples R China. [Zhang, Lianfeng] Chinese Acad Med Sci, Minist Hlth, Key Lab Human Dis Comparat Med, Beijing 100021, Peoples R China. [Zhang, Lianfeng] Chinese Acad Med Sci, Inst Lab Anim Sci, Beijing 100021, Peoples R China. Peking Union Med Coll, Beijing 100021, Peoples R China. RP Zhao, Y (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Transplantat Biol Res Div, Beichen West Rd 1-5, Beijing 100101, Peoples R China. EM qiangwang@ioz.ac.cn; zgli@yahoo.com; zhaoy@ioz.ac.cn FU National Basic Research Program of China [2010CB945301, 2011CB710900, 2010CB529100]; National Natural Science Foundation of China [C81130055, U0832003]; Knowledge Innovation Program of Chinese Academy of Sciences [YSCX2-YW-238]; State Administration of Foreign Experts Affairs of Chinese Academy of Sciences International Partnership Program for Creative Research Teams FX This work was supported by National Basic Research Program of China Grants 2010CB945301, 2011CB710900 (to Y.Z.), and 2010CB529100 (to Z. Li), National Natural Science Foundation of China for General and Key Programs Grants C81130055 and U0832003 (to Y.Z.), Knowledge Innovation Program of Chinese Academy of Sciences Grant YSCX2-YW-238 (to Y.Z.), as well as by the State Administration of Foreign Experts Affairs of Chinese Academy of Sciences International Partnership Program for Creative Research Teams (to Y.Z.). NR 44 TC 7 Z9 7 U1 2 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 130 EP 138 DI 10.4049/jimmunol.1302700 PG 9 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900018 PM 24907345 ER PT J AU Bettini, ML Guy, C Dash, P Vignali, KM Hamm, DE Dobbins, J Gagnon, E Thomas, PG Wucherpfennig, KW Vignali, DAA AF Bettini, Matthew L. Guy, Clifford Dash, Pradyot Vignali, Kate M. Hamm, David E. Dobbins, Jessica Gagnon, Etienne Thomas, Paul G. Wucherpfennig, Kai W. Vignali, Dario A. A. TI Membrane Association of the CD3 epsilon Signaling Domain Is Required for Optimal T Cell Development and Function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR-RETROGENIC MICE; PROLINE-RICH SEQUENCE; IMMUNOLOGICAL SYNAPSE; CONFORMATIONAL-CHANGE; SUBUNIT CONTAINS; THYMIC SELECTION; BINDING MOTIF; TCR; COMPLEX; ZETA AB The TCR:CD3 complex transduces signals that are critical for optimal T cell development and adaptive immunity. In resting T cells, the CD3 cytoplasmic tail associates with the plasma membrane via a proximal basic-rich stretch (BRS). In this study, we show that mice lacking a functional CD3 epsilon-BRS exhibited substantial reductions in thymic cellularity and limited CD4(-)CD8(-) double-negative (DN) 3 to DN4 thymocyte transition, because of enhanced DN4 TCR signaling resulting in increased cell death and TCR downregulation in all subsequent populations. Furthermore, positive, but not negative, T cell selection was affected in mice lacking a functional CD3 epsilon-BRS, which led to limited peripheral T cell function and substantially reduced responsiveness to influenza infection. Collectively, these results indicate that membrane association of the CD3 signaling domain is required for optimal thymocyte development and peripheral T cell function. C1 [Bettini, Matthew L.; Guy, Clifford; Dash, Pradyot; Vignali, Kate M.; Thomas, Paul G.; Vignali, Dario A. A.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Hamm, David E.] Adapt Biotechnol, Seattle, WA 98102 USA. [Dobbins, Jessica; Gagnon, Etienne; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Vignali, DAA (reprint author), Univ Pittsburgh, Sch Med, Dept Immunol, E1052 Biomed Sci Tower,200 Lothrop St, Pittsburgh, PA 15261 USA. EM dvignali@pitt.edu FU National Institutes of Health [R01 AI52199, R01 AI054520, R01 AI107625]; Cancer Research Institute; National Cancer Institute Comprehensive Cancer Center Support CORE Grant [CA21765]; American Lebanese Syrian Associated Charities FX This work was supported by National Institutes of Health Grants R01 AI52199 (to D.A.A.V.), R01 AI054520 (to K.W.W.), and R01 AI107625 (to P.G.T.); a Hartwell postdoctoral fellowship (to M.L.B.); a fellowship by the Cancer Research Institute (to E.G.); National Cancer Institute Comprehensive Cancer Center Support CORE Grant CA21765 (to D.A.A.V.); and the American Lebanese Syrian Associated Charities (to D.A.A.V.). NR 39 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 258 EP 267 DI 10.4049/jimmunol.1400322 PG 10 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900031 PM 24899501 ER PT J AU Kajiwara, Y Schiff, T Voloudakis, G Sosa, MAG Elder, G Bozdagi, O Buxbaum, JD AF Kajiwara, Yuji Schiff, Tamar Voloudakis, Georgios Sosa, Miguel A. Gama Elder, Gregory Bozdagi, Ozlem Buxbaum, Joseph D. TI A Critical Role for Human Caspase-4 in Endotoxin Sensitivity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; NONCANONICAL INFLAMMASOME ACTIVATION; SYSTEMIC INFLAMMATION; INSULIN-RESISTANCE; MICE DEFICIENT; SEPTIC SHOCK; DISEASE; NLRP3; IL-1-BETA; MOUSE AB Response to endotoxins is an important part of the organismal reaction to Gram-negative bacteria and plays a critical role in sepsis and septic shock, as well as other conditions such as metabolic endotoxemia. Humans are generally more sensitive to endotoxins when compared with experimental animals such as mice. Inflammatory caspases mediate endotoxin-induced IL-1 beta secretion and lethality in mice, and caspase-4 is an inflammatory caspase that is found in the human, and not mouse, genome. To test whether caspase-4 is involved in endotoxin sensitivity, we developed a transgenic mouse expressing human caspase-4 in its genomic context. Caspase-4 transgenic mice exhibited significantly higher endotoxin sensitivity, as measured by enhanced cytokine secretion and lethality following LPS challenge. Using bone marrow-derived macrophages, we then observed that caspase-4 can support activation of caspase-1 and secretion of IL-1 beta and IL-18 in response to priming signals (LPS or Pam3CSK4) alone, without the need for second signals to stimulate the assembly of the inflammasome. These findings indicate that the regulation of caspase-1 activity by human caspase-4 could represent a unique mechanism in humans, as compared with laboratory rodents, and may partially explain the higher sensitivity to endotoxins observed in humans. Regulation of the expression, activation, or activity of caspase-4 therefore represents targets for systemic inflammatory response syndrome, sepsis, septic shock, and related disorders. C1 [Kajiwara, Yuji; Voloudakis, Georgios; Sosa, Miguel A. Gama; Elder, Gregory; Bozdagi, Ozlem; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Schiff, Tamar] Baylor Coll Med, Houston, TX 77030 USA. [Sosa, Miguel A. Gama] James J Peters Dept Vet Affairs Med Ctr, Gen Med Res Serv, Bronx, NY 10468 USA. [Elder, Gregory] James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, Bronx, NY 10468 USA. [Elder, Gregory] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. RP Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, One Gustave L Levy Pl,Box 1668,Annenberg 22-24A, New York, NY 10029 USA. EM Joseph.Buxbaum@mssm.edu OI Buxbaum, Joseph/0000-0001-8898-8313 FU Icahn School of Medicine at Mount Sinai Alzheimer Disease Research Center [U01 P50 AG005138-28]; Manasaki Foundation scholarship FX This work was supported by the Icahn School of Medicine at Mount Sinai Alzheimer Disease Research Center (Dr. Mary Sano, principal investigator; O.B. and J.D.B., project leaders; U01 P50 AG005138-28). G.V. was also supported by a Manasaki Foundation scholarship. J.D.B. is the G. Harold and Leila Y. Mathers Professor of Geriatrics and Adult Development. NR 54 TC 30 Z9 31 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 335 EP 343 DI 10.4049/jimmunol.1303424 PG 9 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900039 PM 24879791 ER PT J AU Olson, JJ Nayak, L Ormond, DR Wen, PY Kalkanis, SN AF Olson, Jeffrey J. Nayak, Lakshmi Ormond, D. Ryan Wen, Patrick Y. Kalkanis, Steven N. TI The role of cytotoxic chemotherapy in the management of progressive glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Adult; Chemotherapy; Cytotoxic; Glioblastoma; Mortality; Progressive; Recurrent; Relapsing; Survival; Temozolomide ID RECURRENT MALIGNANT GLIOMA; PHASE-II TRIAL; HIGH-GRADE GLIOMA; TEMOZOLOMIDE-REFRACTORY GLIOBLASTOMA; NEWLY-DIAGNOSED GLIOBLASTOMA; BRAIN-TUMOR CONSORTIUM; NEURO-ONCOLOGIA GICNO; SUPRATENTORIAL GLIOMAS; INTRAVENOUS CARBOPLATIN; 2ND-LINE CHEMOTHERAPY AB What is the impact of cytotoxic chemotherapy on disease control and survival in the adult patient with progressive glioblastoma? This recommendation applies to adults patients with progressive glioblastoma. Temozolomide is recommended as superior to procarbazine in patients with first relapse of glioblastoma after having received nitrosourea chemotherapy or no prior cytotoxic chemotherapy at the time of initial therapy. The use of BCNU-impregnated biodegradable polymer wafers is recommended in the management of progressive glioblastoma as a surgical adjunct when cytoreductive surgery is indicated, taking into account the associated toxicities seen with this modality. Consideration of a variety of cytotoxic chemotherapy agents of uncertain benefit is recommended in the setting of progressive glioblastoma based on the judgment of the treating physician taking into account the individual patients prior treatment exposure, systemic health, and likelihood of tolerance of the toxicities of any given agent. It is recommended in such cases that enrollment in available clinical trials be encouraged. C1 [Olson, Jeffrey J.; Ormond, D. Ryan] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA. [Nayak, Lakshmi; Wen, Patrick Y.] Brigham & Womens Canc Ctr, Dept Neurol, Dana Farber Canc Inst, Boston, MA USA. [Kalkanis, Steven N.] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI USA. RP Olson, JJ (reprint author), Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA. EM jolson@emory.edu FU CNS; Tumor Section of the American Association of Neurological Surgeons FX These guidelines were funded exclusively by the CNS and Tumor Section of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons whom received no funding from outside commercial sources to support the development of this document unless otherwise stated in this section. NR 112 TC 11 Z9 11 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JUL PY 2014 VL 118 IS 3 SI SI BP 501 EP 555 DI 10.1007/s11060-013-1338-5 PG 55 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AK1XC UT WOS:000338211200007 PM 24740194 ER PT J AU Olson, JJ Nayak, L Ormond, DR Wen, PY Kalkanis, SN Ryken, TC AF Olson, Jeffrey J. Nayak, Lakshmi Ormond, D. Ryan Wen, Patrick Y. Kalkanis, Steven N. Ryken, Timothy Charles TI The role of targeted therapies in the management of progressive glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Adult; Glioblastoma; Malignant glioma; Progressive; Recurrent; Relapse; Targeted therapy; Molecular agents; Quality of life; Survival; Mortality ID PHASE-II TRIAL; RECURRENT MALIGNANT GLIOMA; HIGH-GRADE GLIOMAS; BRAIN-TUMOR CONSORTIUM; BEVACIZUMAB PLUS IRINOTECAN; HIGH-DOSE TAMOXIFEN; NEWLY-DIAGNOSED GLIOBLASTOMA; ENDOTHELIAL GROWTH-FACTOR; SINGLE-AGENT BEVACIZUMAB; ANTI-ANGIOGENIC THERAPY AB What is the influence of targeted medical therapies on disease control and survival in the adult patient with progressive glioblastoma? This recommendation applies to adult patients with progressive glioblastoma Level III Treatment with bevacizumab is recommended as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months. Given that there are a large number of therapies are available for progressive glioblastoma that may be applied under selected circumstances dependent on patient characteristics and treating physician judgment, it is strongly recommended that patients with progressive glioblastoma be enrolled in properly designed clinical investigations to provide convincing evidence of therapeutic value. C1 [Olson, Jeffrey J.; Ormond, D. Ryan] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA. [Nayak, Lakshmi; Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nayak, Lakshmi; Wen, Patrick Y.] Brigham & Womens Canc Ctr, Dept Neurol, Boston, MA USA. [Kalkanis, Steven N.] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI USA. [Ryken, Timothy Charles] Iowa Spine & Brain Inst, Dept Neurosurg, Waterloo, IA USA. RP Olson, JJ (reprint author), Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA. EM jolson@emory.edu FU CNS; Tumor Section of the American Association of Neurological Surgeons FX These guidelines were funded exclusively by the CNS and Tumor Section of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons whom received no funding from outside commercial sources to support the development of this document unless otherwise stated in this section. NR 157 TC 11 Z9 11 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JUL PY 2014 VL 118 IS 3 SI SI BP 557 EP 599 DI 10.1007/s11060-013-1339-4 PG 43 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AK1XC UT WOS:000338211200008 PM 24740195 ER PT J AU Colletti, G Frigerio, A Giovanditto, F Biglioli, F Chiapasco, M Grimmer, JF AF Colletti, Giacomo Frigerio, Alice Giovanditto, Federica Biglioli, Federico Chiapasco, Matteo Grimmer, J. Fredrik TI Surgical Treatment of Vascular Malformations of the Facial Bones SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID MANDIBULAR ARTERIOVENOUS-MALFORMATION; VENOUS MALFORMATION; CLASSIFICATION; MANAGEMENT; EMBOLIZATION; HEMANGIOMAS; ANOMALIES; LESIONS; FACE AB Purpose: To characterize intraosseous vascular malformations and describe the most appropriate approach for treatment according to clinical experience and a review of the published data. Materials and Methods: We performed a retrospective review of 11 vascular malformations (7 venous and 4 arteriovenous) of the facial bones treated during a 10-year period using en bloc resection or intraoral aggressive curettage alone or preceded by endovascular embolization. Corrective surgery was planned to address any residual bone deformities. The cases were reviewed at a mean follow-up point of 6 years. Results: Facial symmetry was restored in the cases requiring reconstruction. Tooth sparing was possible in the case of jaw and/or maxillary localization. Recanalization occurred in 14% of the venous and 33% of the arteriovenous malformations. Conclusions: Facial intraosseous venous malformations can be successfully treated using surgery alone. Facial intraosseous arteriovenous malformations will be better addressed using combined approaches. Aggressive curettage will obviate the need for extensive surgical resection in selected cases. (C) 2014 American Association of Oral and Maxillofacial Surgeons C1 [Colletti, Giacomo; Giovanditto, Federica; Biglioli, Federico] Univ Milan, San Paolo Hosp, Div Maxillofacial Surg, Dept Biomed Surg & Dent Sci, I-20121 Milan, Italy. [Frigerio, Alice] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med,Carolyn & Peter Lynch Ctr Laser & Reconst, Div Facial Plast & Reconstruct Surg,Dept Otol & L, Boston, MA USA. [Chiapasco, Matteo] Univ Milan, San Paolo Hosp, Dept Hlth Sci, Div Oral Surg, I-20121 Milan, Italy. [Grimmer, J. Fredrik] Univ Utah, Dept Surg, Primary Childrens Med Ctr, Vasc Anomalies Ctr,Div Otolaryngol, Salt Lake City, UT USA. RP Colletti, G (reprint author), Univ Milan, San Paolo Hosp, Div Maxillofacial Surg, Dept Biomed Surg & Dent Sci, Piazza Repubbl 1-a, I-20121 Milan, Italy. EM giacomo.colletti@gmail.com OI Frigerio, Alice/0000-0001-9202-9553; Colletti, Giacomo/0000-0001-6975-495X NR 28 TC 0 Z9 0 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUL PY 2014 VL 72 IS 7 DI 10.1016/j.joms.2014.02.012 PG 18 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AK4WI UT WOS:000338424500018 ER PT J AU Laviv, A Sohani, AR Troulis, MJ AF Laviv, Amir Sohani, Aliyah R. Troulis, Maria J. TI Lymphoma Mimics Obstructive Sialadenitis: Three Cases SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID PRIMARY MALIGNANT-LYMPHOMA; NON-HODGKINS-LYMPHOMA; FOLLICULAR LYMPHOMA; PAROTID-GLAND; ORAL-CAVITY; CLASSIFICATION; MANAGEMENT; HEAD; NECK AB Obstructive sialadenitis is a common salivary gland disorder usually secondary to viral or bacterial infections, sialolithiasis, duct stricture, or mucous plug. The differential diagnosis also should include dehydration, trauma, and scarring secondary to oral mucosal surgical procedures or neoplasm. It is important to consider neoplasm in these patients, especially when symptoms do not resolve as expected after treatment for obstruction. In a series of 591 cases referred to the Massachusetts General Hospital Oral and Maxillofacial Surgery Service for "obstructive sialadenitis" from 2009 through 2012, 3 patients had obstruction secondary to low-grade follicular lymphoma. (C) 2014 American Association of Oral and Maxillofacial Surgeons C1 [Laviv, Amir] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Pathol Serv, Core Lab, Boston, MA 02114 USA. [Troulis, Maria J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Troulis, Maria J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Residency Training Program, Boston, MA 02114 USA. RP Laviv, A (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren 1201, Boston, MA 02114 USA. EM amirlaviv@gmail.com NR 17 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 2014 VL 72 IS 7 DI 10.1016/j.joms.2014.02.030 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AK4WI UT WOS:000338424500017 ER PT J AU Zhang, M Kim, JC Li, YN Shapiro, BB Porszasz, J Bross, R Feroze, U Upreti, R Martin, D Kalantar-Zadeh, K Kopple, JD AF Zhang, Min Kim, Jun Chul Li, Yinan Shapiro, Bryan B. Porszasz, Janos Bross, Rachelle Feroze, Usama Upreti, Rajeev Martin, David Kalantar-Zadeh, Kamyar Kopple, Joel D. TI Relation Between Anxiety, Depression, and Physical Activity and Performance in Maintenance Hemodialysis Patients SO JOURNAL OF RENAL NUTRITION LA English DT Article ID QUALITY-OF-LIFE; STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; EXERCISE; DISORDERS; HEALTH; METAANALYSIS; ADULTS; MORTALITY; DIALYSIS AB Objective: Maintenance hemodialysis (MHD) patients have a high prevalence of anxiety and depression and decreased daily physical activity (DPA) and exercise capacity. Because affective disorders may affect DPA and physical performance, we investigated possible relationships between anxiety or depression and DPA and physical performance in relatively healthy MHD patients. Design and Methods: This cross-sectional study included 72 relatively healthy MHD patients and 39 normal adults. DPA was measured for 7 days with an Actigraph Activity Monitor (R). Physical performance was assessed using the 6-minute walk (6-MWT), sit-to-stand (STS), and stair-climbing tests. Subjects completed the Beck Anxiety Inventory (BAI), the Beck Depression Inventory-II (BDI), and the Hospital Anxiety and Depression Scale (HADS). Main outcome measures were physical activity counts (expressed as vector magnitude), in the 6-MWT, STS, stair-climbing test, BAI, BDI, and HADS scores. Results: Anxiety and depression by BAI and BDI were identified in 43% and 33% of MHD patients and 2.5% and 5% of normals, respectively (P < .0001 for each comparison). MHD patients without anxiety or depression had decreased DPA and physical performance compared with normals, indicating that these disorders were also independent of anxiety or depression. MHD patients with anxiety and depression generally had the most impaired DPA and physical performance. Higher BAI and BDI scores were each associated with impaired physical performance. In fully adjusted analyses, DPA in MHD patients was negatively correlated with the BDI (r = -0.33, P = .01) but not with the BAI. DPA on the day of hemodialysis (P = .01), and day 1 (P = .03) and day 2 (P = .03) after dialysis each correlated negatively with degree of depression by BDI. In MHD patients, BAI was negatively correlated with 6-MWT (P = .03) and STS (P = .04). Conclusions: In relatively healthy adult MHD patients, anxiety and depression are common and are associated with impaired physical performance. There was a trend toward stronger negative associations between BDI scores and DPA than between BAI scores and DPA. (C) 2014 by the National Kidney Foundation, Inc. All rights reserved. C1 [Zhang, Min; Kim, Jun Chul; Li, Yinan; Shapiro, Bryan B.; Feroze, Usama; Upreti, Rajeev; Kopple, Joel D.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Div Nephrol & Hypertens, Torrance, CA 90509 USA. [Zhang, Min] Tianjin Union Med Ctr, Div Nephrol, Tianjin, Peoples R China. [Kim, Jun Chul] CHA Univ, CHA Gumi Med Ctr, Div Nephrol, Taegu, South Korea. [Li, Yinan] Xiamen Univ, Affiliated Hosp 1, Dept Nephrol, Xiamen, Peoples R China. [Porszasz, Janos] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Rehabil Clin Trials Ctr, Div Resp & Crit Care Physiol & Med, Torrance, CA 90509 USA. [Bross, Rachelle] Univ Calif Los Angeles, Los Angeles Biomed Res Inst, Clin & Translat Sci Inst, Harbor UCLA Med Ctr, Torrance, CA USA. [Bross, Rachelle; Kalantar-Zadeh, Kamyar] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Harold Simmons Ctr Kidney Dis Res & Epidemiol, Torrance, CA 90509 USA. [Martin, David] Harbor UCLA Med Ctr, Dept Psychiat, Div Psychol, Torrance, CA 90509 USA. [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Div Nephrol & Hypertens, Orange, CA 92668 USA. [Kalantar-Zadeh, Kamyar; Kopple, Joel D.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Kopple, Joel D.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Feroze, Usama] VA Boston Hlth Care Syst, Harvard South Shore Psychiat Residency Program, Brockton, MA USA. RP Kopple, JD (reprint author), Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, 1124 West Carson St, Torrance, CA 90509 USA. EM jkopple@labiomed.org RI faraji, milad/L-6671-2015; OI Porszasz, Janos/0000-0002-5823-0031; Kalantar-Zadeh, Kamyar/0000-0002-8666-0725 FU NCATS NIH HHS [UL1 TR000124] NR 48 TC 7 Z9 7 U1 3 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1051-2276 EI 1532-8503 J9 J RENAL NUTR JI J. Renal Nutr. PD JUL PY 2014 VL 24 IS 4 BP 252 EP 260 DI 10.1053/j.jrn.2014.03.002 PG 9 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA AK4VP UT WOS:000338422500008 PM 24788308 ER PT J AU DeJong, SM Gorrindo, T AF DeJong, Sandra M. Gorrindo, Tristan TI To Text or Not to Text: Applying Clinical and Professionalism Principles to Decisions About Text Messaging With Patients SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material C1 [DeJong, Sandra M.] Cambridge Hlth Alliance, Div Child & Adolescent Psychiat, Cambridge, MA 02139 USA. [DeJong, Sandra M.; Gorrindo, Tristan] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Gorrindo, Tristan] Massachusetts Gen Hosp, Div Child & Adolescent Psychiat, Boston, MA 02114 USA. RP DeJong, SM (reprint author), Cambridge Hlth Alliance, 1493 Cambridge St, Cambridge, MA 02139 USA. EM sdejong@challiance.org NR 4 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2014 VL 53 IS 7 BP 713 EP 715 DI 10.1016/j.jaac.2014.05.002 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AK2SI UT WOS:000338269400002 PM 24954818 ER PT J AU Tawakol, A Emami, H Farkouh, M Fayad, ZA Fifer, K Rudd, JHF Subramanian, S Van Dyke, T AF Tawakol, Ahmed Emami, Hamed Farkouh, Michael Fayad, Zahi A. Fifer, Kenneth Rudd, James H. F. Subramanian, Sharath Van Dyke, Thomas TI Is it Not Timely to Consider How to Balance Cardiorenometabolic Benefits and Risks of Statins ? Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID INFLAMMATION C1 [Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, Div Cardiol, 165 Cambridge St Suite 400, Boston, MA 02114 USA. EM atawakol@partners.org NR 4 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 1 PY 2014 VL 63 IS 25 BP 2881 EP 2881 DI 10.1016/j.jacc.2014.03.038 PN A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AK4ZY UT WOS:000338434600022 PM 24794123 ER PT J AU Fiorina, P Vergani, A Bassi, R Niewczas, MA Altintas, MM Pezzolesi, MG D'Addio, F Chin, M Tezza, S Ben Nasr, M Mattinzoli, D Ikehata, M Corradi, D Schumacher, V Buvall, L Yu, CC Chang, JM La Rosa, S Finzi, G Solini, A Vincenti, F Rastaldi, MP Reiser, J Krolewski, AS Mundel, PH Sayegh, MH AF Fiorina, Paolo Vergani, Andrea Bassi, Roberto Niewczas, Monika A. Altintas, Mehmet M. Pezzolesi, Marcus G. D'Addio, Francesca Chin, Melissa Tezza, Sara Ben Nasr, Moufida Mattinzoli, Deborah Ikehata, Masami Corradi, Domenico Schumacher, Valerie Buvall, Lisa Yu, Chih-Chuan Chang, Jer-Ming La Rosa, Stefano Finzi, Giovanna Solini, Anna Vincenti, Flavio Rastaldi, Maria Pia Reiser, Jochen Krolewski, Andrzej S. Mundel, Peter H. Sayegh, Mohamed H. TI Role of Podocyte B7-1 in Diabetic Nephropathy SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RHEUMATOID-ARTHRITIS; NEPHROTIC-SYNDROME; KIDNEY-FUNCTION; UNITED-STATES; TYPE-1; ABATACEPT; MELLITUS; DISEASE; PROTEIN; TRIAL AB Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy. C1 [Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto; D'Addio, Francesca; Chin, Melissa; Tezza, Sara; Ben Nasr, Moufida; Schumacher, Valerie] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol, Boston, MA 02115 USA. [Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto; D'Addio, Francesca] Ist Sci San Raffaele, Dept Med, I-20132 Milan, Italy. [Bassi, Roberto] Univ Salento, DiSTeBA, Lecce, Italy. [Niewczas, Monika A.; Pezzolesi, Marcus G.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Genet & Epidemiol,Res Div, Boston, MA 02115 USA. [Niewczas, Monika A.; Pezzolesi, Marcus G.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Altintas, Mehmet M.; Reiser, Jochen] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. [Mattinzoli, Deborah; Ikehata, Masami; Rastaldi, Maria Pia] Fdn IRCCS Osped Maggiore Policlin, Renal Res Lab, Milan, Italy. [Mattinzoli, Deborah; Ikehata, Masami; Rastaldi, Maria Pia] Fdn DAmico Ric Malattie Renali, Milan, Italy. [Corradi, Domenico] Univ Parma, Unit Pathol, Dept Biomed Biotechnol & Translat Sci, I-43100 Parma, Italy. [Buvall, Lisa; Mundel, Peter H.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Yu, Chih-Chuan] Kaohsiung Med Univ, Coll Med, Grad Inst Med, Kaohsiung, Taiwan. [Yu, Chih-Chuan; Chang, Jer-Ming] Kaohsiung Med Univ, Dept Internal Med, Kaohsiung, Taiwan. [La Rosa, Stefano; Finzi, Giovanna] Osped Circolo Varese, Dept Pathol, Varese, Italy. [Solini, Anna] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy. [Vincenti, Flavio] Univ Calif San Francisco, Kidney Transplant Serv, San Francisco, CA 94143 USA. [Sayegh, Mohamed H.] Brigham & Womens Hosp, Transplantat Res Ctr, Boston, MA 02115 USA. [Sayegh, Mohamed H.] Amer Univ Beirut, Beirut, Lebanon. RP Fiorina, P (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol, 300 Longwood Ave,Enders Bldg,Fifth Floor, Boston, MA 02115 USA. EM paolo.fiorina@childrens.harvard.edu RI Corradi, Domenico/O-1666-2015; Solini, Anna/K-4666-2016; D'Addio, Francesca/F-3417-2017; IKEHATA, MASAMI/H-8020-2016; OI Corradi, Domenico/0000-0002-8836-4778; Solini, Anna/0000-0002-7855-8253; D'Addio, Francesca/0000-0002-0345-0694; Buvall, Lisa/0000-0002-0599-8581; IKEHATA, MASAMI/0000-0001-9835-9991; Altintas, Mehmet/0000-0002-1871-6985 FU Juvenile Diabetes Research Foundation (JDRF); American Society of Nephrology; American Diabetes Association (ADA); Boston Children's Hospital; Harvard Stem Cell Institute [DP-0123-12-00]; Italian Ministry of Health [RF-2010-2303119, RF-2010-2314794, RF-FSR-2008-1213704]; Associazione Medici Diabetologi (AMD)-Societa' Italiana di Diabetologia (SID) Pasquale di Coste scholarship; National Institutes of Health (NIH) [T32DK007726-28]; ADA; American Society of Transplantation/Genentech clinical science fellowship grant; Swedish Research Council; Swedish Governmental Agency for Innovation Systems; NIH [DK57683, DK062472, DK091218, DK073495, DK089394, DK101350, DK41526, DK58549, DK77532] FX P.F. is the recipient of a Juvenile Diabetes Research Foundation (JDRF) career development award, an American Society of Nephrology career development award, and an American Diabetes Association (ADA) mentor-based fellowship grant. P.F. is also supported by grants from Boston Children's Hospital (Translational Research Program), the Harvard Stem Cell Institute (Diabetes Program DP-0123-12-00), and the Italian Ministry of Health (RF-2010-2303119, RF-2010-2314794, and RF-FSR-2008-1213704). A.V. is supported by a Associazione Medici Diabetologi (AMD)-Societa' Italiana di Diabetologia (SID) Pasquale di Coste scholarship, as well as a National Institutes of Health (NIH) research training grant to Boston Children's Hospital in Pediatric Nephrology (T32DK007726-28). A.V. conducted this study as partial fulfillment of his PhD program in Molecular Medicine at San Raffaele University (Milan, Italy). R.B. is supported by an ADA mentor-based fellowship grant to P.F and by an American Society of Transplantation/Genentech clinical science fellowship grant. R.B. conducted this study as partial fulfillment of his PhD program in Biology and Biotechnology at Salento University (Lecce, Italy). L.B. is supported by the Swedish Research Council and by the Swedish Governmental Agency for Innovation Systems. P.M. is supported by grants from the NIH (DK57683, DK062472, and DK091218). J.R. is supported by grants from the NIH (DK073495, DK089394, DK101350) and A.S.K. is supported by grants from the NIH (DK41526, DK58549 and DK77532). NR 44 TC 32 Z9 34 U1 3 U2 15 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1415 EP 1429 DI 10.1681/ASN.2013050518 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500009 PM 24676639 ER PT J AU Adair, BD Altintas, MM Moller, CC Arnaout, MA Reiser, J AF Adair, Brian D. Altintas, Mehmet M. Moeller, Clemens C. Arnaout, M. Amin Reiser, Jochen TI Structure of the Kidney Slit Diaphragm Adapter Protein CD2-Associated Protein as Determined with Electron Microscopy SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; ACTIN-CAPPING PROTEIN; C-CBL; DOWN-REGULATION; SH3 DOMAINS; GLOMERULAR-DISEASE; NEPHROTIC SYNDROME; ARP2/3 COMPLEX; CELL CONTACTS; BINDING-SITE AB CD2-associated protein (CD2AP) is a multidomain scaffolding protein that has a critical role in renal function. CD2AP is expressed in glomerular podocytes at the slit diaphragm, a modified adherens junction that comprises the protein filtration barrier of the kidney, and interacts with a number of protein ligands involved in cytoskeletal remodeling, membrane trafficking, cell motility, and cell survival. The structure of CD2AP is unknown. We used electron microscopy and single particle image analysis to determine the three-dimensional structure of recombinant full-length CD2AP and found that the protein is a tetramer in solution. Image reconstruction of negatively stained protein particles generated a structure at 21 angstrom resolution. The protein assumed a roughly spherical, very loosely packed structure. Analysis of the electron density map revealed that CD2AP consists of a central coiled-coil domain, which forms the tetramer interface, surrounded by four symmetry-related motifs, each containing three globular domains corresponding to the three SH3 domains. The spatial organization exposes the binding sites of all 12 SH3 domains in the tetramer, allowing simultaneous binding to multiple targets. Determination of the structure of CD2AP provides novel insights into the biology of this slit diaphragm protein and lays the groundwork for characterizing the interactions between key molecules of the slit diaphragm that control glomerular filtration. C1 [Adair, Brian D.; Moeller, Clemens C.; Arnaout, M. Amin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Nephrol, Boston, MA 02114 USA. [Altintas, Mehmet M.; Reiser, Jochen] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. [Arnaout, M. Amin] Harvard Univ, Sch Med, Dept Dev & Regenerat Biol, Boston, MA 02114 USA. RP Adair, BD (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM badair@partners.org OI Altintas, Mehmet/0000-0002-1871-6985 FU Rush University; National Institutes of Health [DK088327, DK48549, DK073495, DK089394] FX This work was supported by institutional funds from Rush University and, in part, by National Institutes of Health Grants DK088327 (to M.A.A.), DK48549 (to M.A.A.), DK073495 (to J.R.), and DK089394 (to J.R.). NR 60 TC 2 Z9 2 U1 1 U2 8 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1465 EP 1473 DI 10.1681/ASN.2013090949 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500013 PM 24511139 ER PT J AU Sarnak, MJ Katz, R Newman, A Harris, T Peralta, CA Devarajan, P Bennett, MR Fried, L Ix, JH Satterfield, S Simonsick, EM Parikh, CR Shlipak, MG AF Sarnak, Mark J. Katz, Ronit Newman, Anne Harris, Tamara Peralta, Carmen A. Devarajan, Prasad Bennett, Michael R. Fried, Linda Ix, Joachim H. Satterfield, Suzanne Simonsick, Eleanor M. Parikh, Chirag R. Shlipak, Michael G. CA Hlth ABC Study TI Association of Urinary Injury Biomarkers with Mortality and Cardiovascular Events SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; ACUTE KIDNEY INJURY; GLOMERULAR-FILTRATION-RATE; PROXIMAL TUBULAR CELLS; MOLECULE-1 KIM-1; FUNCTION DECLINE; CARDIAC-SURGERY; RISK; NGAL; INTERLEUKIN-18 AB Kidney damage is a common sequela of several chronic pathologic conditions. Whether biomarkers of kidney damage are prognostic for more severe outcomes is unknown. We measured three urinary bionnarkers (kidney injury molecule-1 [KIM-1], IL-18, and albumin) in 3010 individuals enrolled in the Health, Aging and Body Composition (Health ABC) study and used Cox proportional hazards models to investigate the associations of urinary KIM-1/creatinine (cr), IL-18/cr, and albumin/cr (ACR) with all-cause mortality and cardiovascular disease (CVD). Multivariable models adjusted for demographics, traditional CVD risk factors, and eGFR. Mean age of participants was 74 years, 49% of participants were men, and 41% of participants were black. During the median 12.4 years of follow-up, 1450 deaths and 797 CVD outcomes occurred. Compared with the lowest quartile, successive quartiles had the following adjusted hazard ratios (HRs; 95% confidence intervals [95% as]) for mortality: KIM-1/cr: (1.21; 1.03 to 1.41), (1.13; 0.96 to 1.34), and (1.28; 1.08 to 1.52); IL-18/cr: (1.02; 0.88 to 1.19), (1.16; 0.99 to 1.35), and (1.06; 0.90 to 1.25); ACR: (1.08; 0.91 to 1.27), (1.24; 1.06 to 1.46), and (1.63; 1.39 to 1.91). In similar analyses, only ACR quartiles associated with CVD: (1.19; 0.95 to 1.48), (1.35; 1.08 to 1.67), and (1.54; 1.24 to 1.91). Urinary KIM-1 had a modest association with all-cause mortality but did not associate with CVD, and urinary IL-18 did not associate with either outcome. In contrast, albuminuria strongly associated with all-cause mortality and CVD. Future studies should evaluate reasons for these differences in the prognostic importance of individual kidney injury markers. C1 [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA 02111 USA. [Katz, Ronit] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Newman, Anne] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, NIH, Bethesda, MD 20892 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Devarajan, Prasad; Bennett, Michael R.] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. [Fried, Linda] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Fried, Linda] Univ Pittsburgh, Sch Med, Renal Sect, Pittsburgh, PA USA. [Fried, Linda] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Parikh, Chirag R.] Yale Univ, Dept Med, Sect Nephrol, New Haven, CT 06520 USA. [Parikh, Chirag R.] Yale Univ, Program Appl Translat Res, New Haven, CT USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Biostat, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. RP Sarnak, MJ (reprint author), Tufts Med Ctr, Div Nephrol, Box 391,800 Washington St, Boston, MA 02111 USA. EM msarnak@tuftsmedicalcenter.org RI Bennett, Maxwell/J-8504-2015; Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging [R01-AG027002, R01-AG028050, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by National Institute on Aging Grants R01-AG027002 and R01-AG028050; National Institute on Aging Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; and National Institute of Nursing Research Grant R01-NR012459. This study was also supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 38 TC 12 Z9 12 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1545 EP 1553 DI 10.1681/ASN.2013070713 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500020 PM 24511130 ER PT J AU Slatore, CG Sullivan, DR Pappas, M Humphrey, LL AF Slatore, Christopher G. Sullivan, Donald R. Pappas, Miranda Humphrey, Linda L. TI Patient-Centered Outcomes among Lung Cancer Screening Recipients with Computed Tomography A Systematic Review SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung cancer; Screening; Patient-centered outcomes ID SERVICES-TASK-FORCE; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; NELSON TRIAL; PULMONARY NODULES; FOLLOW-UP; RISK; COMMUNICATION; PARTICIPANTS; STATEMENT AB Introduction: Lung cancer screening using low-dose computed tomography (LDCT) is now widely recommended for adults who are current or former heavy smokers. It is important to evaluate the impact of screening on patient-centered outcomes. Among current and former smokers eligible for lung cancer screening, we sought to determine the consequences of screening with LDCT, and subsequent results, on patient-centered outcomes such as quality of life, distress, and anxiety. Methods: We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth Quarter 2012), MEDLINE (2000 to May 31, 2013), reference lists of articles, and Scopus for relevant English-language studies and systematic reviews. To evaluate the effect of LDCT screening on patient-centered outcomes, we included only randomized controlled trials (RCTs) involving asymptomatic adults. To evaluate the association of particular results and/or recommendations from a screening LDCT with patient-centered outcomes, we included results from RCTs as well as from cohort studies. Results: A total of 8215 abstracts were reviewed. Five publications from two European RCTs and one publication from a cohort study conducted in the United States met inclusion criteria. The process of LDCT lung cancer screening was associated with short-term psychologic discomfort in many people but did not affect distress, worry, or health-related quality of life. False-positive results were associated with short-term increases in distress that returned to levels that were similar to those among people with negative results. Negative results were associated with short-term decreases in distress. Conclusions: As lung cancer screening is implemented in the general population, it will be important to evaluate its association with patient-centered outcomes. People considering lung cancer screening should be aware of the possibility of distress caused by false-positive results. Clinicians may want to consider tailoring communication strategies that can decrease the distress associated with these results. C1 [Slatore, Christopher G.] Portland VA Med Ctr, Portland, OR 97239 USA. [Slatore, Christopher G.] Portland VA Med Ctr, Sect Pulm & Crit Care Med, Portland, OR 97239 USA. [Humphrey, Linda L.] Portland VA Med Ctr, Div Specialty & Hosp Med, Portland, OR 97239 USA. [Slatore, Christopher G.; Sullivan, Donald R.] Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Slatore, Christopher G.; Pappas, Miranda; Humphrey, Linda L.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Pacific Northwest Evidence Based Practice Ctr, Portland, OR 97201 USA. [Humphrey, Linda L.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. RP Slatore, CG (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd,R&D 66, Portland, OR 97239 USA. EM slatore@ohsu.edu OI Slatore, Christopher/0000-0003-0958-8122; Sullivan, Donald/0000-0003-3266-3389 FU Agency for Healthcare Research and Quality [HHSA-290-2007-10057-I-EPC3, 13]; Portland VA Medical Center, Portland, Oregon FX This research was supported by the Agency for Healthcare Research and Quality under Contract No. HHSA-290-2007-10057-I-EPC3, Task Order No. 13. The research reported here was also supported by resources from the Portland VA Medical Center, Portland, Oregon. The Department of Veterans Affairs did not have a role in the conduct of the study, in the collection, management, analysis, or interpretation of data, or in the preparation of the article. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the U.S. Government. NR 44 TC 22 Z9 22 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2014 VL 9 IS 7 BP 927 EP 934 DI 10.1097/JTO.0000000000000210 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AJ9JK UT WOS:000338025600011 PM 24922011 ER PT J AU Levy, B Spira, A Becker, D Evans, T Schnadig, I Camidge, DR Bauman, JE Hausman, D Walker, L Nemunaitis, J Rudin, CM Halmos, B Bowles, DW AF Levy, Benjamin Spira, Alexander Becker, Daniel Evans, Tracey Schnadig, Ian Camidge, D. Ross Bauman, Julie E. Hausman, Diana Walker, Luke Nemunaitis, John Rudin, Charles M. Halmos, Balazs Bowles, Daniel W. TI A Randomized, Phase 2 Trial of Docetaxel with or without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Relapsed or Metastatic Non-Small-Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE PIK3CA; Phosphotidylinositol-3 kinase; Docetaxel; Combination therapy; Non-small-cell lung cancer ID ADVANCED SOLID TUMORS; PI3K INHIBITORS; PATHWAY; THERAPY AB Introduction: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. Methods: Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m(2) intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection. C1 [Levy, Benjamin; Becker, Daniel] Mt Sinai Hlth Syst, St Lukes Hosp, Beth Israel Hosp, New York, NY 10011 USA. [Spira, Alexander] Virginia Canc Specialists, Fairfax, VA USA. [Spira, Alexander; Schnadig, Ian] US Oncol Res, The Woodlands, TX USA. [Evans, Tracey] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Schnadig, Ian] Northwest Canc Specialists, Portland, OR USA. [Camidge, D. Ross; Bowles, Daniel W.] Univ Colorado, Sch Med, Div Med Oncol, Aurora, CO USA. [Bauman, Julie E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Hausman, Diana; Walker, Luke] Oncothyreon Inc, Seattle, WA USA. [Nemunaitis, John] Mary Crowley Canc Res Ctr, Dallas, TX USA. [Rudin, Charles M.] Johns Hopkins Univ, Baltimore, MD USA. [Rudin, Charles M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Halmos, Balazs] Columbia Univ, Med Ctr, New York Presbyterian Hosp, New York, NY USA. [Bowles, Daniel W.] Denver Vet Affairs Med Ctr, Sect Hematol Oncol, Denver, CO USA. RP Levy, B (reprint author), Mt Sinai Hlth Syst, Beth Israel Comprehens Canc Ctr, Albert Einstein Coll Med, 325 W 15th St, New York, NY 10011 USA. EM belevy@chpnet.org OI Rudin, Charles/0000-0001-5204-3465; Becker, Daniel/0000-0001-7230-8432 FU Eli Lilly; Genentech; Pfizer; Oncothyreon; Bristol-Myers Squibb; Lilly; Aveo; Daiichi-Sankyo; Merck; Astra-Zeneca; Boehringer-Ingelheim; Astex; Roche; Novartis FX Disclosure: Dr. Levy serves as a paid consultant and receives payments for lectures from Eli Lilly, Genentech, and Pfizer. Dr. Evans serves as a paid consultant for Eli Lilly and Genentech. Dr. Bauman received grant support from Oncothyreon, Bristol-Myers Squibb, Genentech, and Lilly, and is a paid consultant for Aveo. Drs. Walker and Hausman are full time employees of Oncothyreon. Dr. Walker has received travel support to meetings for the study as well as travel unrelated to the study. Dr. Rudin was a past consultant for Celgene. Dr. Halmos has received grant support from Oncothyreon, Pfizer, Daiichi-Sankyo, Eli Lilly, Bristol-Myers Squibb, Merck, Astra-Zeneca, Boehringer-Ingelheim, Astex, Roche, and Novartis. The other authors declare no conflict of interest. NR 14 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2014 VL 9 IS 7 BP 1031 EP 1035 DI 10.1097/JTO.0000000000000183 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AJ9JK UT WOS:000338025600024 PM 24926548 ER PT J AU Oser, MG Janne, PA AF Oser, Matthew G. Jaenne, Pasi A. TI A Severe Photosensitivity Dermatitis Caused by Crizotinib SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article ID LUNG-CANCER C1 [Oser, Matthew G.; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Oser, Matthew G.; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,HIM 223, Boston, MA 02215 USA. EM pjanne@partners.org FU Pfizer; Chugai Oncology FX Disclosure: P.A.J. has received consulting fees from Pfizer and Chugai Oncology. M.G.O. declares no conflict of interest. NR 5 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2014 VL 9 IS 7 BP E51 EP E53 DI 10.1097/JTO.0000000000000163 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AJ9JK UT WOS:000338025600002 PM 24926554 ER PT J AU Matsumura, JS Melissano, G Cambria, RP Dake, MD Mehta, S Svensson, LG Moore, RD AF Matsumura, Jon S. Melissano, Germano Cambria, Richard P. Dake, Michael D. Mehta, Shraddha Svensson, Lars G. Moore, Randy D. CA Zenith TX2 Clinical Trial Investig TI Five-year results of thoracic endovascular aortic repair with the Zenith TX2 SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID ANEURYSM REPAIR; TRIAL; GRAFT AB Background: This trial evaluated thoracic endovascular aortic repair (TEVAR) compared with open surgical repair of descending thoracic aortic aneurysms and large ulcers at 42 international sites. Whereas several studies demonstrate early safety and utility advantages with TEVAR, longer follow-up is important because of concerns about durability of TEVAR. Methods: This prospective, nonrandomized study enrolled 160 TEVAR patients treated with the Cook Zenith TX2 and 70 open surgical repair patients. Results: Although follow-up was limited, 5-year mortality rate was similar at 37% for both groups. Aneurysm-related mortality rate was 5.9% with TEVAR compared with 12% with open surgical repair (P =.11). There were no ruptures of the treated aneurysms in either group or open conversions in the TEVAR group. Predefined severe morbidity occurred at a significantly lower rate in TEVAR (21%) compared with open surgical repair (39%; P <.001). Aneurysm growth was seen by core laboratory in 5.9% of patients and endoleak in 5.7% of patients. Secondary intervention rates were similar between TEVAR (8%) and open surgical repair (12%; P = .49) patients. Conclusions: Five-year results indicate similar all-cause mortality and aneurysm-related mortality with TEVAR compared with open repair. There was a persistent reduction of severe complications with TEVAR. Reinterventions occurred with similar frequency. TEVAR with the TX2 is a safe and effective alternative to open surgical repair for the treatment of anatomically suitable descending thoracic aortic aneurysms and ulcers. C1 [Matsumura, Jon S.] Univ Wisconsin, Madison, WI USA. [Melissano, Germano] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Milan, Italy. [Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dake, Michael D.] Stanford Univ, Palo Alto, CA 94304 USA. [Mehta, Shraddha] MED Inst Inc, W Lafayette, IN USA. [Svensson, Lars G.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Moore, Randy D.] Univ Calgary, Calgary, AB, Canada. RP Matsumura, JS (reprint author), G5 325 Clin Sci Ctr, 600 Highland Ave, Madison, WI 53792 USA. EM ellis@surgery.wisc.edu NR 15 TC 21 Z9 21 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUL PY 2014 VL 60 IS 1 BP 1 EP 10 DI 10.1016/j.jvs.2014.01.043 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AK5FG UT WOS:000338449500001 PM 24636714 ER PT J AU Walker, JP Hiramoto, JS Gasper, WJ Auyang, P Conte, MS Rapp, JH Lovett, DH Owens, CD AF Walker, Joy P. Hiramoto, Jade S. Gasper, Warren J. Auyang, Philip Conte, Michael S. Rapp, Joseph H. Lovett, David H. Owens, Christopher D. TI Vitamin D deficiency is associated with mortality and adverse vascular access outcomes in patients with end-stage renal disease SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Vascular Annual Meeting of the Society-for-Vascular-Surgery (SVS) CY MAY 29-JUN 01, 2013 CL San Francisco, CA SP Soc Vasc Surg ID CHRONIC KIDNEY-DISEASE; HEMODIALYSIS-PATIENTS; MINERAL METABOLISM; CARDIOVASCULAR-DISEASE; ENDOTHELIAL FUNCTION; UNITED-STATES; DATA SYSTEM; INFLAMMATION; SUPPLEMENTATION; IMPACT AB Background: Plasma 25 hydroxycholecalciferol (vitamin D) deficiency has been associated with adverse cardiovascular outcomes in epidemiologic studies. Chronic kidney disease is associated with loss of 1 alpha-hydroxylase and consequently vitamin D deficiency. We hypothesized that vitamin D deficiency was associated with increased mortality and increased vascular access failure in patients undergoing permanent vascular access for end-stage renal disease. Methods: This retrospective cohort study analyzed 128 patients undergoing permanent vascular access surgery between 2003 and 2012 for whom concurrent plasma vitamin D levels were also available. Levels were considered deficient at < 20 ng/mL. Multivariable analysis was used to determine the association between vitamin D and mortality and vascular access outcomes. Results: The mean age was 66.7 years, 96.8% were male, 32.0% were African American, and 60.9% had diabetes mellitus. In the entire cohort, 55.5% were vitamin D-deficient, despite similar rates of repletion among the vitamin D-deficient and nondeficient groups. During a median follow-up of 2.73 years, there were 40 deaths (31%). Vitamin D-deficient patients tended to be younger (P = .01) and to have higher total cholesterol (P = .001) and lower albumin (P = .017) and calcium (P = .007) levels. Despite their younger age, mortality was significantly higher (P = .026) and vascular access failure was increased (P = .008) in the vitamin D-deficient group. Multivariate logistic regression analysis found vitamin Ddeficiency (odds ratio [OR], 3.64; 95% confidence interval [CI], 1.12-11.79; P = .031), hemodialysis through a central catheter (OR, 3.08; 95% CI, 1.04-9.12; P = .042), coronary artery disease (OR, 3.08; 95% CI, 1.06-8.94; P = .039), increased age (OR, 1.09; 95% CI, 1.03-1.15; P = .001), and albumin (OR, 0.27; 95% CI, 0.09-0.83; P = .023) remained independent predictors of mortality. Vitamin D deficiency (hazard ratio [HR], 2.34; 95% CI, 1.17-4.71; P = .02), a synthetic graft (HR, 3.50; 95% CI, 1.38-8.89; P = .009), and hyperlipidemia (HR, 0.42; 95% CI, 0.22-0.81; P = .01) were independent predictors of vascular access failure in a Cox proportional hazard model. Conclusions: Vitamin D deficiency is highly prevalent in patients undergoing vascular access procedures. Patients who are deficient in vitamin D have worse survival and worse vascular access outcomes. Further study is warranted to assess whether aggressive vitamin D repletion will improve outcomes in this population. C1 [Walker, Joy P.; Hiramoto, Jade S.; Gasper, Warren J.; Conte, Michael S.; Rapp, Joseph H.; Owens, Christopher D.] Univ Calif San Francisco, Dept Vasc & Endovasc Surg, San Francisco, CA 94143 USA. [Auyang, Philip] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Lovett, David H.] San Francisco Vet Adm Med Ctr, Dept Vasc Surg, San Francisco, CA USA. RP Walker, JP (reprint author), 513 Parnassus Ave,S-321, San Francisco, CA 94127 USA. EM joy.walker@ucsfmedctr.org FU NHLBI NIH HHS [K23 HL092163, K23 HL-92163]; NIDDK NIH HHS [T32 DK007219] NR 41 TC 3 Z9 3 U1 0 U2 4 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 2014 VL 60 IS 1 BP 176 EP 183 DI 10.1016/j.jvs.2014.01.037 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AK5FG UT WOS:000338449500031 PM 24582700 ER PT J AU Graham, BM Milad, MR AF Graham, Bronwyn M. Milad, Mohammed R. TI Inhibition of estradiol synthesis impairs fear extinction in male rats SO LEARNING & MEMORY LA English DT Article ID ESTROGEN-RECEPTOR-BETA; POSTTRAUMATIC-STRESS; AROMATASE-ACTIVITY; PREFRONTAL CORTEX; FEMALE RATS; BRAIN; WOMEN; MEMORY; NEUROSCIENCE; DISORDERS AB Emerging research has demonstrated that the sex hormone estradiol regulates fear extinction in female rodents and women. Estradiol may also regulate fear extinction in males, given its role in synaptic plasticity in both sexes. Here we report that inhibition of estradiol synthesis during extinction training, via the aromatase inhibitor fadrozole, significantly impairs extinction recall in male rats. This deficit in extinction recall is not due to state-dependent memory formation and is completely abolished by coadministration of estradiol. Our data suggest that estradiol may be just as important in the regulation of fear extinction in males as it is in females. C1 [Graham, Bronwyn M.; Milad, Mohammed R.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Graham, Bronwyn M.; Milad, Mohammed R.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Milad, MR (reprint author), Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM milad@nmr.mgh.harvard.edu FU National Institute of Mental Health (NIMH) [R01MH097880-01]; Department of Psychiatry at Massachusetts General Hospital FX This work was supported by the National Institute of Mental Health (NIMH) grant R01MH097880-01 and funds from the Department of Psychiatry at Massachusetts General Hospital to M.R.M. We thank members of the Milad laboratory for helpful comments on earlier versions of the manuscript. NR 28 TC 16 Z9 16 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 EI 1549-5485 J9 LEARN MEMORY JI Learn. Mem. PD JUL PY 2014 VL 21 IS 7 BP 347 EP 350 DI 10.1101/lm.034926.114 PG 4 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AK5ZT UT WOS:000338507100004 PM 24939838 ER PT J AU Tirumani, H Ramaiya, NH Weinblatt, ME Leibner, HA Creager, MA LaCasce, AS AF Tirumani, Harsha Ramaiya, Nikhil H. Weinblatt, Michael E. Leibner, Helen A. Creager, Mark A. LaCasce, Ann S. TI Large vessel vasculopathy in Epstein-Barr virus-positive diffuse large B-cell lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Letter ID EARLY MANIFESTATION; SJOGRENS-SYNDROME; VASCULITIS C1 [Tirumani, Harsha; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [LaCasce, Ann S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lymphoma Program, Boston, MA 02215 USA. [Tirumani, Harsha; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Weinblatt, Michael E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02215 USA. [Creager, Mark A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02215 USA. [Leibner, Helen A.] Brigham Internal Med Associates, Boston, MA USA. RP Tirumani, H (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM stirumani@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUL PY 2014 VL 55 IS 7 BP 1654 EP 1656 DI 10.3109/10428194.2013.842987 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA AK1SL UT WOS:000338196200035 ER PT J AU Ramesh, N Massaad, MJ Kumar, L Koduru, S Sasahara, Y Anton, I Bhasin, M Libermann, T Geha, R AF Ramesh, Narayanaswamy Massaad, Michel J. Kumar, Lalit Koduru, Suresh Sasahara, Yoji Anton, Ines Bhasin, Manoj Libermann, Towia Geha, Raif TI Binding of the WASP/N-WASP-Interacting Protein WIP to Actin Regulates Focal Adhesion Assembly and Adhesion SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SERUM RESPONSE FACTOR; ALDRICH-SYNDROME PROTEIN; N-WASP; CELLS; DYNAMICS; POLYMERIZATION; CYTOSKELETON; KINASE; METASTASIS; ACTIVATION AB The actin cytoskeleton is essential for cell adhesion and migration, functions important for tumor invasion. In addition to binding N-WASP/WASP, WIP binds and stabilizes F-actin. WIP-/- fibroblasts were used to test the role of WIP in F-actin function. WIP-/- cells had defective focal adhesion (FA), stress fiber assembly, and adherence to substrates, functions that were restored by transduction of wild-type WIP. Protein and mRNA levels of several FA constituents regulated by the myocardin-related transcription factor (MRTF)-serum response factor (SRF) transcription factor complex were reduced in WIP-/- fibroblasts. The level of G-actin, which sequesters MRTF in the cytoplasm, was increased, and nuclear localization of MRTF-A and SRF was reduced, in WIP-/- fibroblasts. Transfection of an MRTF-A mutant that constitutively translocates to the nucleus or transfection of constitutively active SRF restored FA and stress fiber assembly. Fibroblasts from knock-in mice expressing a WIP mutant that fails to bind actin phenocopied WIP-/- fibroblasts. Thus, WIP is a novel regulator of FA assembly and cell adhesion. C1 [Ramesh, Narayanaswamy; Massaad, Michel J.; Kumar, Lalit; Koduru, Suresh; Geha, Raif] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Ramesh, Narayanaswamy; Massaad, Michel J.; Kumar, Lalit; Koduru, Suresh; Geha, Raif] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Sasahara, Yoji] Tohoku Univ, Grad Sch Med, Dept Pediat, Sendai, Miyagi 980, Japan. [Anton, Ines] CSIC, CNB, Madrid, Spain. [Bhasin, Manoj; Libermann, Towia] Beth Israel Deaconess Med Ctr, BIDMC Genom & Prote Ctr, Boston, MA 02215 USA. [Bhasin, Manoj; Libermann, Towia] Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Boston, MA 02215 USA. [Bhasin, Manoj; Libermann, Towia] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Geha, R (reprint author), Childrens Hosp, Div Immunol, 300 Longwood Ave, Boston, MA 02115 USA. EM narayanaswamy.ramesh@childrens.harvard.edu; raif.geha@childrens.harvard.edu RI Anton, Ines/G-6090-2015; OI Libermann, Towia/0000-0002-4006-8179 FU USPHS [HL-059561] FX We thank Richard Treisman for generously providing MRTF, MRTFxxx, and SRF-VP16 plasmids. We thank Pallavi Banerjee for her help. This work was supported by USPHS grant HL-059561. NR 60 TC 6 Z9 6 U1 0 U2 5 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 2014 VL 34 IS 14 BP 2600 EP 2610 DI 10.1128/MCB.00017-14 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AK5BV UT WOS:000338439800004 PM 24797074 ER PT J AU Kiem, HP Baum, C Bushman, FD Byrne, BJ Carter, BJ Cavagnaro, J Malech, HL Mendell, JR Naldini, LM Sorrentino, BP Williams, DA Flotte, TR AF Kiem, Hans-Peter Baum, Christopher Bushman, Frederic D. Byrne, Barry J. Carter, Barrie J. Cavagnaro, Joy Malech, Harry L. Mendell, Jerry R. Naldini, Luigi M. Sorrentino, Brian P. Williams, David A. Flotte, Terence R. TI Charting a Clear Path: The ASGCT Standardized Pathways Conference SO MOLECULAR THERAPY LA English DT News Item ID SEVERE COMBINED IMMUNODEFICIENCY; RETROVIRAL VECTOR DESIGN; GENE-THERAPY; BIODISTRIBUTION; ACTIVATION; DISEASE C1 [Kiem, Hans-Peter] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98104 USA. [Kiem, Hans-Peter] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Baum, Christopher] Hannover Med Sch, Dept Expt Hematol, Hannover, Germany. [Bushman, Frederic D.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Byrne, Barry J.] Univ Florida, Coll Med, Dept Pediat, Div Cellular & Mol Therapy, Gainesville, FL USA. [Byrne, Barry J.] Univ Florida, Coll Med, Dept Pediat, Div Pediat, Gainesville, FL USA. [Byrne, Barry J.] Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL USA. [Carter, Barrie J.] BioMarin Pharmaceut, San Rafael, CA USA. [Cavagnaro, Joy] Access BIO, Boyce, VA USA. [Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Mendell, Jerry R.] Nationwide Childrens Hosp, Paul D Wellstone Ctr, Columbus, OH USA. [Naldini, Luigi M.] San Raffaele Telethon Inst Gene Therapy TIGET, San Raffaele Sci Inst, Div Regenerat Med Stem Cells & Gene Therapy, Milan, Italy. [Sorrentino, Brian P.] St Jude Childrens Res Hosp, Dept Hematol, Div Expt Hematol, Memphis, TN 38105 USA. [Williams, David A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. [Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA USA. [Flotte, Terence R.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. RP Kiem, HP (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,Mail Stop D1-100, Seattle, WA 98109 USA. EM hkiem@fhcrc.org OI Malech, Harry/0000-0001-5874-5775 FU NIDDK NIH HHS [R01 DK098252] NR 16 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JUL PY 2014 VL 22 IS 7 BP 1235 EP 1238 DI 10.1038/mt.2014.95 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AK1QH UT WOS:000338189800002 PM 24981438 ER PT J AU Tang, YJ Gholamin, S Schubert, S Willardson, MI Lee, A Bandopadhayay, P Bergthold, L Masoud, S Nguyen, B Vue, N Balansay, B Yu, FR Oh, S Woo, P Chen, S Ponnuswami, A Monje, M Atwood, SX Whitson, RJ Mitra, S Cheshier, SH Qi, J Beroukhim, R Tang, JY Wechsler-Reya, R Oro, AE Link, BA Bradner, JE Cho, YJ AF Tang, Yujie Gholamin, Sharareh Schubert, Simone Willardson, Minde I. Lee, Alex Bandopadhayay, Pratiti Bergthold, Guillame Masoud, Sabran Nguyen, Brian Vue, Nujsaubnusi Balansay, Brianna Yu, Furong Oh, Sekyung Woo, Pamelyn Chen, Spenser Ponnuswami, Anitha Monje, Michelle Atwood, Scott X. Whitson, Ramon J. Mitra, Siddhartha Cheshier, Samuel H. Qi, Jun Beroukhim, Rameen Tang, Jean Y. Wechsler-Reya, Rob Oro, Anthony E. Link, Brian A. Bradner, James E. Cho, Yoon-Jae TI Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition SO NATURE MEDICINE LA English DT Article ID BASAL-CELL CARCINOMA; SONIC-HEDGEHOG; PATCHED GENE; PROTEIN BRD4; SELECTIVE-INHIBITION; NEURONAL PRECURSORS; SUPER-ENHANCERS; HUMAN GLI2; P-TEFB; MEDULLOBLASTOMA AB Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GM and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists. C1 [Tang, Yujie; Schubert, Simone; Masoud, Sabran; Nguyen, Brian; Vue, Nujsaubnusi; Balansay, Brianna; Yu, Furong; Oh, Sekyung; Woo, Pamelyn; Chen, Spenser; Ponnuswami, Anitha; Monje, Michelle; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Tang, Yujie; Gholamin, Sharareh; Schubert, Simone; Yu, Furong; Oh, Sekyung; Mitra, Siddhartha; Cheshier, Samuel H.; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Willardson, Minde I.; Link, Brian A.] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. [Lee, Alex; Atwood, Scott X.; Whitson, Ramon J.; Tang, Jean Y.; Oro, Anthony E.] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA. [Bandopadhayay, Pratiti; Bergthold, Guillame; Beroukhim, Rameen; Bradner, James E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bandopadhayay, Pratiti; Bergthold, Guillame] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bandopadhayay, Pratiti; Bergthold, Guillame] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Bandopadhayay, Pratiti; Beroukhim, Rameen; Bradner, James E.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Qi, Jun; Beroukhim, Rameen; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wechsler-Reya, Rob] Sanford Burnham Med Res, La Jolla, CA USA. [Cho, Yoon-Jae] Stanford Univ, Med Ctr, Stanford Canc Inst, Stanford, CA 94305 USA. RP Cho, YJ (reprint author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. EM yjcho1@stanford.edu OI Oh, Sekyung/0000-0002-6880-5281 FU St. Baldrick's Foundation Scholar Award; Beirne Faculty Scholar Endowment; US National Institutes of Health (NIH) [U01-CA176287]; Alex's Lemonade Stand Foundation Young Investigator Award; Damon-Runyon Cancer Research Foundation; NIH [R01-CA159859]; pilot project grant from the Medical College of Wisconsin Cancer Center-Advancing a Healthier Wisconsin; California Institute of Regenerative Medicine [LA1-01747] FX This work was supported the St. Baldrick's Foundation Scholar Award (Y.-J.C.), a Beirne Faculty Scholar Endowment (Y.-J.C.), US National Institutes of Health (NIH) grant U01-CA176287 (Y.-J.C.), an Alex's Lemonade Stand Foundation Young Investigator Award (Y.T.), the Damon-Runyon Cancer Research Foundation (J.Q. and J.E.B.), NIH R01-CA159859 (R.W.-R.) and a pilot project grant from the Medical College of Wisconsin Cancer Center-Advancing a Healthier Wisconsin (B.A.L.). R.W.-R. is the recipient of a Leadership Award (LA1-01747) from the California Institute of Regenerative Medicine. We thank the Stanford Functional Genomics Facility (SFGF) and the Protein and Nucleic Acid (PAN) facility for their assistance in generating gene expression microarray data and reagents. We thank M. Scott (Stanford), C. Rudin (Memorial Sloan-Kettering Cancer Center), P. Beachy (Stanford), A. Sweet-Cordero (Stanford), P.-T. Chang (University of California, San Francisco), R. Karlstrom (University of Massachusetts, Amherst) and J.K. Chen (Stanford) for reagents, helpful suggestions and/or critical reading of the manuscript. NR 60 TC 72 Z9 72 U1 5 U2 27 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 2014 VL 20 IS 7 BP 732 EP 740 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AK8PF UT WOS:000338689500015 PM 24973920 ER PT J AU Ludwig, LS Gazda, HT Eng, JC Eichhorn, SW Thiru, P Ghazvinian, R George, TI Gotlib, JR Beggs, AH Sieff, CA Lodish, HF Lander, ES Sankaran, VG AF Ludwig, Leif S. Gazda, Hanna T. Eng, Jennifer C. Eichhorn, Stephen W. Thiru, Prathapan Ghazvinian, Roxanne George, Tracy I. Gotlib, Jason R. Beggs, Alan H. Sieff, Colin A. Lodish, Harvey F. Lander, Eric S. Sankaran, Vijay G. TI Altered translation of GATA1 in Diamond-Blackfan anemia SO NATURE MEDICINE LA English DT Article ID MESSENGER-RNA TRANSLATION; RIBOSOMAL-PROTEIN S19; HUMAN ERYTHROBLASTS; MAMMALIAN-CELLS; BONE-MARROW; GENE; ERYTHROPOIESIS; DEFICIENCY; INITIATION; EXPRESSION AB Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA)1,2, congenital asplenia(3) and T cell leukemwia(4). Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown(5). Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease. C1 [Ludwig, Leif S.; Sieff, Colin A.; Sankaran, Vijay G.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol & Oncol, Boston, MA 02115 USA. [Ludwig, Leif S.; Sieff, Colin A.; Sankaran, Vijay G.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Ludwig, Leif S.; Eng, Jennifer C.; Eichhorn, Stephen W.; Thiru, Prathapan; Lodish, Harvey F.; Sankaran, Vijay G.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Ludwig, Leif S.; Gazda, Hanna T.; Eng, Jennifer C.; Lodish, Harvey F.; Lander, Eric S.; Sankaran, Vijay G.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Ludwig, Leif S.] Free Univ Berlin, Inst Chem & Biochem, Berlin, Germany. [Ludwig, Leif S.] Charite, D-13353 Berlin, Germany. [Gazda, Hanna T.; Ghazvinian, Roxanne; Beggs, Alan H.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA USA. [Gazda, Hanna T.; Beggs, Alan H.; Sieff, Colin A.; Sankaran, Vijay G.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Eichhorn, Stephen W.; Lodish, Harvey F.; Lander, Eric S.] MIT, Dept Biol, Cambridge, MA USA. [George, Tracy I.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Gotlib, Jason R.] Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol & Oncol, Boston, MA 02115 USA. EM sankaran@broadinstitute.org OI Beggs, Alan/0000-0001-8818-0568; Ludwig, Leif/0000-0002-2916-2164 FU German National Academic Foundation; US National Institutes of Health (NIH) [R01 HL107558, K02 HL111156]; DBA Foundation; NIH [P01 HL32262, U54 HG003067-09, R21 HL120791-01]; March of Dimes Basil O'Connor Scholar Award FX We are grateful to the patients with DBA and their families for their inspiration and encouragement. We thank A. Wakabayashi and J. Ulirsch for valuable assistance and D.G. Nathan, S.H. Orkin, D.A. Williams, S.T. Chou, G.W. Bell, C.R. Walkley, J. Flygare and D.P. Bartel for valuable comments and advice. We are grateful to L. Solomon, L. Gaffney and T. DiCesare for assistance with illustrations. This work was supported by the German National Academic Foundation (to L.S.L.), US National Institutes of Health (NIH) grants R01 HL107558 and K02 HL111156 and a grant from the DBA Foundation (to H.T.G.), NIH grant P01 HL32262 (to H.F.L.), NIH grant U54 HG003067-09 (to E.S.L.) and NIH grant R21 HL120791-01 and a March of Dimes Basil O'Connor Scholar Award (to V.G.S.). NR 40 TC 47 Z9 49 U1 0 U2 8 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 2014 VL 20 IS 7 BP 748 EP 753 DI 10.1038/nm.3557 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AK8PF UT WOS:000338689500017 PM 24952648 ER PT J AU Heidt, T Sager, HB Courties, G Dutta, P Iwamoto, Y Zaltsman, A von zur Muhlen, C Bode, C Fricchione, GL Denninger, J Lin, CP Vinegoni, C Libby, P Swirski, FK Weissleder, R Nahrendorf, M AF Heidt, Timo Sager, Hendrik B. Courties, Gabriel Dutta, Partha Iwamoto, Yoshiko Zaltsman, Alex von zur Muhlen, Constantin Bode, Christoph Fricchione, Gregory L. Denninger, John Lin, Charles P. Vinegoni, Claudio Libby, Peter Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias TI Chronic variable stress activates hematopoietic stem cells SO NATURE MEDICINE LA English DT Article ID BONE-MARROW NICHE; MYOCARDIAL-INFARCTION; PROGENITOR CELLS; SOCIAL STRESS; IN-VIVO; ATHEROSCLEROSIS; MICE; MYELOPOIESIS; REGENERATION; REPOPULATION AB Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis(1,2). Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex(3,4). It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the beta(3)-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans. C1 [Heidt, Timo; Sager, Hendrik B.; Courties, Gabriel; Dutta, Partha; Iwamoto, Yoshiko; Zaltsman, Alex; Lin, Charles P.; Vinegoni, Claudio; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Heidt, Timo; Sager, Hendrik B.; Courties, Gabriel; Dutta, Partha; Iwamoto, Yoshiko; Zaltsman, Alex; Lin, Charles P.; Vinegoni, Claudio; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA USA. [von zur Muhlen, Constantin; Bode, Christoph] Univ Heart Ctr, Dept Cardiol & Angiol 1, Freiburg, Germany. [Fricchione, Gregory L.; Denninger, John] Massachusetts Gen Hosp, Div Psychiat & Med, Boston, MA 02114 USA. [Fricchione, Gregory L.; Denninger, John] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. [Libby, Peter] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu FU US National Institutes of Health [R01-HL117829, R01-HL096576]; Deutsche Forschungsgemeinschaft [HE-6382/1-1, SA1668/2-1]; [HHSN268201000044C] FX We thank the team at the Center for Systems Biology Mouse Imaging Program, especially J. Truelove and D. Jeon, for help with imaging, M. Stein, I. Neudorfer and F. Meixner for help with the clinical study and L. Prickett-Rice, K. Folz-Donahue, M. Weglarz, M. Waring and A. Chicoine for assistance with cell sorting. We thank P. Frenette (Albert Einstein College of Medicine) and B. Lowell (Beth Israel Deaconess Medical Center) for providing Adrb3-/- mice and G. Enikolopov (Cold Spring Harbor Laboratory) for providing nestin-GFP mice. We thank the ICU team at the University Hospital Freiburg, Germany. This work was funded in part by US National Institutes of Health grants R01-HL114477, R01-HL117829 and R01-HL096576 (to M.N.) and grant HHSN268201000044C (to R.W.). T.H. and H.B.S. are funded by the Deutsche Forschungsgemeinschaft (HE-6382/1-1 to T.H. and SA1668/2-1 to H.B.S.). NR 40 TC 92 Z9 92 U1 3 U2 36 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 2014 VL 20 IS 7 BP 754 EP 758 DI 10.1038/nm.3589 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AK8PF UT WOS:000338689500018 PM 24952646 ER PT J AU Berendsen, TA Bruinsma, BG Puts, CF Saeidi, N Usta, OB Uygun, BE Izamis, ML Toner, M Yarmush, ML Uygun, K AF Berendsen, Tim A. Bruinsma, Bote G. Puts, Catheleyne F. Saeidi, Nima Usta, O. Berk Uygun, Basak E. Izamis, Maria-Louisa Toner, Mehmet Yarmush, Martin L. Uygun, Korkut TI Supercooling enables long-term transplantation survival following 4 days of liver preservation SO NATURE MEDICINE LA English DT Article ID SUBNORMOTHERMIC MACHINE PERFUSION; COLD-STORAGE; UW SOLUTION; RAT-LIVER; CRYOPRESERVATION; GRAFTS; VITRIFICATION; RECOVERY; IMPROVES AB The realization of long-term human organ preservation will have groundbreaking effects on the current practice of transplantation. Herein we present a new technique based on subzero nonfreezing preservation and extracorporeal machine perfusion that allows transplantation of rat livers preserved for up to four days, thereby tripling the viable preservation duration. C1 [Berendsen, Tim A.; Bruinsma, Bote G.; Puts, Catheleyne F.; Saeidi, Nima; Usta, O. Berk; Uygun, Basak E.; Izamis, Maria-Louisa; Toner, Mehmet; Yarmush, Martin L.; Uygun, Korkut] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02163 USA. [Berendsen, Tim A.] Univ Med Ctr, Dept Surg, Utrecht, Netherlands. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Uygun, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02163 USA. EM myarmush@mgh.harvard.edu; uygun.korkut@mgh.harvard.edu RI USTA, O. Berk/A-5818-2008; Uygun, Basak/I-1792-2012 OI USTA, O. Berk/0000-0001-9328-568X; Uygun, Basak/0000-0002-2600-7900 FU US National Institutes of Health [R0IEB008678, R0IDK096075, R01DK084053, R00DK080942, R00DK088962, F32 DK095558]; Shriners Hospitals for Children FX Funding from the US National Institutes of Health (grants R0IEB008678, R0IDK096075, R01DK084053, R00DK080942, R00DK088962 and F32 DK095558) and the Shriners Hospitals for Children is gratefully acknowledged. NR 40 TC 22 Z9 24 U1 1 U2 12 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 2014 VL 20 IS 7 BP 790 EP 793 DI 10.1038/nm.3588 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AK8PF UT WOS:000338689500024 PM 24973919 ER PT J AU Kharchenko, PV Silberstein, L Scadden, DT AF Kharchenko, Peter V. Silberstein, Lev Scadden, David T. TI Bayesian approach to single-cell differential expression analysis SO NATURE METHODS LA English DT Article ID MESSENGER-RNA-SEQ; GENE-EXPRESSION; NOISE AB Single-cell data provide a means to dissect the composition of complex tissues and specialized cellular environments. However, the analysis of such measurements is complicated by high levels of technical noise and intrinsic biological variability. We describe a probabilistic model of expression-magnitude distortions typical of single-cell RNA-sequencing measurements, which enables detection of differential expression signatures and identification of subpopulations of cells in a way that is more tolerant of noise. C1 [Kharchenko, Peter V.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Kharchenko, Peter V.] Childrens Hosp, Hematol Oncol Program, Boston, MA 02115 USA. [Kharchenko, Peter V.; Silberstein, Lev; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA USA. [Silberstein, Lev; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Silberstein, Lev; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Kharchenko, PV (reprint author), Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. EM peter.kharchenko@post.harvard.edu FU US National Institutes of Health (NIH) [K25AG037596]; Leukemia and Lymphoma Research UK and Leukemia and Lymphoma Society; NIH [R01DK050234-15A1, R01HL097794-03] FX We thank X. Wang (Harvard Medical School) for help with packaging the implementation and F. Ferrari (Harvard Medical School) and M.B. Johnson (Children's Hospital, Boston) for critical review of the manuscript and SCDE implementation. This work was supported by US National Institutes of Health (NIH) grant K25AG037596 to P.V.K., fellowship awards from Leukemia and Lymphoma Research UK and Leukemia and Lymphoma Society to L.S. and NIH grants R01DK050234-15A1 and R01HL097794-03 to D.T.S. NR 23 TC 82 Z9 84 U1 8 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD JUL PY 2014 VL 11 IS 7 BP 740 EP U184 DI 10.1038/NMETH.2967 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AK3KE UT WOS:000338321400018 PM 24836921 ER PT J AU Fenno, LE Mattis, J Ramakrishnan, C Hyun, M Lee, SY He, M Tucciarone, J Selimbeyoglu, A Berndt, A Grosenick, L Zalocusky, KA Bernstein, H Swanson, H Perry, C Diester, I Boyce, FM Bass, CE Neve, R Huang, ZJ Deisseroth, K AF Fenno, Lief E. Mattis, Joanna Ramakrishnan, Charu Hyun, Minsuk Lee, Soo Yeun He, Miao Tucciarone, Jason Selimbeyoglu, Aslihan Berndt, Andre Grosenick, Logan Zalocusky, Kelly A. Bernstein, Hannah Swanson, Haley Perry, Chelsey Diester, Ilka Boyce, Frederick M. Bass, Caroline E. Neve, Rachael Huang, Z. Josh Deisseroth, Karl TI Targeting cells with single vectors using multiple-feature Boolean logic SO NATURE METHODS LA English DT Article ID IN-VIVO; EXPRESSION CASSETTES; MAMMALIAN-CELLS; GENE-EXPRESSION; NEURAL CIRCUITS; NEURONS; BRAIN; RECOMBINATION; HIPPOCAMPUS; AREA AB Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology. C1 [Fenno, Lief E.; Mattis, Joanna; He, Miao; Selimbeyoglu, Aslihan] Stanford Univ, Dept Neurosci, Stanford, CA 94305 USA. [Fenno, Lief E.; Mattis, Joanna; Ramakrishnan, Charu; Hyun, Minsuk; Lee, Soo Yeun; Berndt, Andre; Grosenick, Logan; Diester, Ilka; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Lee, Soo Yeun; Zalocusky, Kelly A.; Swanson, Haley; Perry, Chelsey] Stanford Univ, CNC Program, Stanford, CA 94305 USA. [He, Miao; Tucciarone, Jason; Huang, Z. Josh] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Tucciarone, Jason] SUNY Stony Brook, 5Program Neurosci, Stony Brook, NY 11794 USA. [Bernstein, Hannah] NYU, Sch Med, Dept Neurosci & Physiol, New York, NY USA. [Diester, Ilka] Ernst Struengmann Inst Neurosci, Frankfurt, Germany. [Boyce, Frederick M.] Massachusetts Gen Hosp, Dept Neurol, Cambridge, MA USA. [Bass, Caroline E.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Pharmacol & Toxicol, Buffalo, NY 14260 USA. [Neve, Rachael] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Deisseroth, Karl] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Deisseroth, K (reprint author), Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. EM deissero@stanford.edu OI Ramakrishnan, Charu/0000-0002-3474-6332; Huang, Z. Josh/0000-0003-0592-028X; Bass, Caroline/0000-0002-5856-6387 FU US National Institutes of Health [NINDS P30 NS069375-01A1]; Stanford Medical Scientist Training Program (MSTP); Stanford Bio-X Fellowship; Samsung Scholarship; Robertson Neuroscience Fund of Cold Spring Harbor Laboratory; Stony Brook University MSTP; Howard Hughes Medical Institute International Student Fellowship; National Science Foundation (NSF) [0801700]; NSF Graduate Research Fellowship Program; New York University MSTP; Human Frontiers Science Project and German Academic Exchange Service (DAAD); US National Institute on Drug Abuse (NIDA) [DA024763]; Wiegers Family Fund; US National Institute of Mental Health; NIDA; Defense Advanced Research Projects Agency REPAIR Program; Keck Foundation; McKnight Foundation; Gatsby Charitable Foundation; Snyder Foundation; Woo Foundation; Tarlton Foundation; Albert Yu and Mary Bechman Foundation FX We thank M. Kay (Stanford) for providing the pRC-DJ plasmid used to produce AAV-DJ; M. Bigos at the Stanford Shared FACS Facility for assistance with experiment planning and data analysis; S. Roy for extensive discussions regarding intron function and structure; P. Wu for technical assistance in mouse engineering and characterization; and the entire Deisseroth lab for helpful discussions. The Neuroscience Gene Vector and Virus Core at Stanford is funded in part by US National Institutes of Health grant # NINDS P30 NS069375-01A1. This work is supported by the Stanford Medical Scientist Training Program (MSTP; L.E.F. and J.M.), a Stanford Bio-X Fellowship (J.M. and M. Hyun), the Samsung Scholarship (M. Hyun), the Robertson Neuroscience Fund of Cold Spring Harbor Laboratory (M. He, J.T. and Z.J.H.), the Stony Brook University MSTP (J.T.), a Howard Hughes Medical Institute International Student Fellowship (A.S.), National Science Foundation (NSF) grant 0801700 (L.G.), the NSF Graduate Research Fellowship Program (K.A.Z.), the New York University MSTP (H.B.), the Human Frontiers Science Project and German Academic Exchange Service (DAAD; I.D.), and US National Institute on Drug Abuse (NIDA) DA024763 (C.E.B.). K.D. is supported by the Wiegers Family Fund, US National Institute of Mental Health, NIDA, Defense Advanced Research Projects Agency REPAIR Program, Keck Foundation, McKnight Foundation, Gatsby Charitable Foundation, Snyder Foundation, Woo Foundation, Tarlton Foundation, and Albert Yu and Mary Bechman Foundation. All tools and methods are distributed and supported freely at http://www.optogenetics.org/and Addgene. NR 44 TC 78 Z9 78 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD JUL PY 2014 VL 11 IS 7 BP 763 EP U116 DI 10.1038/NMETH.2996 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AK3KE UT WOS:000338321400022 PM 24908100 ER PT J AU Maurovich-Horvat, P Ferencik, M Voros, S Merkely, B Hoffmann, U AF Maurovich-Horvat, Pal Ferencik, Maros Voros, Szilard Merkely, Bela Hoffmann, Udo TI Comprehensive plaque assessment by coronary CT angiography SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID MULTIDETECTOR COMPUTED-TOMOGRAPHY; FRACTIONAL FLOW RESERVE; NAPKIN-RING SIGN; ENDOTHELIAL SHEAR-STRESS; COMPUTATIONAL FLUID-DYNAMICS; THIN-CAP FIBROATHEROMA; DUAL-SOURCE CT; INTRAVASCULAR-ULTRASOUND; ATHEROSCLEROTIC PLAQUE; MYOCARDIAL-INFARCTION AB Most acute coronary syndromes are caused by sudden luminal thrombosis due to atherosclerotic plaque rupture or erosion. Preventing such an event seems to be the only effective strategy to reduce mortality and morbidity of coronary heart disease. Coronary lesions prone to rupture have a distinct morphology compared with stable plaques, and provide a unique opportunity for noninvasive imaging to identify vulnerable plaques before they lead to clinical events. The submillimeter spatial resolution and excellent image quality of modern computed tomography (CT) scanners allow coronary atherosclerotic lesions to be detected, characterized, and quantified. Large plaque volume, low CT attenuation, napkin-ring sign, positive remodelling, and spotty calcification are all associated with a high risk of acute cardiovascular events in patients. Computation fluid dynamics allow the calculation of lesion-specific endothelial shear stress and fractional flow reserve, which add functional information to plaque assessment using CT. The combination of morphologic and functional characteristics of coronary plaques might enable noninvasive detection of vulnerable plaques in the future. C1 [Maurovich-Horvat, Pal; Merkely, Bela] Semmelweis Univ, Heart & Vasc Ctr, MTA SE Lendulet Cardiovasc Imaging Res Grp, H-1025 Budapest, Hungary. [Ferencik, Maros; Hoffmann, Udo] Harvard Univ, Cardiac MR PET CT Program, Div Cardiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ferencik, Maros; Hoffmann, Udo] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Voros, Szilard] SUNY Stony Brook, Stony Brook, NY 11794 USA. RP Hoffmann, U (reprint author), Harvard Univ, Cardiac MR PET CT Program, Div Cardiol, Massachusetts Gen Hosp, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@mgh.harvard.edu OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU European Union; State of Hungary; European Social Fund in the framework of 'National Excellence Program' [TAMOP 4.2.4. A/1-11-1-2012-0001]; American Heart Association [13FTF16450001] FX P.M-H. acknowledges support from the European Union, State of Hungary, and European Social Fund in the framework of TAMOP 4.2.4. A/1-11-1-2012-0001 'National Excellence Program'. M.F. acknowledges support from the American Heart Association (grant number: 13FTF16450001). NR 128 TC 43 Z9 47 U1 4 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD JUL PY 2014 VL 11 IS 7 BP 390 EP 402 DI 10.1038/nrcardio.2014.60 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AK1LE UT WOS:000338175800004 PM 24755916 ER PT J AU Miyamoto, DT Sequist, LV Lee, RJ AF Miyamoto, David T. Sequist, Lecia V. Lee, Richard J. TI Circulating tumour cells-monitoring treatment response in prostate cancer SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID METASTATIC BREAST-CANCER; BONE METASTASES; PERIPHERAL-BLOOD; MEMBRANE ANTIGEN; EPITHELIAL-CELLS; F-18-FDG PET/CT; CLINICAL-TRIALS; UP-REGULATION; RARE CELLS; END-POINTS AB The availability of new therapeutic options for the treatment of metastatic castration-resistant prostate cancer (mCRPC) has heightened the importance of monitoring and assessing treatment response. Accordingly, there is an unmet clinical need for reliable biomarkers that can be used to guide therapy. Circulating tumour cells (CTCs) are rare cells that are shed from primary and metastatic tumour deposits into the peripheral circulation, and represent a means of performing noninvasive tumour sampling. Indeed, enumeration of CTCs before and after therapy has shown that CTC burden correlates with prognosis in patients with mCRPC. Moreover, studies have demonstrated the potential of molecular analysis of CTCs in monitoring and predicting response to therapy in patients. This Review describes the challenges associated with monitoring treatment response in mCRPC, and the advancements in CTC-analysis technologies applied to such assessments and, ultimately, guiding prostate cancer treatment. C1 [Miyamoto, David T.] Massachusetts Gen Hosp, MGH Canc Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. [Sequist, Lecia V.; Lee, Richard J.] Massachusetts Gen Hosp, MGH Canc Ctr, Dept Med, Boston, MA 02114 USA. RP Miyamoto, DT (reprint author), Massachusetts Gen Hosp, MGH Canc Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. EM dmiyamoto@partners.org FU Department of Defence Prostate Cancer Research Program [W81XWH-09-1-0471, W81XWH-12-1-0153]; Conquer Cancer Foundation; Prostate Cancer Foundation; Mazzone Program/Dana-Farber Harvard Cancer Center; Stand Up To Cancer FX The authors thank S. Maheswaran and D. Haber for reading the manuscript and for helpful discussions before submission. The authors acknowledge research support from the Department of Defence Prostate Cancer Research Program (award W81XWH-09-1-0471 to R.J.L.; award W81XWH-12-1-0153 to D.T.M.), the Conquer Cancer Foundation (Career Development Award to R.J.L.), the Prostate Cancer Foundation (Young Investigator Award to R.J.L.), the Mazzone Program/Dana-Farber Harvard Cancer Center (Career Development Award to D.T.M.), and Stand Up To Cancer (L.V.S.). NR 88 TC 40 Z9 41 U1 0 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD JUL PY 2014 VL 11 IS 7 BP 401 EP 412 DI 10.1038/nrclinonc.2014.82 PG 12 WC Oncology SC Oncology GA AK5QG UT WOS:000338480400004 PM 24821215 ER PT J AU Stolp, J Turka, LA Wood, KJ AF Stolp, Jessica Turka, Laurence A. Wood, Kathryn J. TI B cells with immune-regulating function in transplantation SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; COLLAGEN-INDUCED ARTHRITIS; T-CELLS; B10 CELLS; KIDNEY-TRANSPLANTATION; RENAL-TRANSPLANTATION; OPERATIONAL TOLERANCE; NATURAL ANTIBODY; IL-10 PRODUCTION; DENDRITIC CELLS AB In transplantation, the contribution of B cells to the rejection or acceptance of the allograft is a topic of major interest. The presence of donor-specific antibodies in transplant recipients is often associated with decreased graft function and rejection, clearly indicating a pathogenetic role of B cells in transplantation. However, data from studies in humans and rodents suggest that under certain conditions, B cells have the capacity to control or regulate the immune response to a transplanted organ. Although a great deal of attention has been focused on B cells in human and murine models of autoimmunity, our understanding of the role of these cells in transplantation is limited at present. Indeed, results in this setting are controversial and seem to depend on the model system used or the clinical situation studied. Here, we review the current understanding of the various phenotypes and roles that have been associated with immune-regulating B cells. We also discuss the mechanisms employed by subsets of these regulatory B cells to control the immune response in transplant recipients and in animal models of transplantation. C1 [Stolp, Jessica; Wood, Kathryn J.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg Sci, Transplantat Res Immunol Grp, Oxford OX3 9DU, England. [Turka, Laurence A.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Charlestown, MA 02129 USA. RP Wood, KJ (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg Sci, Transplantat Res Immunol Grp, Oxford OX3 9DU, England. EM kathryn.wood@nds.ox.ac.uk FU Wellcome Trust; UK Medical Research Council; British Heart Foundation; European Union through the ONE Study, Translating Research into Action for Diabetes (TRIAD); Biomarker Driven Personal Immunosuppression (Bio-DRIM); Immune Tolerance Network FX The authors' work is funded by grants from the Wellcome Trust, UK Medical Research Council, British Heart Foundation and European Union through the ONE Study, Translating Research into Action for Diabetes (TRIAD) and Biomarker Driven Personal Immunosuppression (Bio-DRIM) projects, and the Immune Tolerance Network. NR 97 TC 20 Z9 22 U1 3 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD JUL PY 2014 VL 10 IS 7 BP 389 EP 397 DI 10.1038/nrneph.2014.80 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AK5PY UT WOS:000338479500006 PM 24846332 ER PT J AU van Vuurden, DG Aronica, E Hulleman, E Wedekind, LE Biesmans, D Malekzadeh, A Bugiani, M Geerts, D Noske, DP Vandertop, WP Kaspers, GJL Cloos, J Wurdinger, T van der Stoop, PPM AF van Vuurden, Dannis G. Aronica, Eleonora Hulleman, Esther Wedekind, Laurine E. Biesmans, Dennis Malekzadeh, Arjan Bugiani, Marianna Geerts, Dirk Noske, David P. Vandertop, W. Peter Kaspers, Gertjan J. L. Cloos, Jacqueline Wuerdinger, Thomas van der Stoop, Petra P. M. TI Pre-B-cell leukemia homeobox interacting protein 1 is overexpressed in astrocytoma and promotes tumor cell growth and migration SO NEURO-ONCOLOGY LA English DT Article DE astrocyte; astrocytoma; ependymoma; glioma; PBXIP1; progenitor ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; SUBVENTRICULAR ZONE; MALIGNANT GLIOMA; GENE-EXPRESSION; RECEPTOR; EPENDYMOMA; BRAIN; HPIP; DIFFERENTIATION AB Glial brain tumors cause considerable mortality and morbidity in children and adults. Innovative targets for therapy are needed to improve survival and reduce long-term sequelae. The aim of this study was to find a candidate tumor-promoting protein, abundantly expressed in tumor cells but not in normal brain tissues, as a potential target for therapy. In silico proteomics and genomics, immunohistochemistry, and immunofluorescence microscopy validation were performed. RNA interference was used to ascertain the functional role of the overexpressed candidate target protein. In silico proteomics and genomics revealed pre-B-cell leukemia homeobox (PBX) interacting protein 1 (PBXIP1) overexpression in adult and childhood high-grade glioma and ependymoma compared with normal brain. PBXIP1 is a PBX-family interacting microtubule-binding protein with a putative role in migration and proliferation of cancer cells. Immunohistochemical studies in glial tumors validated PBXIP1 expression in astrocytoma and ependymoma but not in oligodendroglioma. RNAi-mediated PBXIP1-knockdown in glioblastoma cell lines strongly reduced proliferation and migration and induced morphological changes, indicating that PBXIP1 knockdown decreases glioma cell viability and motility through rearrangements of the actin cytoskeleton. Furthermore, expression of PBXIP1 was observed in radial glia and astrocytic progenitor cells in human fetal tissues, suggesting that PBXIP1 is an astroglial progenitor cell marker during human embryonic development. PBXIP1 is a novel protein overexpressed in astrocytoma and ependymoma, involved in tumor cell proliferation and migration, that warrants further exploration as a novel therapeutic target in these tumors. C1 [van Vuurden, Dannis G.; Hulleman, Esther; Biesmans, Dennis; Kaspers, Gertjan J. L.; Cloos, Jacqueline] Vrije Univ Amsterdam, Med Ctr, Dept Pediat Oncol Hematol, NL-1007 MB Amsterdam, Netherlands. [van Vuurden, Dannis G.; Hulleman, Esther; Wedekind, Laurine E.; Biesmans, Dennis; Malekzadeh, Arjan; Noske, David P.; Wuerdinger, Thomas; van der Stoop, Petra P. M.] Vrije Univ Amsterdam, Med Ctr, Neurooncol Res Grp, NL-1007 MB Amsterdam, Netherlands. [van Vuurden, Dannis G.; Hulleman, Esther; Wedekind, Laurine E.; Noske, David P.; Vandertop, W. Peter; Wuerdinger, Thomas; van der Stoop, Petra P. M.] Vrije Univ Amsterdam, Med Ctr, Neurosurg Ctr Amsterdam, NL-1007 MB Amsterdam, Netherlands. [Bugiani, Marianna] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. [Cloos, Jacqueline] Vrije Univ Amsterdam, Med Ctr, Dept Hematol, NL-1007 MB Amsterdam, Netherlands. [Aronica, Eleonora] Univ Amsterdam, Acad Med Ctr, Dept Neuro Pathol, NL-1105 AZ Amsterdam, Netherlands. [Aronica, Eleonora] Univ Amsterdam, Ctr Neurosci, Swammerdam Inst Life Sci, Amsterdam, Netherlands. [Geerts, Dirk] Erasmus Univ, Med Ctr, Sophia Childrens Hosp, Rotterdam, Netherlands. [Wuerdinger, Thomas] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wuerdinger, Thomas] Harvard Univ, Sch Med, Dept Neurol, Mol Neurogenet Unit, Boston, MA 02115 USA. RP van Vuurden, DG (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Pediat Oncol Hematol, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM dg.vanvuurden@vumc.nl OI Geerts, Dirk/0000-0002-6386-8187; Van Vuurden, Dannis/0000-0002-1364-9007 NR 45 TC 7 Z9 7 U1 0 U2 5 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 2014 VL 16 IS 7 BP 946 EP 959 DI 10.1093/neuonc/not308 PG 14 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AK0SR UT WOS:000338126100006 PM 24470547 ER PT J AU Bluher, S Panagiotou, G Petroff, D Markert, J Wagner, A Klemm, T Filippaios, A Keller, A Mantzoros, CS AF Blueher, Susann Panagiotou, Grigorios Petroff, David Markert, Jana Wagner, Antje Klemm, Thorsten Filippaios, Andreas Keller, Alexandra Mantzoros, Christos S. TI Effects of a 1-Year Exercise and Lifestyle Intervention on Irisin, Adipokines, and Inflammatory Markers in Obese Children SO OBESITY LA English DT Article ID TUMOR-NECROSIS-FACTOR; BODY-MASS INDEX; INSULIN-RESISTANCE; METABOLIC SYNDROME; ADIPOSE-TISSUE; HUMANS; SERUM; ADIPONECTIN; ADOLESCENTS; GLUCOSE AB Objective: Exercise improves weight status and metabolism. Irisin, a novel myokine, may be involved in the regulation of metabolic function. The effect of an exercise and dietary lifestyle intervention for 1-year on irisin, adipokines (leptin, adiponectin, resistin) and inflammatory markers (C-reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFR-II) was evaluated, and predictors of irisin levels were characterized in obese children. Methods: Parameters were assessed at baseline and at follow-up for 65 obese children who completed the program (7-18 years, 54%boys). Their relation to weight status and metabolic risk was analyzed. Results: Anthropometric and metabolic parameters improved after completion of the program. Circulating irisin levels at baseline were 111.0 +/- 8.0 ng ml(-1) and increased after the intervention by 12% [6%, 17%], P = 0.00003. There was no evidence for differences in irisin levels between genders and across age. Moreover, changes in irisin did not correlate with those in BMI-SDS, adipokines or inflammatory markers. Leptin decreased after the intervention (Delta 5.3 ng ml(-1), [3.2, 6.3], P = 10(-7)). Anthropometric measures were significantly associated with leptin and inflammatory markers. Conclusions: A 1-year long lifestyle intervention program is associated with improvement in anthropometric and metabolic parameters and leads to an elevation in irisin levels in obese children. C1 [Blueher, Susann; Markert, Jana] Univ Leipzig, Med Ctr, IFB Adipos Dis, D-04109 Leipzig, Germany. [Panagiotou, Grigorios; Filippaios, Andreas; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Petroff, David] Univ Leipzig, Coordinat Ctr Clin Studies, D-04109 Leipzig, Germany. [Wagner, Antje] KLAKS eV, Leipzig, Germany. [Klemm, Thorsten] MVZ Lab Dr Reising Ackermann & Colleagues, Leipzig, Germany. [Keller, Alexandra] Pediat Med Ctr, Leipzig, Germany. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Endocrinol Sect, Boston VA Healthcare Syst, Boston, MA USA. RP Bluher, S (reprint author), Univ Leipzig, Med Ctr, IFB Adipos Dis, D-04109 Leipzig, Germany. EM susann.blueher@medizin.uni-leipzig.de OI Panagiotou, Grigorios/0000-0003-0690-1478 FU Federal Ministry of Education and Research, Germany (Integrated Research and Treatment Center IFB "Adiposity Diseases,") [FKZ: 01E01001] FX Part of the work was supported by the Federal Ministry of Education and Research, Germany (Integrated Research and Treatment Center IFB "Adiposity Diseases," FKZ: 01E01001). NR 40 TC 22 Z9 24 U1 0 U2 15 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 2014 VL 22 IS 7 BP 1701 EP 1708 DI 10.1002/oby.20739 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AJ9MM UT WOS:000338035400018 PM 24644099 ER PT J AU Stoneham, SJ Hale, JP Rodriguez-Galindo, C Dang, H Olson, T Murray, M Amatruda, JF Thornton, C Arul, GS Billmire, D Krailo, M Stark, D Covens, A Hurteau, J Stenning, S Nicholson, JC Gershenson, D Frazier, AL AF Stoneham, Sara J. Hale, Juliet P. Rodriguez-Galindo, Carlos Dang, Ha Olson, Thomas Murray, Matthew Amatruda, James F. Thornton, Claire Arul, G. Suren Billmire, Deborah Krailo, Mark Stark, Dan Covens, Al Hurteau, Jean Stenning, Sally Nicholson, James C. Gershenson, David Frazier, A. Lindsay TI Adolescents and Young Adults With a "Rare" Cancer: Getting Past Semantics to Optimal Care for Patients With Germ Cell Tumors SO ONCOLOGIST LA English DT Editorial Material DE Adolescence; Young adults; Germ cell tumors; Risk stratification ID LONG-TERM SURVIVORS; TESTICULAR-CANCER; CLINICAL-TRIALS; CHEMOTHERAPY; CISPLATIN; PLATINUM; ENGLAND; INTERMEDIATE; PROTOCOLS; TEENAGERS C1 [Stoneham, Sara J.] Univ Coll London Hosp Trusts, Childrens & Young Persons Canc Serv, London NW1 2PQ, England. [Hale, Juliet P.] Newcastle Upon Tyne Hosp Trust, Dept Paediat Oncol, Royal Victoria Infirm, Newcastle Upon Tyne, Tyne & Wear, England. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Boston Childrens Hosp, Boston, MA USA. [Dang, Ha; Krailo, Mark] Childrens Oncol Grp, Monrovia, CA USA. [Olson, Thomas] Emory Univ, Dept Pediat Oncol, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Murray, Matthew; Nicholson, James C.] Cambridge Univ Hosp NHS Fdn Trust, Dept Paediat Oncol, Cambridge, England. [Murray, Matthew] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Amatruda, James F.; Gershenson, David] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Amatruda, James F.; Gershenson, David] Childrens Med Ctr, Dallas, TX 75235 USA. [Thornton, Claire] Belfast Hlth Trust, Dept Pathol, Royal Victoria Hosp, Belfast, Antrim, North Ireland. [Arul, G. Suren] Birmingham Childrens Hosp NHS Fdn Trust, Dept Pediat Surg, Birmingham, W Midlands, England. [Billmire, Deborah] James Whitcomb Riley Hosp Children, Indianapolis, IN 46202 USA. [Stark, Dan] St James Univ Hosp, Dept Med Oncol, St Jamess Inst Oncol, Leeds LS9 7TF, W Yorkshire, England. [Covens, Al] Univ Toronto, Dept Gynecol Oncol, Sunnybrook Hlth Sci Ctr, Toronto, ON M5S 1A1, Canada. [Hurteau, Jean] North Shore Univ Hlth Syst, Dept Gynecol Oncol, Evanston, IL USA. [Stenning, Sally] MRC, Clin Trials Unit, London, England. RP Stoneham, SJ (reprint author), Univ Coll London Hosp Trusts, Dept Paediat & Child Hlth, 6th Floor Cent,250 Euston Rd, London NW1 2PQ, England. EM sara.stoneham@uclh.nhs.uk FU Medical Research Council [MC_U122861331]; NCI NIH HHS [U10 CA180886, U10 CA180899] NR 37 TC 2 Z9 2 U1 1 U2 3 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD JUL PY 2014 VL 19 IS 7 BP 689 EP 692 DI 10.1634/theoncologist.2014-0009 PG 4 WC Oncology SC Oncology GA AK1QM UT WOS:000338190600002 PM 24899644 ER PT J AU Chabner, BA AF Chabner, Bruce A. TI The Untimely Passing of a Great Man: Eddie Reed, MD, 1953-2014 In Memoriam SO ONCOLOGIST LA English DT Biographical-Item C1 [Chabner, Bruce A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Chabner, BA (reprint author), 10 North Grove St,LRH 214, Boston, MA 02114 USA. EM bchabner@partners.org NR 0 TC 1 Z9 1 U1 0 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD JUL PY 2014 VL 19 IS 7 BP 786 EP 787 DI 10.1634/theoncologist.2014-0231 PG 2 WC Oncology SC Oncology GA AK1QM UT WOS:000338190600016 ER PT J AU Bvochara-Nsingo, M Grover, S Gierga, DP Makufa, R Efstathiou, JA Dixit, N Clayman, RH Russell, AH Lin, LL Kasese, J AF Bvochara-Nsingo, Memory Grover, Surbhi Gierga, David P. Makufa, Remigio Efstathiou, Jason A. Dixit, Nayha Clayman, Rebecca H. Russell, Anthony H. Lin, Lilie L. Kasese, Joseph TI Cervical Brachytherapy Exchange: Steps Toward Oncology Capacity Building in Botswana SO ONCOLOGIST LA English DT Letter ID ATOMIC-ENERGY AGENCY; CANCER; COUNTRIES; RESOURCES; AFRICA C1 [Bvochara-Nsingo, Memory; Makufa, Remigio] Gaborone Private Hosp, Dept Radiat Oncol, Gaborone, Botswana. [Grover, Surbhi; Dixit, Nayha; Lin, Lilie L.] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Gierga, David P.; Efstathiou, Jason A.; Clayman, Rebecca H.; Russell, Anthony H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Kasese, Joseph] Bokamoso Private Hosp, Dept Oncol, Gaborone, Botswana. RP Bvochara-Nsingo, M (reprint author), Gaborone Private Hosp, Dept Radiat Oncol, Gaborone, Botswana. NR 9 TC 7 Z9 7 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD JUL PY 2014 VL 19 IS 7 BP E1 EP E2 DI 10.1634/theoncologist.2013-0393 PG 2 WC Oncology SC Oncology GA AK1QM UT WOS:000338190600001 PM 24928614 ER PT J AU Sandholm, J Tuomela, J Kauppila, JH Harris, KW Graves, D Selander, KS AF Sandholm, Jouko Tuomela, Johanna Kauppila, Joonas H. Harris, Kevin W. Graves, David Selander, Katri S. TI Hypoxia regulates Toll-like receptor-9 expression and invasive function in human brain cancer cells in vitro SO ONCOLOGY LETTERS LA English DT Article DE Toll-like receptor-9; hypoxia; invasion; brain cancer ID PROSTATE-CANCER; BREAST-CANCER; SUBCELLULAR-LOCALIZATION; HELICOBACTER-PYLORI; CELLULAR INVASION; TISSUE INHIBITOR; EPITHELIAL-CELLS; DENDRITIC CELLS; BACTERIAL-DNA; TLR9 AB Toll-like receptor-9 (TLR9) is a cellular DNA sensor of the innate immune system. TLR9 is widely expressed in a number of tumors, including brain cancer; however, little is known regarding its regulation and involvement in cancer pathophysiology. The present study demonstrated that hypoxia upregulates and downregulates TLR9 expression in human brain cancer cells in vitro, in a cell-specific manner. In addition, hypoxia-induced TLR9 upregulation was associated with hypoxia-induced invasion; however, such invasion was not detected in cells where hypoxia had suppressed TLR9 expression. Furthermore, suppression of TLR9 expression through TLR9 siRNA resulted in an upregulation of matrix metalloproteinase (MMP)-2, -9 and -13 and tissue inhibitor of matrix metalloproteinases-3 (TIMP-3) mRNA, and a decreased invasion of cells in normoxia, in a cell-specific manner. In cells where hypoxia induced TLR9 expression, TLR9 expression and invasion were reduced by TLR9 siRNA. The decreased invasion observed in hypoxia was associated with the decreased expression of the MMPs and a concomitant increase in TIMP-3 expression. In conclusion, hypoxia regulates the invasion of brain cancer cells in vitro in a TLR9-dependent manner, which is considered to be associated with a complex expression pattern of TLR9-regulated mediators and inhibitors of invasion. C1 [Sandholm, Jouko; Tuomela, Johanna; Harris, Kevin W.; Selander, Katri S.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Kauppila, Joonas H.] Oulu Univ Hosp, Dept Pathol, Oulu 90029, Finland. [Kauppila, Joonas H.] Oulu Univ Hosp, Dept Surg, Oulu 90029, Finland. [Kauppila, Joonas H.] Univ Oulu, Dept Anat & Cell Biol, FIN-90570 Oulu, Finland. [Harris, Kevin W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Graves, David] Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA. RP Selander, KS (reprint author), Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, 1825 Univ Blvd, Birmingham, AL 35294 USA. EM katriselander@uabmc.edu RI Kauppila, Joonas/P-1363-2015; OI Kauppila, Joonas/0000-0001-6740-3726; Tuomela, Johanna/0000-0003-4390-4563 FU Oulu University Scholarship Foundation; Cancer Foundation of Northern Finland; Lapland Cultural Foundation; Department of Defense [BC095831] FX The authors would like to thank Ms Christine Pressey for skillful assistance with the qPCR assays. The present study was funded by grants from the Oulu University Scholarship Foundation and Cancer Foundation of Northern Finland (J.H.K), the Lapland Cultural Foundation (K.S.S) and the Department of Defense (K.S.S. and D.G., grant no. BC095831). NR 53 TC 5 Z9 5 U1 2 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 EI 1792-1082 J9 ONCOL LETT JI Oncol. Lett. PD JUL PY 2014 VL 8 IS 1 BP 266 EP 274 DI 10.3892/ol.2014.2095 PG 9 WC Oncology SC Oncology GA AK1ML UT WOS:000338179100050 ER PT J AU Tariman, JD Doorenbos, A Schepp, KG Singhal, S Berry, DL AF Tariman, Joseph D. Doorenbos, Ardith Schepp, Karen G. Singhal, Seema Berry, Donna L. TI Older Adults Newly Diagnosed With Symptomatic Myeloma and Treatment Decision Making SO ONCOLOGY NURSING FORUM LA English DT Article DE decision making; decisional role preferences; patient education; multiple myeloma ID CANCER-PATIENTS; BREAST-CANCER; HEALTH-CARE; INFORMATION NEEDS; PREFERRED ROLES; PREFERENCES; PARTICIPATION; INVOLVEMENT; EXPERIENCE; TRIAL AB Purpose/Objectives: To describe the preferences for participation in decision making of older adult patients newly diagnosed with symptomatic myeloma and to explore the association between sociodemographic variables and decisional role preferences. Design: Descriptive, cross-sectional design. Setting: Participants' homes and two large academic cancer centers in Seattle, WA, and Chicago, IL. Sample: A convenience sample of 20 older adults (60 years of age and older) with symptomatic myeloma diagnosed within the past six months. Methods: The Control Preferences Scale was administered followed by an in-person, one-time, semistructured interview Main Research Variables: Role preferences for participation in treatment decision making, age, gender, race, work status, personal relationship status, education, and income. Findings: Fifty-five percent of the participants preferred a shared role with the physician and 40% preferred to make the decisions after seriously considering the opinion of their physicians. Only one participant preferred to leave the decision to the doctor, as long as the doctor considered the patient's treatment preferences. Conclusions: The study findings indicate that older adults newly diagnosed with myeloma want to participate in treatment decision making. Oncology nurses must respect the patient's desired role preference and oncology clinicians must listen to the patient and allow him or her to be autonomous in making treatment decisions. Implications for Nursing: Nurses and other oncology clinicians can elicit a patient's preferred level of participation in treatment decision making. Oncology nurses can make sure patients receive disease- and treatment-related information, encourage them to express their decisional role preference to the physician, develop a culture of mutual respect and value their desire for autonomy for treatment decision making, acknowledge that the right to make a treatment choice belongs to the patient, and provide support during treatment decision making throughout the care continuum. C1 [Tariman, Joseph D.] Northwestern Univ, Div Hematol & Oncol, Med Fac Fdn, Chicago, IL 60611 USA. [Doorenbos, Ardith; Schepp, Karen G.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Singhal, Seema] Northwestern Univ, Div Hematol & Oncol, Multiple Myeloma Program, Chicago, IL 60611 USA. [Berry, Donna L.] Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02115 USA. RP Tariman, JD (reprint author), Northwestern Univ, Div Hematol & Oncol, Med Fac Fdn, Chicago, IL 60611 USA. EM jtariman@nmff.org FU National Institutes of Health [NIH-NR07106, F31NR011124]; Achievement Rewards for College Scientists (ARCS) Foundation FX Joseph D. Tariman, PhD, APN-BC, is an advanced practice nurse in the Division of Hematology and Oncology at the Northwestern University Medical Faculty Foundation in Chicago, IL; Ardith Doorenbos, PhD, RN, FAAN, and Karen G. Schepp, PhD, RN, PMHCNS-BC, FAAN, are associate professors in the School of Nursing at the University of Washington in Seattle; Seema Singhal, MD, is the director of the multiple myeloma program in the Division of Hematology and Oncology at Northwestern University; and Donna L. Berry, PhD, RN, AOCN (R), FAAN, is the director of the Phyllis F. Cantor Center at the Dana-Farber Cancer Institute in Boston, MA. The study was supported by the National Institutes of Health [NIH-NR07106, F31NR011124] and the Achievement Rewards for College Scientists (ARCS) Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health and the ARCS Foundation. Tariman can be reached at jtariman@nmff.org, with copy to editor at ONFEditor@ons.org. (Submitted October 2013. Accepted for publication February 24, 2014.) NR 37 TC 4 Z9 5 U1 1 U2 7 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD JUL PY 2014 VL 41 IS 4 BP 411 EP 419 DI 10.1188/14.ONF.411-419 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA AK5PK UT WOS:000338478000007 PM 24969250 ER PT J AU Lee, MK Dodson, TB Nalliah, RP Karimbux, NY Allareddy, V AF Lee, Min Kyeong Dodson, Thomas B. Nalliah, Romesh P. Karimbux, Nadeem Y. Allareddy, Veerasathpurush TI Nine-year trend analysis of hospitalizations attributed to oral and oropharyngeal cancers in the United States SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS; ACCURACY; GROWTH AB Objectives. This study examines 9-year discharge patterns and changes in outcomes in oral cancer hospitalizations in the United States. Study Design. All hospitalizations with primary diagnosis of oral and oropharyngeal cancers were selected from 2000 to 2008 Nationwide Inpatient Sample. Association between outcomes (in-hospital mortality, length of stay [LOS], hospital charges, and discharge status) and independent variables was examined using multivariable regression analyses. Results. Of 146,928 hospitalizations, 5310 died in hospitals. Mean LOS was 6.7 days. Mean hospitalization charges ranged from $47,331 to $62,885. After adjusting for confounders, in-hospital morality and charges did not vary while LOS decreased. Hospitalizations occurring in 2004-2008 were more likely to be discharged to long-term facilities (odds ratio 1.24-1.59, P < .05) compared with those in 2000. Conclusion. Our study demonstrates changes in longitudinal trends in socio-demographic and hospital-related factors. Our results do not provide compelling evidence on whether hospitals are saving cost or shifting cost to another type of facility. C1 [Lee, Min Kyeong] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Ctr Appl Clin Invest, Boston, MA 02114 USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Dodson, Thomas B.; Nalliah, Romesh P.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Karimbux, Nadeem Y.] Tufts Univ, Dept Periodontol, Sch Dent Med, Boston, MA 02111 USA. [Allareddy, Veerasathpurush] Boston Childrens Hospital, Boston, MA USA. RP Lee, MK (reprint author), Harvard Univ, Sch Dent Med, Dept Dev Biol, 188 Longwood Ave, Boston, MA 02115 USA. EM minkyeong_lee@hsdm.harvard.edu NR 19 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD JUL PY 2014 VL 118 IS 1 BP 47 EP 67 DI 10.1016/j.oooo.2013.01.019 PG 21 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AK1RF UT WOS:000338192600013 PM 23570664 ER PT J AU Cucu, D Chiritoiu, G Petrescu, S Babes, A Stanica, L Duda, DG Horii, A Dima, SO Popescu, I AF Cucu, Dana Chiritoiu, Gabriela Petrescu, Stefana Babes, Alexandru Stanica, Luciana Duda, Dan G. Horii, Akira Dima, Simona Olimpia Popescu, Irinel TI Characterization of Functional Transient Receptor Potential Melastatin 8 Channels in Human Pancreatic Ductal Adenocarcinoma Cells SO PANCREAS LA English DT Article DE pancreatic adenocarcinoma; transient receptor potential melastatin 8; menthol; migration ID EPITHELIAL-CELLS; TRPM8 EXPRESSION; CANCER; MOTILITY; PROLIFERATION; MIGRATION; CALCIUM AB Objective: Recently, the transient receptor potentialmelastatin 8 (TRPM8) channel has emerged as a putative biomarker for pancreatic ductal adenocarcinoma (PDA). This study aimed to evaluate the expression of TRPM8 and its modulation by specific agonists and antagonists in PDA cells. Methods: We examined the protein expression of TRPM8 in 3 different PDA cell lines and compared it with a nontumoral epithelial cell line of human pancreatic origin using Western blotting and immunocytochemical analysis. To assess the function of TRPM8 channels, we measured the TRPM8 currents in whole-cell mode of the patch clamp technique. To explore the putative involvement of TRPM8 in cell migration, we investigated the motility of PDA cells using the scratch-wound assay. Results: Pancreatic ductal adenocarcinoma cells express functional plasma membrane TRPM8 channels, which are responsive after exposure to agonists (menthol and icilin) and antagonists N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride salt. The silencing of TRPM8 expression by small interfering RNA augments the migration of PDA cells. Conversely, the activated form of TRPM8 inhibits PDA cell motility. Conclusions: An unglycosylated TRPM8 protein is expressed and is functional in the membrane of PDA cells. Transient receptor potential melastatin 8 inhibits the migration of PDA cells, suggesting a putative role as a biomarker or target for this channel for PDA therapy. C1 [Cucu, Dana; Dima, Simona Olimpia; Popescu, Irinel] Fundeni Clin Inst, Ctr Digest Dis & Liver Transplantat, Bucharest 022328, Romania. [Chiritoiu, Gabriela; Petrescu, Stefana] Acad Romana, Dept Mol & Cell Biol, Inst Biochem, Bucharest, Romania. [Babes, Alexandru; Stanica, Luciana] Univ Bucharest, Fac Biol, Dept Anat Physiol & Biophys, Bucharest, Romania. [Duda, Dan G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Horii, Akira] Tohoku Univ, Div Mol Pathol, Dept Pathol, Grad Sch Med, Sendai, Miyagi 980, Japan. RP Cucu, D (reprint author), Fundeni Clin Inst, Ctr Digest Dis & Liver Transplantat, Funndeni 258, Bucharest 022328, Romania. EM danacucu@gmail.com RI Babes, Alexandru/A-6212-2010; Petrescu, Stefana/I-9240-2012; POPESCU, IRINEL/B-3048-2008; Dima, Simona Olimpia/B-8822-2017; OI Petrescu, Stefana/0000-0002-4047-0811; Babes, Alexandru/0000-0002-7110-6908 FU European Social Fund [89/1.5/S/60746, 90/2012]; Romanian Research Council (CNCS) [PN2 Idei 117/2011] FX This study was supported by the European Social Fund project no. 89/1.5/S/60746 and project PN II PCCA no. 90/2012. A. B. was supported by grant PN2 Idei 117/2011 from the Romanian Research Council (CNCS). NR 24 TC 4 Z9 4 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD JUL PY 2014 VL 43 IS 5 BP 795 EP 800 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AK0UY UT WOS:000338132700018 PM 24658318 ER PT J AU Liu, JY Chen, JY Ehrlich, S Walton, E White, T Perrone-Bizzozero, N Bustillo, J Turner, JA Calhoun, VD AF Liu, Jingyu Chen, Jiayu Ehrlich, Stefan Walton, Esther White, Tonya Perrone-Bizzozero, Nora Bustillo, Juan Turner, Jessica A. Calhoun, Vince D. TI Methylation Patterns in Whole Blood Correlate With Symptoms in Schizophrenia Patients SO SCHIZOPHRENIA BULLETIN LA English DT Article DE hyper- or hypomethylation; gene expression; reality distortion symptom; inflammatory response ID SQUAMOUS-CELL CARCINOMA; GLOBAL DNA METHYLATION; MB-COMT PROMOTER; BIPOLAR DISORDER; SPECTRUM DISORDERS; ALCOHOL DEPENDENCE; DOWN-REGULATION; DOUBLE-BLIND; EPIGENETICS; SMOKING AB DNA methylation, one of the main epigenetic mechanisms to regulate gene expression, appears to be involved in the development of schizophrenia (SZ). In this study, we investigated 7562 DNA methylation markers in blood from 98 SZ patients and 108 healthy controls. A linear regression model including age, gender, race, alcohol, nicotine and cannabis use status, and diagnosis was implemented to identify C-phosphate-G (CpG) sites significantly associated with diagnosis. These CpG sites were further validated using an independent data set. Sixteen CpG sites were identified with hyper- or hypomethylation in patients. A further verification of expression of the corresponding genes identified 7 genes whose expression levels were also significantly altered in patients. While such altered methylation patterns showed no correlation with disorganized symptoms and negative symptoms in patients, 11 CpG sites significantly correlated with reality distortion symptoms. The direction of the correlations indicates that methylation changes possibly play a protective mechanism to lessen delusion and hallucination symptoms in patients. Pathway analyses showed that the most significant biological function of the differentially methylated CpGs is inflammatory response with CD224, LAX1, TXK, PRF1, CD7, MPG, and MPO genes directly involved in activations of T cells, B cells, and natural killer cells or in cytotoxic reaction. Our results suggest that such methylation changes may modulate aspects of the immune response and hence protect against the neurobiological substrate of reality distortion symptoms in SZ patients. C1 [Liu, Jingyu; Chen, Jiayu; Turner, Jessica A.; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Liu, Jingyu; Chen, Jiayu; Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Ehrlich, Stefan; Walton, Esther] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Child & Adolescent Psychiat, Dresden, Germany. [Ehrlich, Stefan; Walton, Esther] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [White, Tonya] Erasmus Univ, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Perrone-Bizzozero, Nora; Calhoun, Vince D.] Univ New Mexico, Dept Neurosci, Albuquerque, NM 87131 USA. [Bustillo, Juan; Turner, Jessica A.; Calhoun, Vince D.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. RP Liu, JY (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM jliu@mrn.org RI Turner, Jessica/H-7282-2015; OI Turner, Jessica/0000-0003-0076-8434; Ehrlich, Stefan/0000-0003-2132-4445; Walton, Esther/0000-0002-0935-2200; Liu, Jingyu/0000-0002-1724-7523 FU National Institutes of Health [R01EB005846, R33DA027626] FX National Institutes of Health (R01EB005846 to V.C. and R33DA027626 to J.L.). NR 56 TC 28 Z9 29 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 IS 4 BP 769 EP 776 DI 10.1093/schbul/sbt080 PG 8 WC Psychiatry SC Psychiatry GA AK0UC UT WOS:000338130300009 PM 23734059 ER PT J AU Ford, JM Palzes, VA Roach, BJ Mathalon, DH AF Ford, Judith M. Palzes, Vanessa A. Roach, Brian J. Mathalon, Daniel H. TI Did I Do That? Abnormal Predictive Processes in Schizophrenia When Button Pressing to Deliver a Tone SO SCHIZOPHRENIA BULLETIN LA English DT Article DE predictive coding; efference copy; corollary discharge; ERPs ID SELF-INITIATED SOUNDS; HUMAN AUDITORY-CORTEX; COROLLARY DISCHARGE DYSFUNCTION; RESPONSES; SYMPTOMS; ATTENUATION; SUPPRESSION; ERP; N1; HALLUCINATIONS AB Motor actions are preceded by an efference copy of the motor command, resulting in a corollary discharge of the expected sensation in sensory cortex. These mechanisms allow animals to predict sensations, suppress responses to self-generated sensations, and thereby process sensations efficiently and economically. During talking, patients with schizophrenia show less evidence of pretalking activity and less suppression of the speech sound, consistent with dysfunction of efference copy and corollary discharge, respectively. We asked if patterns seen in talking would generalize to pressing a button to hear a tone, a paradigm translatable to less vocal animals. In 26 patients [23 schizophrenia, 3 schizoaffective (SZ)] and 22 healthy controls (HC), suppression of the N1 component of the auditory event-related potential was estimated by comparing N1 to tones delivered by button presses and N1 to those tones played back. The lateralized readiness potential (LRP) associated with the motor plan preceding presses to deliver tones was estimated by comparing right and left hemispheres' neural activity. The relationship between N1 suppression and LRP amplitude was assessed. LRP preceding button presses to deliver tones was larger in HC than SZ, as was N1 suppression. LRP amplitude and N1 suppression were correlated in both groups, suggesting stronger efference copies are associated with stronger corollary discharges. SZ have reduced N1 suppression, reflecting corollary discharge action, and smaller LRPs preceding button presses to deliver tones, reflecting the efference copy of the motor plan. Effects seen during vocalization largely extend to other motor acts more translatable to lab animals. C1 [Ford, Judith M.; Palzes, Vanessa A.; Roach, Brian J.; Mathalon, Daniel H.] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Ford, Judith M.; Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Ford, JM (reprint author), 4150 Clement St, San Francisco, CA 94121 USA. EM Judith.Ford@ucsf.edu OI Roach, Brian/0000-0002-3264-1465 FU Department of Veterans Affairs [I01CX000497]; National Institute of Mental Health [MH-58262] FX Department of Veterans Affairs (I01CX000497); National Institute of Mental Health (MH-58262 to J.M.F.). NR 50 TC 18 Z9 18 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 IS 4 BP 804 EP 812 DI 10.1093/schbul/sbt072 PG 9 WC Psychiatry SC Psychiatry GA AK0UC UT WOS:000338130300013 PM 23754836 ER PT J AU Smith, MJ Horan, WP Cobia, DJ Karpouzian, TM Fox, JM Reilly, JL Breiter, HC AF Smith, Matthew J. Horan, William P. Cobia, Derin J. Karpouzian, Tatiana M. Fox, Jaclyn M. Reilly, James L. Breiter, Hans C. TI Performance-Based Empathy Mediates the Influence of Working Memory on Social Competence in Schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE empathy; functional outcomes; working memory; social cognition ID FACIAL AFFECT RECOGNITION; NEUROCOGNITIVE DEFICITS; FUNCTIONAL-SIGNIFICANCE; COGNITION; ACCURACY; SYMPTOMS; CAPACITY; MATRICS; IMPAIRMENTS; PERCEPTION AB Empathic deficits have been linked to poor functioning in schizophrenia, but this work is mostly limited to self-report data. This study examined whether performance-based empathy measures account for incremental variance in social competence and social attainment above and beyond self-reported empathy, neurocognition, and clinical symptoms. Given the importance of working memory in theoretical models of empathy and in the prediction of functioning in schizophrenia, we also examined whether empathy mediates the relationship between working memory and functioning. Sixty outpatients and 45 healthy controls were compared on performance-based measures of 3 key components of empathic responding, including facial affect perception, emotional empathy (affective responsiveness), and cognitive empathy (emotional perspective-taking). Participants also completed measures of self-reported empathy, neurocognition, clinical symptoms, and social competence and attainment. Patients demonstrated lower accuracy than controls across the 3 performance-based empathy measures. Among patients, these measures showed minimal relations to self-reported empathy but significantly correlated with working memory and other neurocognitive functions as well as symptom levels. Furthermore, cognitive empathy explained significant incremental variance in social competence (Delta R-2 = .07, P < .05) and was found to mediate the relation between working memory and social competence. Performance-based measures of empathy were sensitive to functionally relevant disturbances in schizophrenia. Working memory deficits appear to have an important effect on these disruptions in empathy. Empathy is emerging as a promising new area for social cognitive research and for novel recovery-oriented treatment development. C1 [Smith, Matthew J.; Cobia, Derin J.; Karpouzian, Tatiana M.; Fox, Jaclyn M.; Reilly, James L.; Breiter, Hans C.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Horan, William P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychait & Biobehav Sci, Los Angeles, CA 90095 USA. [Horan, William P.] VA Greater Los Angeles Healthcare Syst, MIRECC VISN22, Los Angeles, CA USA. [Breiter, Hans C.] Northwestern Univ, Feinberg Sch Med, Warren Wright Adolescent Ctr, Chicago, IL 60611 USA. RP Smith, MJ (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, 446 E Ontario,Suite 7-100, Chicago, IL 60611 USA. EM matthewsmith@northwestern.edu OI Smith, Matthew/0000-0002-0079-1477; Cobia, Derin/0000-0003-2339-958X FU Department of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine FX Department of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine. NR 102 TC 20 Z9 20 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 IS 4 BP 824 EP 834 DI 10.1093/schbul/sbt084 PG 11 WC Psychiatry SC Psychiatry GA AK0UC UT WOS:000338130300015 PM 23770935 ER PT J AU von Hohenberg, CC Pasternak, O Kubicki, M Ballinger, T Vu, MA Swisher, T Green, K Giwerc, M Dahlben, B Goldstein, JM Woo, TUW Petryshen, TL Mesholam-Gately, RI Woodberry, KA Thermenos, HW Mulert, C McCarley, RW Seidman, LJ Shenton, ME AF von Hohenberg, Christian Clemm Pasternak, Ofer Kubicki, Marek Ballinger, Thomas Vu, Mai-Anh Swisher, Tali Green, Katie Giwerc, Michelle Dahlben, Brian Goldstein, Jill M. Woo, Tsung-Ung W. Petryshen, Tracey L. Mesholam-Gately, Raquelle I. Woodberry, Kristen A. Thermenos, Heidi W. Mulert, Christoph McCarley, Robert W. Seidman, Larry J. Shenton, Martha E. TI White Matter Microstructure in Individuals at Clinical High Risk of Psychosis: A Whole-Brain Diffusion Tensor Imaging Study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; prodrome; TBSS; radial diffusivity; mean diffusivity; parietal lobe ID ULTRA-HIGH-RISK; EARLY-ONSET SCHIZOPHRENIA; IN-VIVO; VOXELWISE ANALYSIS; PRODROME; CONNECTIVITY; RELIABILITY; INTERRATER; INTERVIEW; VALIDITY AB Background: The study of individuals at clinical high risk (CHR) for psychosis provides an important opportunity for unraveling pathological mechanisms underlying schizophrenia and related disorders. A small number of diffusion tensor magnetic resonance imaging (DTI) studies in CHR samples have yielded anatomically inconsistent results. The present study is the first to apply tract-based spatial statistics (TBSS) to perform a whole-brain DTI analysis in CHR subjects. Methods: A total of 28 individuals meeting CHR criteria and 34 healthy controls underwent DTI. TBSS was used for a group comparison of fractional anisotropy (FA), as well as axial, radial, and mean diffusivity (AD, RD, and MD). Conversion to psychosis was monitored during a mean follow-up period of 12.3 months. Results: The rate of conversion to psychosis was relatively low (4%). TBSS revealed increased MD in several clusters in the right hemisphere, most notably in the superior longitudinal fasciculus (SLF), posterior corona radiata, and corpus callosum (splenium and body). Increased RD was restricted to a smaller area in the posterior parietal lobe. Conclusion: We present further evidence that white matter microstructure is abnormal in CHR individuals, even in a sample in which the vast majority do not transition to psychosis over the following year. In accord with previous studies on CHR individuals and patients with early-onset schizophrenia, our findings suggest an important pathological role for the parietal lobe and especially the SLF. The latter is known to undergo particularly dynamic microstructural changes during adolescence and early adulthood, a critical phase for the development of psychotic illness. C1 [von Hohenberg, Christian Clemm; Pasternak, Ofer; Kubicki, Marek; Ballinger, Thomas; Vu, Mai-Anh; Swisher, Tali; Green, Katie; Giwerc, Michelle; Dahlben, Brian; Shenton, Martha E.] Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA 02215 USA. [von Hohenberg, Christian Clemm; Pasternak, Ofer; Kubicki, Marek; Ballinger, Thomas; Vu, Mai-Anh; Swisher, Tali; Green, Katie; Giwerc, Michelle; Dahlben, Brian; Goldstein, Jill M.; Shenton, Martha E.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [von Hohenberg, Christian Clemm] Univ Munich, Fac Med, Dept Psychiat, Munich, Germany. [von Hohenberg, Christian Clemm; Mulert, Christoph] Univ Med Ctr Hamburg Eppendorf, Imaging Ctr NeuroImage Nord, Psychiat Neuroimaging Branch, Hamburg, Germany. [von Hohenberg, Christian Clemm; Mulert, Christoph] Univ Med Ctr Hamburg Eppendorf, Dept Psychiat & Psychotherapy, Hamburg, Germany. [Pasternak, Ofer; Kubicki, Marek; Goldstein, Jill M.; Petryshen, Tracey L.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Thermenos, Heidi W.; McCarley, Robert W.; Seidman, Larry J.; Shenton, Martha E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Kubicki, Marek; Shenton, Martha E.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02215 USA. [Goldstein, Jill M.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Psychiat, Boston, MA 02215 USA. [Goldstein, Jill M.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Med, Boston, MA 02215 USA. [Woo, Tsung-Ung W.] Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat, Boston, MA 02215 USA. [Petryshen, Tracey L.] Massachusetts Gen Hosp, Ctr Human Genet, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Petryshen, Tracey L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Thermenos, Heidi W.; Seidman, Larry J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Boston, MA 02215 USA. [Thermenos, Heidi W.; Seidman, Larry J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02215 USA. [Thermenos, Heidi W.; Seidman, Larry J.] Massachusetts Inst Technol Harvard Med Sch & MGH, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [McCarley, Robert W.; Shenton, Martha E.] Vet Affairs Boston Healthcare Syst, Brockton Div, Neurosci Lab, Clin Neurosci Div, Brockton, MA USA. RP von Hohenberg, CC (reprint author), Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, 1249 Boylston St, Boston, MA 02215 USA. EM clemm@bwh.harvard.edu RI McCarley, Robert/N-5562-2014; Mulert, Christoph/F-2576-2012 OI McCarley, Robert/0000-0001-5705-7495; FU National Institutes of Health [P50 MH 080272, UO1 MH081928, R01M H074794]; Commonwealth Research Center of the Massachusetts Department of Mental Health [SCDMH82101008006]; Veterans Affairs Merit Awards; Veterans Affairs Schizophrenia Center; National Alliance for Research in Schizophrenia and Depression Distinguished Investigator Award; Brain & Behavior Research Foundation; National Center for Research Resources [UL1RR025758, M01RR01032, P41RR14075]; Beth Israel Deaconess Medical Center; Shared Instrumentation Grants [1S10RR023401, 1S10RR019307, 1S10RR023043] FX National Institutes of Health [P50 MH 080272 to R.W.M., M.E.S., and L.J.S.; UO1 MH081928 to L.J.S.; R01M H074794 to O.P., M.K., and M.E.S.]; the Commonwealth Research Center of the Massachusetts Department of Mental Health (SCDMH82101008006 to L.J.S.); Veterans Affairs Merit Awards to M.E.S. and R.W.M.; Veterans Affairs Schizophrenia Center to R.W.M. and M.E.S.; National Alliance for Research in Schizophrenia and Depression Distinguished Investigator Award to M.E.S. and O.P.; National Alliance for Research in Schizophrenia and Depression Young Investigator Grant from the Brain & Behavior Research Foundation to O.P.; Clinical Translational Science Award (UL1RR025758) and General Clinical Research Center Grant (M01RR01032) from the National Center for Research Resources to Harvard University and Beth Israel Deaconess Medical Center; the National Center for Research Resources (P41RR14075); Shared Instrumentation Grants (1S10RR023401, 1S10RR019307, 1S10RR023043). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 40 TC 25 Z9 25 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 IS 4 BP 895 EP 903 DI 10.1093/schbul/sbt079 PG 9 WC Psychiatry SC Psychiatry GA AK0UC UT WOS:000338130300022 PM 23737549 ER PT J AU Goudriaan, A de Leeuw, C Ripke, S Hultman, CM Sklar, P Sullivan, PF Smit, AB Posthuma, D Verheijen, MHG AF Goudriaan, Andrea de Leeuw, Christiaan Ripke, Stephan Hultman, Christina M. Sklar, Pamela Sullivan, Patrick F. Smit, August B. Posthuma, Danielle Verheijen, Mark H. G. TI Specific Glial Functions Contribute to Schizophrenia Susceptibility SO SCHIZOPHRENIA BULLETIN LA English DT Article DE GWAS; PGC; gene set analysis; psychiatric disease; glia; genome-wide association ID OLIGODENDROCYTE DYSFUNCTION; SYNAPTIC CONNECTIVITY; PATHWAY ANALYSIS; GENE-EXPRESSION; WHITE-MATTER; HUMAN HEIGHT; HUMAN BRAIN; MICROGLIA; ASTROCYTES; TRANSCRIPTOME AB Schizophrenia is a highly polygenic brain disorder. The main hypothesis for disease etiology in schizophrenia primarily focuses on the role of dysfunctional synaptic transmission. Previous studies have therefore directed their investigations toward the role of neuronal dysfunction. However, recent studies have shown that apart from neurons, glial cells also play a major role in synaptic transmission. Therefore, we investigated the potential causal involvement of the 3 principle glial cell lineages in risk to schizophrenia. We performed a functional gene set analysis to test for the combined effects of genetic variants in glial type-specific genes for association with schizophrenia. We used genome-wide association data from the largest schizophrenia sample to date, including 13 689 cases and 18 226 healthy controls. Our results show that astrocyte and oligodendrocyte gene sets, but not microglia gene sets, are associated with an increased risk for schizophrenia. The astrocyte and oligodendrocyte findings are related to astrocyte signaling at the synapse, myelin membrane integrity, glial development, and epigenetic control. Together, these results show that genetic alterations underlying specific glial cell type functions increase susceptibility to schizophrenia and provide evidence that the neuronal hypothesis of schizophrenia should be extended to include the role of glia. C1 [Goudriaan, Andrea; Smit, August B.; Verheijen, Mark H. G.] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, NL-1081 HV Amsterdam, Netherlands. [de Leeuw, Christiaan; Posthuma, Danielle] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, NL-1081 HV Amsterdam, Netherlands. [de Leeuw, Christiaan] Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] Broad Inst Harvard & Massachusetts Inst Technol, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Hultman, Christina M.; Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sklar, Pamela] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Ctr Psychiat Genom, Chapel Hill, NC USA. [Posthuma, Danielle] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, NL-1081 HV Amsterdam, Netherlands. [Posthuma, Danielle] Erasmus Univ, Sophia Child Hosp, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. RP Posthuma, D (reprint author), Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, Neurosci Campus Amsterdam,Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. EM danielle.posthuma@vu.nl FU Netherlands Scientific Organization [NWO 480-05-003]; NWO Complexity project [645.000.003]; European Union [HEALTHF2-2009-242167]; Royal Netherlands Academy of Arts and Sciences; Center for Medical Systems Biology FX Netherlands Scientific Organization (NWO 480-05-003); NWO Complexity project (645.000.003); European Union Seventh Framework Program ('SynSys' project) (HEALTHF2-2009-242167); Visiting Professorship grant from Royal Netherlands Academy of Arts and Sciences (P.S.); Center for Medical Systems Biology (A.B.S.). NR 70 TC 26 Z9 27 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 IS 4 BP 925 EP 935 DI 10.1093/schbul/sbt109 PG 11 WC Psychiatry SC Psychiatry GA AK0UC UT WOS:000338130300025 PM 23956119 ER PT J AU Ffytche, DH Wible, CG AF Ffytche, Dominic H. Wible, Cynthia G. TI From Tones in Tinnitus to Sensed Social Interaction in Schizophrenia: How Understanding Cortical Organization Can Inform the Study of Hallucinations and Psychosis SO SCHIZOPHRENIA BULLETIN LA English DT Article DE temporal parietal junction; heteromodal cortex; unimodal cortex; multimodality hallucination; network ID SUPERIOR TEMPORAL SULCUS; TRANSCRANIAL MAGNETIC STIMULATION; AUDITORY VERBAL HALLUCINATIONS; LATERAL GENICULATE-NUCLEUS; ILLUSORY SHADOW PERSON; VISUAL HALLUCINATIONS; PARIETAL JUNCTION; ELECTRICAL-STIMULATION; BIOLOGICAL MOTION; TEMPOROPARIETAL JUNCTION AB The content, modality, and perceptual attributes of hallucinations and other psychotic symptoms may be related to neural representation at a single cell and population level in the cerebral cortex. A brief survey of some principles and examples of cortical representation and organization will be presented together with evidence for a correspondence between the neurobiology of brain areas activated at the time of a hallucination and the content of the corresponding hallucinatory and psychotic experiences. Contrasting the hallucinations of schizophrenia with other conditions, we highlight phenomenological aspects of hallucinations that are ignored in clinical practice but carry potentially important information about the brain regions and dysfunctions underlying them. Knowledge of cortical representation and organization are being used to develop animal models of hallucination and to test treatments that are now beginning to translate to the clinical domain. C1 [Ffytche, Dominic H.] Kings Coll London, Dept Old Age Psychiat, Inst Psychiat, London WC2R 2LS, England. [Wible, Cynthia G.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02301 USA. RP Wible, CG (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, 940 Belmont St,Psychiat 116A, Brockton, MA 02301 USA. EM cindy@bwh.harvard.edu OI ffytche, Dominic/0000-0002-4214-9642 FU Second Meeting of the International Consortium on Hallucination Research; National Institute of Mental Health [1R01 MH067080-01A2, 1R01 MH52807]; National Institute for Health Research [RP-PG-0610-10100]; National Institutes Health [MH40799]; VA Merit; REAP; Medical Center of Excellence Award FX The Second Meeting of the International Consortium on Hallucination Research3; National Institute of Mental Health (1R01 MH067080-01A2 to C. G. W., 1R01 MH52807); National Institute for Health Research (RP-PG-0610-10100 to D. H. F.); National Institutes Health (MH40799); a VA Merit, REAP, and Medical Center of Excellence Award (principal investigator: R. W. McCarley). NR 127 TC 4 Z9 4 U1 4 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 SU 4 BP S305 EP S316 DI 10.1093/schbul/sbu041 PG 12 WC Psychiatry SC Psychiatry GA AK0US UT WOS:000338132100013 PM 24936089 ER PT J AU Ford, JM Morris, SE Hoffman, RE Sommer, I Waters, F McCarthy-Jones, S Thoma, RJ Turner, JA Keedy, SK Badcock, JC Cuthbert, BN AF Ford, Judith M. Morris, Sarah E. Hoffman, Ralph E. Sommer, Iris Waters, Flavie McCarthy-Jones, Simon Thoma, Robert J. Turner, Jessica A. Keedy, Sarah K. Badcock, Johanna C. Cuthbert, Bruce N. TI Studying Hallucinations Within the NIMH RDoC Framework SO SCHIZOPHRENIA BULLETIN LA English DT Article DE Hallucinations; Research Domain Criteria; RDoC ID AUDITORY VERBAL HALLUCINATIONS; INNER SPEECH; COGNITIVE NEUROPSYCHIATRY; COROLLARY DISCHARGE; SCHIZOPHRENIA; THOUGHT; PSYCHOPATHOLOGY; DIRECTIONS; DISORDERS; VOICES AB We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of functioning. We start with a description of the objectives of the RDoC project and its domains and constructs. Because the RDoC initiative asks investigators to study phenomena across the wellness spectrum and different diagnoses, we address whether hallucinations experienced in nonclinical populations are the same as those experienced by people with psychotic diagnoses, and whether hallucinations studied in one clinical group can inform our understanding of the same phenomenon in another. We then discuss the phenomenology of hallucinations and how different RDoC domains might be relevant to their study. We end with a discussion of various challenges and potential next steps to advance the application of the RDoC approach to this area of research. C1 [Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Morris, Sarah E.; Cuthbert, Bruce N.] NIMH, Div Adult Translat Res, Bethesda, MD 20892 USA. [Hoffman, Ralph E.] Yale New Haven Psychiat Hosp, Dept Psychiat, New Haven, CT USA. [Sommer, Iris] Univ Med Ctr, Dept Psychiat, Utrecht, Netherlands. [Waters, Flavie] Univ Western Australia, Ctr Clin Res Neuropsychiat, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Waters, Flavie] North Metro Hlth Serv Mental Hlth, Graylands Hosp, Perth, WA, Australia. [McCarthy-Jones, Simon] Macquarie Univ, ARC Ctr Excellence Cognit & Its Disorders, Dept Cognit Sci, Sydney, NSW 2109, Australia. [McCarthy-Jones, Simon] Univ Durham, Dept Psychol, Durham DH1 3LE, England. [Thoma, Robert J.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [Turner, Jessica A.] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. [Turner, Jessica A.] Georgia State Univ, Inst Neurosci, Atlanta, GA 30303 USA. [Keedy, Sarah K.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Badcock, Johanna C.] Univ Western Australia, Sch Psychol, Crawley, WA, Australia. [Badcock, Johanna C.] North Metropolitan Hlth Serv Mental Hlth, Clin Res Ctr, Mt Claremont, WA, Australia. RP Ford, JM (reprint author), San Francisco VA Med Ctr, Psychiat Serv 116D, 4150 Clement St, San Francisco, CA 94121 USA. EM judith.ford@ucsf.edu RI Keedy, Sarah/H-6557-2014; Badcock, Johanna/C-3682-2013; Turner, Jessica/H-7282-2015 OI Keedy, Sarah/0000-0002-2139-9271; Badcock, Johanna/0000-0003-4629-2929; Turner, Jessica/0000-0003-0076-8434 FU National Institute of Mental Health [MH058262, MH067073, MH073673]; Veterans Administration; VIDI from the Netherlands Organization for Scientific Research; National Institutes of Health [2P20GM103472-06]; Wellcome Trust [WT098455]; Macquarie University; [K23MH092702]; [P20RR021938 Phase 1NCRR COBRE] FX National Institute of Mental Health (MH058262 [J.M.F.], MH067073 [R. E. H.], MH073673 [R. E. H.]); Veterans Administration (J.M.F.); VIDI grant from the Netherlands Organization for Scientific Research (I. E. C. S.); K23MH092702 (S. K. K.); National Institutes of Health 2P20GM103472-06 (R.J.T.; J.A.T.); P20RR021938 Phase 1NCRR COBRE (R.J.T.); Wellcome Trust Grant (WT098455 to S.M.-J.); Macquarie University Research Fellowship (S.M.-J.). NR 61 TC 35 Z9 35 U1 5 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 SU 4 BP S295 EP S304 DI 10.1093/schbul/sbu011 PG 10 WC Psychiatry SC Psychiatry GA AK0US UT WOS:000338132100012 PM 24847862 ER PT J AU Cotlarciuc, I Malik, R Holliday, EG Ahmadi, KR Pare, G Psaty, BM Fornage, M Hasan, N Rinne, PE Ikram, MA Markus, HS Rosand, J Mitchell, BD Kittner, SJ Meschia, JF van Meurs, JBJ Uitterlinden, AG Worrall, BB Dichgans, M Sharma, P AF Cotlarciuc, Ioana Malik, Rainer Holliday, Elizabeth G. Ahmadi, Kourosh R. Pare, Guillaume Psaty, Bruce M. Fornage, Myriam Hasan, Nazeeha Rinne, Paul E. Ikram, M. Arfan Markus, Hugh S. Rosand, Jonathan Mitchell, Braxton D. Kittner, Steven J. Meschia, James F. van Meurs, Joyce B. J. Uitterlinden, Andre G. Worrall, Bradford B. Dichgans, Martin Sharma, Pankaj CA METASTROKE Int Stroke Genetics Consortium TI Effect of Genetic Variants Associated With Plasma Homocysteine Levels on Stroke Risk SO STROKE LA English DT Article DE genetic association studies; genetic risk score; homocysteine; stroke ID GENOME-WIDE ASSOCIATION; TRANSIENT ISCHEMIC ATTACK; PLACEBO-CONTROLLED TRIAL; SMALL VESSEL DISEASE; B-VITAMINS; URIC-ACID; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; METAANALYSIS; SUBTYPES AB Background and Purpose-Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. Methods-Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. Results-One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. Conclusions-This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS. C1 [Cotlarciuc, Ioana; Hasan, Nazeeha; Rinne, Paul E.; Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, Cerebrovasc Res Unit, Dept Med, London W6 8RF, England. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Med Ctr, Inst Stroke & Dementia Res, Munich, Germany. [Holliday, Elizabeth G.] Univ Newcastle, Sch Med & Publ Hlth, Ctr Clin Epidemiol & Biostat, Callaghan, NSW 2308, Australia. [Ahmadi, Kourosh R.] Univ Surrey, Fac Hlth & Med Sci, Dept Nutr Sci, Guildford GU2 5XH, Surrey, England. [Pare, Guillaume] McMaster Univ, Dept Pathol, Hamilton, ON, Canada. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Ikram, M. Arfan] Erasmus MC Univ, Med Ctr, Dept Epidemiol Neurol & Radiol, Rotterdam, Netherlands. [van Meurs, Joyce B. J.; Uitterlinden, Andre G.] Erasmus MC Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Markus, Hugh S.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England. [Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Mitchell, Braxton D.; Kittner, Steven J.] Vet Affairs Med Ctr, Baltimore, MD USA. [Mitchell, Braxton D.; Kittner, Steven J.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Kittner, Steven J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Dichgans, Martin] Munich Cluster Syst Neurol, Munich, Germany. RP Cotlarciuc, I (reprint author), Univ London Imperial Coll Sci Technol & Med, Cerebrovasc Res Unit, Dept Med, Fulham Palace Rd, London W6 8RF, England. EM i.cotlarciuc@imperial.ac.uk OI Ikram, Mohammad Arfan/0000-0003-0372-8585; Mitchell, Braxton/0000-0003-4920-4744 FU Department of Health (United Kingdom); Henry Smith Charity; British Council; United Kingdom-India Education and Research Institute; Qatar National Research Foundation; Wellcome Trust; UK Medical Research Council; Australian National and Medical Health Research Council; National Institutes of Health, National Heart, Lung, and Blood Institute; National Institutes of Health, National Institute on Aging; National Institutes of Health, National Human Genome Research Institute; National Institutes of Health, National Institute of Neurological Disorders and Stroke; American Heart Association-Bugher Foundation Centers for Stroke Prevention FX This study was supported by the Department of Health (United Kingdom), Henry Smith Charity, British Council, United Kingdom-India Education and Research Institute, and the Qatar National Research Foundation. Genotpying of the cohorts within METASTROKE was supported by the Wellcome Trust, UK Medical Research Council, Australian National and Medical Health Research Council, National Institutes of Health, including National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Human Genome Research Institute, the National Institute of Neurological Disorders and Stroke, and the American Heart Association-Bugher Foundation Centers for Stroke Prevention. NR 31 TC 9 Z9 9 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 1920 EP 1924 DI 10.1161/STROKEAHA.114.005208 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400014 PM 24846872 ER PT J AU Mahmoodi, BK Yatsuya, H Matsushita, K Sang, YY Gottesman, RF Astor, BC Woodward, M Longstreth, WT Psaty, BM Shlipak, MG Folsom, AR Gansevoort, RT Coresh, J AF Mahmoodi, Bakhtawar K. Yatsuya, Hiroshi Matsushita, Kunihiro Sang, Yinying Gottesman, Rebecca F. Astor, Brad C. Woodward, Mark Longstreth, W. T., Jr. Psaty, Bruce M. Shlipak, Michael G. Folsom, Aaron R. Gansevoort, Ron T. Coresh, Josef TI Association of Kidney Disease Measures With Ischemic Versus Hemorrhagic Strokes Pooled Analyses of 4 Prospective Community-Based Cohorts SO STROKE LA English DT Article DE cardiovascular; epidemiology; renal insufficiency; chronic; risk factors; stroke ID GLOMERULAR-FILTRATION-RATE; GENERAL-POPULATION; CYSTATIN C; INTRACEREBRAL HEMORRHAGE; CARDIOVASCULAR-DISEASE; INCIDENT STROKE; BLOOD-PRESSURE; OLDER-ADULTS; ALL-CAUSE; RISK AB Background and purpose-Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke. Methods-We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression. Results-Among 29 595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280 549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m(2) were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure. Conclusions-Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations. C1 [Mahmoodi, Bakhtawar K.; Matsushita, Kunihiro; Sang, Yinying; Woodward, Mark; Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mahmoodi, Bakhtawar K.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands. [Yatsuya, Hiroshi] Fujita Hlth Univ, Dept Publ Hlth, Toyoake, Aichi, Japan. [Gottesman, Rebecca F.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Astor, Brad C.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. [Astor, Brad C.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53706 USA. [Woodward, Mark] Univ Sydney, George Inst, Sydney, NSW 2006, Australia. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94143 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Coresh, J (reprint author), 2024 East Monument St,Suite 2-600, Baltimore, MD 21287 USA. EM coresh@jhu.edu RI Woodward, Mark/D-8492-2015 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN26820110 0007C, HHSN268201100008C, HHSN268201100009C, HHSN 268201100010C, HHSN268201100011C, HHSN268201100 012C]; NHLBI [HL080295, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Institute on Aging [AG023629]; Dutch Kidney Foundation; Dutch Heart Foundation; Dutch Government (NWO); US National Institutes of Health; University Medical Center Groningen; [HHSN268201200036C]; [N01HC85239]; [N01 HC55222]; [N01HC85079]; [N01HC85080]; [N01HC85081]; [N01HC85082]; [N01HC85083]; [N01HC85086] FX Atherosclerosis Risk in Communities Study (ARIC): The Atherosclerosis Risk in Communities Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN26820110 0007C, HHSN268201100008C, HHSN268201100009C, HHSN 268201100010C, HHSN268201100011C, and HHSN268201100 012C). We thank the staff and participants of the ARIC study for their important contributions. Cardiovascular Health Study (CHS): This research was supported by contracts HHSN268201200036C, N01HC85239, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. We thank the staff and participants of the CHS study for their important contributions. Multi-Ethnic Study of Atherosclerosis (MESA): This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the NHLBI. We thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Prevention of REnal and Vascular ENd-stage Disease (PREVEND): The PREVEND study is supported by several grants from the Dutch Kidney Foundation, and grants from the Dutch Heart Foundation, the Dutch Government (NWO), the US National Institutes of Health, and the University Medical Center Groningen. We thank the staff and participants of the PREVEND study for their important contributions. None of the aforementioned sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the article. NR 29 TC 16 Z9 17 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 1925 EP 1931 DI 10.1161/STROKEAHA.114.004900 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400015 PM 24876078 ER PT J AU Boan, AD Feng, WW Ovbiagele, B Bachman, DL Ellis, C Adams, RJ Kautz, SA Lackland, DT AF Boan, Andrea D. Feng, Wuwei (Wayne) Ovbiagele, Bruce Bachman, David L. Ellis, Charles Adams, Robert J. Kautz, Steven A. Lackland, Daniel T. TI Persistent Racial Disparity in Stroke Hospitalization and Economic Impact in Young Adults in the Buckle of Stroke Belt SO STROKE LA English DT Article DE epidemiology; fees and charges; middle aged; minority health; stroke ID AMERICAN-HEART-ASSOCIATION; UNITED-STATES; BIRACIAL POPULATION; SEEKING TREATMENT; RECURRENT STROKE; TEMPORAL TRENDS; SOUTH-CAROLINA; BLOOD-PRESSURE; RISK; HEALTH AB Background and Purpose-Mounting evidence points to a decline in stroke incidence. However, little is known about recent patterns of stroke hospitalization within the buckle of the stroke belt. This study aims to investigate the age-and race-specific secular trends in stroke hospitalization rates, inpatient stroke mortality rates, and related hospitalization charges during the past decade in South Carolina. Methods-Patients from 2001 to 2010 were identified from the State Inpatient Hospital Discharge Database with a primary discharge diagnosis of stroke (International Classification of Diseases, Ninth Revision codes: 430-434, 436, 437.1). Age- and race-stroke-specific hospitalization rates, hospital charges, charges associated with racial disparity, and 30-day stroke mortality rates were compared between blacks and whites. Results-Of the 84 179 stroke hospitalizations, 31 137 (37.0%) were from patients aged < 65 years and 29 846 (35.5%) were blacks. Stroke hospitalization rates decreased in the older population (aged >= 65 years) for both blacks and whites (P<0.001) but increased among the younger group (aged <65 years; P=0.004); however, this increase was mainly driven by a 17.3% rise among blacks (P=0.001), with no difference seen among whites (P=0.84). Of hospital charges totaling $2.77 billion, $453.2 million (16.4%) are associated with racial disparity (79.6% from patients aged < 65 years). Thirty-day stroke mortality rates decreased in all age-race-stroke-specific groups (P<0.001). Conclusions-The stroke hospitalization rate increased in the young blacks only, which results in a severe and persistent racial disparity. It highlights the urgent need for a racial disparity reduction in the younger population to alleviate the healthcare burden. C1 [Boan, Andrea D.; Feng, Wuwei (Wayne); Ovbiagele, Bruce; Bachman, David L.; Adams, Robert J.; Kautz, Steven A.; Lackland, Daniel T.] Med Univ S Carolina, Stroke Ctr, Dept Neurosci, Charleston, SC 29425 USA. [Feng, Wuwei (Wayne); Ellis, Charles; Kautz, Steven A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Ovbiagele, Bruce; Kautz, Steven A.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Feng, WW (reprint author), MUSC Stroke Ctr, Dept Neurosci, 19 Hagood Ave,STE 501, Charleston, SC 29425 USA. EM feng@musc.edu FU Southeastern Virtual Institute for Heath Equality and Wellness; US Army Medical Research and Materiel Command; Telemedicine & Advanced Technology Research Center [W81XWH-10-2-0057]; Stroke Education and Prevention-South Carolina; Health Sciences South Carolina; Consortium for Southeastern Hypertension Control FX This research was supported by Southeastern Virtual Institute for Heath Equality and Wellness, US Army Medical Research and Materiel Command and Telemedicine & Advanced Technology Research Center (W81XWH-10-2-0057); Stroke Education and Prevention-South Carolina, Health Sciences South Carolina; and Consortium for Southeastern Hypertension Control. NR 37 TC 7 Z9 7 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 1932 EP 1938 DI 10.1161/STROKEAHA.114.004853 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400016 PM 24947293 ER PT J AU Bernard, TJ Rivkin, MJ Scholz, K deVeber, G Kirton, A Gill, JC Chan, AK Hovinga, CA Ichord, RN Grotta, JC Jordan, LC Benedict, S Friedman, NR Dowling, MM Elbers, J Torres, M Sultan, S Cummings, DD Grabowski, EF McMillan, HJ Beslow, LA Amlie-Lefond, C AF Bernard, Timothy J. Rivkin, Michael J. Scholz, Kelley deVeber, Gabrielle Kirton, Adam Gill, Joan Cox Chan, Anthony K. Hovinga, Collin A. Ichord, Rebecca N. Grotta, James C. Jordan, Lori C. Benedict, Susan Friedman, Neil R. Dowling, Michael M. Elbers, Jorina Torres, Marcela Sultan, Sally Cummings, Dana D. Grabowski, Eric F. McMillan, Hugh J. Beslow, Lauren A. Amlie-Lefond, Catherine CA Thrombolysis Pediat Stroke Study TI Emergence of the Primary Pediatric Stroke Center Impact of the Thrombolysis in Pediatric Stroke Trial SO STROKE LA English DT Article DE child; stroke; thrombolytic therapy ID ARTERIAL ISCHEMIC-STROKE; EARLY MANAGEMENT; CHILDREN; ASSOCIATION; GUIDELINES; COUNCIL; DISEASE AB Background and Purpose-In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial. Methods-We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy. Results-Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P <= 0.001). Conclusions-Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator. C1 [Bernard, Timothy J.] Childrens Hosp Colorado, Dept Neurol, Aurora, CO USA. [Rivkin, Michael J.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Rivkin, Michael J.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA. [Rivkin, Michael J.] Boston Childrens Hosp, Dept Radiol, Boston, MA USA. [deVeber, Gabrielle] Hosp Sick Children, Dept Neurol, Toronto, ON M5G 1X8, Canada. [Kirton, Adam] Univ Calgary, Alberta Childrens Hosp Res Inst, Dept Neurol, Calgary, AB, Canada. [Gill, Joan Cox] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Gill, Joan Cox] BloodCtr Wisconsin, Milwaukee, WI USA. [Chan, Anthony K.] McMaster Univ, Dept Pediat, Hamilton, ON, Canada. [Hovinga, Collin A.] Dell Childrens Med Ctr, Dept Pediat, Austin, TX USA. [Ichord, Rebecca N.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Gill, Joan Cox] Mem Hermann Hosp, Dept Neurol, Houston, TX USA. [Jordan, Lori C.] Vanderbilt Univ, Div Pediat Neurol, Nashville, TN 37235 USA. [Benedict, Susan] Primary Childrens Med Ctr, Dept Neurol, Salt Lake City, UT 84103 USA. [Friedman, Neil R.] Cleveland Clin, Dept Neurol, Cleveland, OH USA. [Dowling, Michael M.] UT Southwestern Med Ctr, Dept Pediat & Neurol, Dallas, TX USA. [Elbers, Jorina] Stanford Univ, Dept Neurol, Stanford, CA 94305 USA. [Torres, Marcela] Cook Childrens Med Ctr, Dept Hematol & Oncol, Ft Worth, TX USA. [Sultan, Sally] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Cummings, Dana D.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Div Child Neurol, Med Ctr, Pittsburgh, PA 15260 USA. [Grabowski, Eric F.] Mass Gen Hosp Children, Dept Pediat, Div Pediat Hematol Oncol, Boston, MA USA. [Grabowski, Eric F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McMillan, Hugh J.] Childrens Hosp Eastern Ontario, Dept Neurol, Ottawa, ON K1H 8L1, Canada. [Beslow, Lauren A.] Yale New Haven Childrens Hosp, Dept Pediat, New Haven, CT USA. [Beslow, Lauren A.] Yale New Haven Childrens Hosp, Dept Neurol, New Haven, CT USA. [Scholz, Kelley; Amlie-Lefond, Catherine] Seattle Childrens Hosp, Dept Neurol, Seattle, WA USA. [Amlie-Lefond, Catherine] Univ Washington, Dept Neurol, Seattle, WA 98105 USA. RP Amlie-Lefond, C (reprint author), Univ Washington, Seattle Childrens Hosp, Dept Neurol, MB 7-420,4800 Sand Point Way NE, Seattle, WA 98105 USA. EM Calefond@uw.edu RI Kirton, Adam/L-8875-2016; OI Friedman, Neil/0000-0002-7349-7981; Chan, Anthony K. C./0000-0003-1551-3995 FU National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health [R01NS065818]; National Institutes of Health, National Heart, Lung, and Blood Institute [1K23HL096895-01A1]; ASA/Bugher Foundation Stroke Collaborative Research Center [14BFSC17540000]; NINDS [R01NS065818]; NINDS of the National Institutes of Health [R01NS065818] FX Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health under Award No. R01NS065818. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Bernard was supported by a grant from the National Institutes of Health, National Heart, Lung, and Blood Institute (1K23HL096895-01A1), and the ASA/Bugher Foundation Stroke Collaborative Research Center (14BFSC17540000). Dr Rivkin was supported by NINDS R01NS065818. Dr Rivkin, K. Scholz, and Drs deVeber, Kirton, Gill, Chan, Hovinga, Ichord, and Amlie-Lefond were supported by NINDS of the National Institutes of Health under Award No. R01NS065818. NR 17 TC 37 Z9 38 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 2018 EP 2023 DI 10.1161/STROKEAHA.114.004919 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400029 PM 24916908 ER PT J AU Lich, KH Tian, Y Beadles, CA Williams, LS Bravata, DM Cheng, EM Bosworth, HB Homer, JB Matchar, DB AF Lich, Kristen Hassmiller Tian, Yuan Beadles, Christopher A. Williams, Linda S. Bravata, Dawn M. Cheng, Eric M. Bosworth, Hayden B. Homer, Jack B. Matchar, David B. TI Strategic Planning to Reduce the Burden of Stroke Among Veterans Using Simulation Modeling to Inform Decision Making SO STROKE LA English DT Article DE comparative effectiveness research; computer simulation; health planning; stroke; Veterans ID ISCHEMIC-STROKE; ATRIAL-FIBRILLATION; TASK-FORCE; CARE; HEALTH; PREVENTION; OUTCOMES; QUALITY; ORGANIZATION; ASSOCIATION AB Background and Purpose-Reducing the burden of stroke is a priority for the Veterans Affairs Health System, reflected by the creation of the Veterans Affairs Stroke Quality Enhancement Research Initiative. To inform the initiative's strategic planning, we estimated the relative population-level impact and efficiency of distinct approaches to improving stroke care in the US Veteran population to inform policy and practice. Methods-A System Dynamics stroke model of the Veteran population was constructed to evaluate the relative impact of 15 intervention scenarios including both broad and targeted primary and secondary prevention and acute care/rehabilitation on cumulative (20 years) outcomes including quality-adjusted life years (QALYs) gained, strokes prevented, stroke fatalities prevented, and the number-needed-to-treat per QALY gained. Results-At the population level, a broad hypertension control effort yielded the largest increase in QALYs (35 517), followed by targeted prevention addressing hypertension and anticoagulation among Veterans with prior cardiovascular disease (27 856) and hypertension control among diabetics (23 100). Adjusting QALYs gained by the number of Veterans needed to treat, thrombolytic therapy with tissue-type plasminogen activator was most efficient, needing 3.1 Veterans to be treated per QALY gained. This was followed by rehabilitation (3.9) and targeted prevention addressing hypertension and anticoagulation among those with prior cardiovascular disease (5.1). Probabilistic sensitivity analysis showed that the ranking of interventions was robust to uncertainty in input parameter values. Conclusions-Prevention strategies tend to have larger population impacts, though interventions targeting specific high-risk groups tend to be more efficient in terms of number-needed-to-treat per QALY gained. C1 [Lich, Kristen Hassmiller] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Tian, Yuan; Matchar, David B.] Duke NUS Grad Med Sch, Program Hlth Serv & Syst Res, Singapore, Singapore. [Beadles, Christopher A.; Bosworth, Hayden B.] Durham VAMC, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Williams, Linda S.; Bravata, Dawn M.] VHA Hlth Serv Res & Dev Stroke Qual Enhancement R, Indianapolis, IN USA. [Williams, Linda S.; Bravata, Dawn M.] Richard L Roudebush VHA Med Ctr, VHA Hlth Serv Res & Dev Ctr Excellence Implementi, Indianapolis, IN USA. [Williams, Linda S.; Bravata, Dawn M.] Regenstrief Inst Hlth Care, Indianapolis, IN USA. [Williams, Linda S.] VA Ctr Appl Syst Engn, Vet Engn Resource Ctr, Dept Vet Affairs, Indianapolis, IN USA. [Bravata, Dawn M.] Indiana Univ Sch Med, Dept Internal Med, Indianapolis, IN 46202 USA. [Cheng, Eric M.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA 90073 USA. [Cheng, Eric M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Bosworth, Hayden B.; Matchar, David B.] Duke Univ, Dept Med, Div Gen Internal Med, Durham, NC USA. [Homer, Jack B.] Homer Consulting, Voorhees, NJ USA. [Matchar, David B.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. RP Lich, KH (reprint author), UNC Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, 135 Dauer Dr,Campus Box 7411, Chapel Hill, NC 27599 USA. EM klich@unc.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service Quality Enhancement Research Initiative [RRP 07-295]; National Center for Research Resources [KL2RR025746]; National Institutes of Health/National Institute of Neurological Disorders and Stroke [K23NS058571]; Singapore Ministry of Health's National Medical Research Council under its STaR Award Grant; VA HSRD [08-027] FX This research was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service Quality Enhancement Research Initiative (RRP 07-295). Effort by the following authors was also supported by the following grants: K.H.L. by award number KL2RR025746 from the National Center for Research Resources; D.B.M. by award number K23NS058571 from the National Institutes of Health/National Institute of Neurological Disorders and Stroke and the Singapore Ministry of Health's National Medical Research Council under its STaR Award Grant; and H. B. B. by a senior career scientist award from VA HSR&D (08-027). The authors take sole responsibility for the scientific validity and accuracy of the methodology, results, statistical analyses, and conclusions presented. NR 34 TC 2 Z9 2 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 2078 EP 2084 DI 10.1161/STROKEAHA.114.004694 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400039 PM 24923722 ER PT J AU Xing, CH Wang, XS Cheng, CJ Montaner, J Mandeville, E Leung, W van Leyen, K Lok, J Wang, XY Lo, EH AF Xing, Changhong Wang, Xiaoshu Cheng, Chongjie Montaner, Joan Mandeville, Emiri Leung, Wendy van Leyen, Klaus Lok, Josephine Wang, Xiaoying Lo, Eng H. TI Neuronal Production of Lipocalin-2 as a Help-Me Signal for Glial Activation SO STROKE LA English DT Article DE astrocytes; lipocalins; microglia; neurons ID NECROSIS-FACTOR-ALPHA; NEUTROPHIL GELATINASE; INFLAMMATORY MEDIATORS; MACROPHAGE ACTIVATION; CEREBRAL-ISCHEMIA; STROKE; INJURY; ASTROCYTES; BRAIN; MECHANISMS AB Background and Purpose-We explored the hypothesis that injured neurons release lipocalin-2 as a help me signal. Methods-In vivo lipocalin-2 responses were assessed in rat focal cerebral ischemia and human stroke brain samples using a combination of ELISA and immunostaining. In vitro, microglia and astrocytes were exposed to lipocalin-2, and various markers and assays of glial activation were quantified. Functional relevance of neuron-to-glia lipocalin-2 signaling was examined by transferring conditioned media from lipocalin-2-activated microglia and astrocytes onto neurons to see whether activated glia could protect neurons against oxygen-glucose deprivation and promote neuroplasticity. Results-In human stroke samples and rat cerebral ischemia, neuronal expression of lipocalin-2 was significantly increased. In primary cell cultures, exposing microglia and astrocytes to lipocalin-2 resulted in glial activation. In microglia, lipocalin-2 converted resting ramified shapes into a long-rod morphology with reduced branching, increased interleukin-10 release, and enhanced phagocytosis. In astrocytes, lipocalin-2 upregulated glial fibrillary acid protein, brain-derived neurotropic factor, and thrombospondin-1. Conditioned media from lipocalin-2-treated astrocytes upregulated synaptotagmin, and conditioned media from lipocalin-2-treated microglia upregulated synaptophysin and post-synaptic density 95 (PSD95) and protected neurons against oxygen-glucose deprivation. Conclusions-These findings provide proof of concept that lipocalin-2 is released by injured neurons as a help me distress signal that activates microglia and astrocytes into potentially prorecovery phenotypes. C1 [Xing, Changhong; Wang, Xiaoshu; Cheng, Chongjie; Mandeville, Emiri; Leung, Wendy; van Leyen, Klaus; Lok, Josephine; Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Xing, Changhong; Wang, Xiaoshu; Cheng, Chongjie; Mandeville, Emiri; Leung, Wendy; van Leyen, Klaus; Lok, Josephine; Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Xing, Changhong; Wang, Xiaoshu; Cheng, Chongjie; Mandeville, Emiri; Leung, Wendy; van Leyen, Klaus; Lok, Josephine; Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA 02129 USA. [Wang, Xiaoshu; Cheng, Chongjie] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing, Peoples R China. [Montaner, Joan] Vall dHebron Univ Hosp Res Inst, Neurovasc Res Lab, Barcelona, Spain. RP Lo, EH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, MGH E 149-2401, Charlestown, MA 02129 USA. EM xing.changhong@mgh.harvard.edu; Lo@helix.mgh.harvard.edu RI Montaner, Joan/D-3063-2015; IBIS, NEUROVASCULAR/O-1855-2015 FU National Institutes of Health; Rappaport Foundation FX This work was supported in part by National Institutes of Health and the Rappaport Foundation. NR 44 TC 11 Z9 11 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 2085 EP 2092 DI 10.1161/STROKEAHA.114.005733 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400040 PM 24916903 ER PT J AU Kernan, WN Ovbiagele, B Black, HR Bravata, DM Chimowitz, MI Ezekowitz, MD Fang, MC Fisher, M Furie, KL Heck, DV Johnston, SC Kasner, SE Kittner, SJ Mitchell, PH Rich, MW Richardson, D Schwamm, LH Wilson, JA AF Kernan, Walter N. Ovbiagele, Bruce Black, Henry R. Bravata, Dawn M. Chimowitz, Marc I. Ezekowitz, Michael D. Fang, Margaret C. Fisher, Marc Furie, Karen L. Heck, Donald V. Johnston, S. Claiborne (Clay) Kasner, Scott E. Kittner, Steven J. Mitchell, Pamela H. Rich, Michael W. Richardson, DeJuran Schwamm, Lee H. Wilson, John A. CA Amer Heart Assoc Stroke Council Council Cardiovasc Stroke Nursing Council Clinical Cardiology Council Peripheral Vasc Dis TI Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association SO STROKE LA English DT Article DE AHA Scientific Statements; atrial fibrillation; carotid stenosis; hypertension; ischemia; ischemic attack, transient; prevention; stroke ID RANDOMIZED CONTROLLED-TRIAL; PATENT FORAMEN OVALE; SICKLE-CELL-DISEASE; HIGH-RISK PATIENTS; MITRAL-VALVE-PROLAPSE; TERM-FOLLOW-UP; INTRACRANIAL ARTERIAL-STENOSIS; POSITIVE AIRWAY PRESSURE; PLACEBO-CONTROLLED TRIAL; OBSTRUCTIVE SLEEP-APNEA AB The aim of this updated guideline is to provide comprehensive and timely evidence-based recommendations on the prevention of future stroke among survivors of ischemic stroke or transient ischemic attack. The guideline is addressed to all clinicians who manage secondary prevention for these patients. Evidence-based recommendations are provided for control of risk factors, intervention for vascular obstruction, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke. Recommendations are also provided for the prevention of recurrent stroke in a variety of specific circumstances, including aortic arch atherosclerosis, arterial dissection, patent foramen ovale, hyperhomocysteinemia, hypercoagulable states, antiphospholipid antibody syndrome, sickle cell disease, cerebral venous sinus thrombosis, and pregnancy. Special sections address use of antithrombotic and anticoagulation therapy after an intracranial hemorrhage and implementation of guidelines. C1 [Kernan, Walter N.] Yale Univ, New Haven, CT 06520 USA. [Ovbiagele, Bruce; Chimowitz, Marc I.] Med Univ S Carolina, Charleston, SC USA. [Black, Henry R.] NYU, Sch Med, New York, NY 10003 USA. [Bravata, Dawn M.] Dept Vet Affairs, Washington, DC USA. [Ezekowitz, Michael D.] Lankenau Med Ctr, Wynnewood, PA USA. [Fang, Margaret C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Fisher, Marc] Univ Massachusetts, Mem Hlth Care, Amherst, MA 01003 USA. [Furie, Karen L.; Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Heck, Donald V.] Triad Radiol Associates, Forsyth Med Ctr, Winston Salem, NC USA. [Johnston, S. Claiborne (Clay)] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kasner, Scott E.] Univ Penn, Philadelphia, PA 19104 USA. [Kittner, Steven J.] Baltimore Vet Adm Med Ctr, Baltimore, MD USA. [Kittner, Steven J.] Univ Maryland, Sch Med, College Pk, MD USA. [Mitchell, Pamela H.] Univ Washington, Seattle, WA 98195 USA. [Rich, Michael W.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Richardson, DeJuran] Rush Univ, Lake Forest Coll, Med Ctr, Chicago, IL USA. [Wilson, John A.] Wake Forest Sch Med, Winston Salem, NC USA. RP Kernan, WN (reprint author), Yale Univ, New Haven, CT 06520 USA. EM kelle.ramsay@wolterskluwer.com OI Schwamm, Lee/0000-0003-0592-9145 NR 840 TC 580 Z9 629 U1 16 U2 99 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2014 VL 45 IS 7 BP 2160 EP 2236 DI 10.1161/STR.0000000000000024 PG 77 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AK0TV UT WOS:000338129400058 PM 24788967 ER PT J AU Dixon, RF Rao, L AF Dixon, Ronald F. Rao, Latha TI Asynchronous Virtual Visits for the Follow-Up of Chronic Conditions SO TELEMEDICINE AND E-HEALTH LA English DT Article DE e-health; telehealth; telemedicine; technology ID PRIMARY-CARE; MEDICINE AB Background: Both primary care and specialty care in many areas face access constraints. Tools to evaluate and engage patients with chronic disease, without having them present to the clinic, are needed. Asynchronous virtual care has been explored as one of the ways to deliver care more efficiently, yet this has not been integrated into a busy practice environment. This pilot study aims to assess the utility of a Web platform that allows patients with chronic disease to be evaluated for follow-up care, thereby avoiding an office visit. Materials and Methods: Patients with 10 common chronic conditions were recruited into the study at a busy primary care clinic. Instead of booking an in-office follow-up visit, they were directed online to complete a questionnaire pertaining to their condition 7-28 days after their office visit. Their physician would review their responses and make treatment decisions, informing the patient online. Patient and physician satisfaction was measured using a validated Likert scale after each visit. Results: Patients were satisfied with the Web site and process as a way to receive their follow-up care. Clinicians were satisfied in making clinical decisions with the information received via the Web site. The clinician time spent for the overall encounter was significantly shorter than for an in-person follow-up visit. Conclusions: Clinicians and patients are interested in tools that improve patient health, are convenient, and save time for both parties. Targeting patients with chronic illness and leveraging available technology to deliver the care are very satisfactory to both clinicians and patients. Asynchronous virtual visits for patients with chronic medical conditions are an effective way to evaluate and manage patients, while providing physicians significant time savings. These visits have the potential to reduce in-office follow-up visits across primary care, potentially improving access and reducing costs. C1 [Dixon, Ronald F.; Rao, Latha] Massachusetts Gen Hosp Beacon Hill Primary Care, Boston, MA 02114 USA. [Dixon, Ronald F.] Ctr Integrat Med & Technol CIMIT, Boston, MA USA. RP Dixon, RF (reprint author), Massachusetts Gen Hosp Beacon Hill Primary Care, 165 Cambridge St, Boston, MA 02114 USA. EM rdixon@partners.org NR 10 TC 5 Z9 6 U1 2 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD JUL PY 2014 VL 20 IS 7 BP 669 EP 672 DI 10.1089/tmj.2013.0211 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AK1PN UT WOS:000338187400012 PM 24784174 ER PT J AU Caban-Martinez, AJ Lowe, KA Herrick, R Kenwood, C Gagne, JJ Becker, JF Schneider, SP Dennerlein, JT Sorensen, G AF Caban-Martinez, Alberto J. Lowe, Kincaid A. Herrick, Robert Kenwood, Christopher Gagne, Joshua J. Becker, Jamie F. Schneider, Scott P. Dennerlein, Jack T. Sorensen, Glorian TI Construction workers working in musculoskeletal pain and engaging in leisure-time physical activity: Findings from a mixed-methods pilot study SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE musculoskeletal pain; physical activity; construction workers; mixedmethods ID BACK-PAIN; HEALTH; VALIDITY; OSTEOARTHRITIS; DISORDER; JOINT AB Background While exercise has been shown to be beneficial for some musculoskeletal pain conditions, construction workers who are regularly burdened with musculoskeletal pain may engage less in leisure-time physical activity (LTPA) due to pain. In a small pilot study, we investigate how musculoskeletal pain may influence participation in LTPA among construction workers. Methods A sequential explanatory mixed-methods design was employed using a jobsite-based survey (n=43) among workers at two commercial construction sites and one focus group (n=5). Results Over 93% of these construction workers reported engaging in LTPA and 70% reported musculoskeletal pain. Fifty-seven percent of workers who met either moderate or vigorous LTPA guidelines reported lower extremity pain (i.e., ankle, knee) compared with 21% of those who did not engage in either LTPA (P=0.04). Focus group analyses indicate that workers felt they already get significant physical activity out of their job because they are moving all the time and not sitting behind a desk. Workers also felt they have no choice but to work through pain and discomfort [as the worker] needs to do anything to get the job done. Conclusion Pilot study findings suggest that construction workers not only engage in either moderate or vigorous LTPA despite musculoskeletal pain but workers in pain engage in more LTPA than construction workers without pain. Am. J. Ind. Med. 57:819-825, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Caban-Martinez, Alberto J.; Herrick, Robert; Dennerlein, Jack T.; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Lowe, Kincaid A.] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. [Kenwood, Christopher] New England Res Inst, Watertown, MA 02172 USA. [Gagne, Joshua J.; Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Becker, Jamie F.; Schneider, Scott P.] Laborers Hlth & Safety Fund North Amer, Washington, DC USA. [Dennerlein, Jack T.] Northeastern Univ, Bouve Coll Hlth Sci, Dept Phys Therapy Movement & Rehabil Sci, Boston, MA 02115 USA. RP Caban-Martinez, AJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 401 Pk Dr,Landmark Ctr Bldg,3F,West 112, Boston, MA 02215 USA. EM acaban@hsph.harvard.edu OI Dennerlein, Jack/0000-0001-7703-643X FU National Institute for Occupational Safety and Health (NIOSH) [U19 OH008861]; NIOSH Center of Excellence; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [T32 AR055885]; Women's Hospital, Harvard Medical School; Harvard School of Public Health FX This work was supported by National Institute for Occupational Safety and Health (NIOSH) grant U19 OH008861 (PI: Sorensen) to the Harvard School of Public Health Center for Work, Health, and Wellbeing, a NIOSH Center of Excellence to Promote a Healthier Work Force and from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant T32 AR055885 (PI: Katz) to the Clinical Orthopedic and Musculoskeletal Education and Training (COMET) Program at Brigham and Women's Hospital, Harvard Medical School and Harvard School of Public Health (Trainee: Caban-Martinez). NR 23 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD JUL PY 2014 VL 57 IS 7 BP 819 EP 825 DI 10.1002/ajim.22332 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AJ9JS UT WOS:000338026600009 PM 24760608 ER PT J AU Feke, GT Bex, PJ Taylor, CP Rhee, DJ Turalba, AV Chen, TC Wand, M Pasquale, LR AF Feke, Gilbert T. Bex, Peter J. Taylor, Christopher P. Rhee, Douglas J. Turalba, Angela V. Chen, Teresa C. Wand, Martin Pasquale, Louis R. TI Effect of Brimonidine on Retinal Vascular Autoregulation and Short-term Visual Function in Normal Tension Glaucoma SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OPEN-ANGLE GLAUCOMA; NITRIC-OXIDE SYNTHASE; BLOOD-FLOW; VITREOUS CONCENTRATION; INTRAOCULAR-PRESSURE; PERFUSION-PRESSURE; GENE VARIANTS; ASSOCIATION; TARTRATE; POLYMORPHISMS AB PURPOSE: To assess whether brimonidine 0.15% alters retinal vascular autoregulation and short-term visual function in normal tension glaucoma patients who demonstrate retinal vascular dysregulation. DESIGN: Nonrandomized clinical trial. METHODS: In this prospective study, 46 normal tension glaucoma patients not previously treated with brimonidine underwent retinal vascular autoregulation testing and visual function assessment using frequency doubling technology perimetry and equivalent noise motion sensitivity testing. We measured blood flow in a major temporal retinal artery with subjects seated and then while reclined for 30 minutes. Patients having a change in retinal blood flow with posture change outside the range previously found in healthy subjects were classified as having retinal vascular dysregulation. They were treated with brimonidine 0.15% for 8 weeks and designated for retesting. RESULTS: Twenty-three patients demonstrated retinal vascular dysregulation at the initial visit. Younger age (P = .050) and diabetes (P = .055) were marginally significant risk factors for retinal vascular dysregulation. After the 8-week course with brimonidine, 14 of the 17 patients who completed the study showed a return of posture-induced retinal blood flow changes to levels consistent with normal retinal vascular autoregulation (P < .0001). We found no significant changes in frequency doubling technology perimetry or in motion detection parameters following treatment with brimondine (P > .09 for all tests performed). CONCLUSIONS: Brimonidine significantly improved impaired retinal vascular autoregulation in normal tension glaucoma patients, but short-term alteration in visual function could not be demonstrated. (C) 2014 by Elsevier Inc. All rights reserved.) C1 [Feke, Gilbert T.; Rhee, Douglas J.; Turalba, Angela V.; Chen, Teresa C.; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [Bex, Peter J.; Taylor, Christopher P.] Harvard Univ, Schepens Eye Res Inst, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Wand, Martin] Consulting Ophthalmologists, Farmington, CT USA. RP Pasquale, LR (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM Louis_Pasquale@meei.harvard.edu OI Pasquale, Louis/0000-0002-5835-3496 FU Allergan; Merck; National Eye Institute [RO1 EY015473]; Paul and Sylvia Margolis Fund, Waltham, Massachusetts; National Institute of Health [R01 EY018664]; Research to Prevent Blindness Award; Harvard Glaucoma Center of Excellence; Harvard Distinguished Scholar Award; Allergan, Inc.; ClinicalTrials.gov [NCT01105065] FX The authors indicate the following: D.J.R.: consultancy: Aerie, Alcon, Allergan, Aquesys, Glaukos, Ivantis, Johnson and Johnson, Merck, Santen; grants: Alcon, Merck, Aquesys; stock: Aerie. L.R.P.: For work outside the scope of this project, received financial support from Allergan, Merck, and the National Eye Institute (grant # RO1 EY015473) for research purposes. Support was provided by the Paul and Sylvia Margolis Fund, Waltham, Massachusetts (L.R.P.) and by the National Institute of Health Grant #R01 EY018664 (P.J.B.). Additional support was provided by a, Research to Prevent Blindness Award (L.R.P.), the Harvard Glaucoma Center of Excellence, and a Harvard Distinguished Scholar Award (L.R.P.). The Glaucoma Service at Massachusetts Eye & Ear Infirmary was. a recipient of a Horizon Grant from Allergan, Inc. The study was registered with ClinicalTrials.gov (identifier: NCT01105065). Author contributions: design of the study (G.T.F., L.R.P.); conduct of the study (G.T.F., P.J.B., C.P.T., L.R.P.); collection, management, and analysis of the data (G.T.F., P.J.B., C.P.T., L.R.P.); interpretation of the data (G.T.F., P.J.B., L.R.P.); preparation of the manuscript (G.T.F.,P.J.B., L.R.P.); review and approval of the manuscript (G.T.F., P.J.B., D.J.R., A.V.T., T.C.C., M.W., L.R.P.). NR 39 TC 5 Z9 5 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUL PY 2014 VL 158 IS 1 BP 105 EP 112 DI 10.1016/j.ajo.2014.03.015 PG 8 WC Ophthalmology SC Ophthalmology GA AK0IY UT WOS:000338097300015 PM 24709811 ER PT J AU Chen, YW Chhabra, N Liu, YCC Zender, CA AF Chen, Yunwei Chhabra, Nipun Liu, Yi-Chun Carol Zender, Chad A. TI Lateral arm microvascular free tissue reconstruction of a large neck keloid SO AMERICAN JOURNAL OF OTOLARYNGOLOGY LA English DT Article ID EXCISED KELOIDS; THERAPY; SCARS AB Keloid scars pose a surgical challenge in the region of the head and neck. We present a rare case of a large infected and recurrent neck keloid that failed multiple prior reconstructive attempts. Ultimately, the tissue was resected and the surgical bed was repaired with a lateral arm microvascular free flap. This repair emphasizes the need for adequate coverage of the defect while maintaining neck mobility, ease of swallowing, and cosmesis. This is the second report in the literature of free tissue transfer as treatment for a large keloid scar, and the first to show the feasibility of early post operative low dose irradiation of the surgical bed. Published by Elsevier Inc. C1 [Chen, Yunwei] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Chhabra, Nipun] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Liu, Yi-Chun Carol; Zender, Chad A.] Case Western Reserve Univ, Ear Nose & Throat Inst, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. RP Liu, YCC (reprint author), Univ Hosp Case Med Ctr, Dept Otolaryngol Head & Neck Surg, 11100 Euclid Ave,LKS 5045,Room 4535, Cleveland, OH 44106 USA. EM yichun.liu@uhhospitals.org NR 12 TC 3 Z9 3 U1 0 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 0196-0709 EI 1532-818X J9 AM J OTOLARYNG JI Am. J. Otolaryngol. PD JUL-AUG PY 2014 VL 35 IS 4 BP 514 EP 516 DI 10.1016/j.amjoto.2014.01.008 PG 3 WC Otorhinolaryngology SC Otorhinolaryngology GA AK0GM UT WOS:000338090900009 PM 24703777 ER PT J AU Raskind, MA McCaslin, C Jakupcak, M AF Raskind, Murray A. McCaslin, Creed Jakupcak, Matthew TI Violence in War and Violence Back Home SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID POSTTRAUMATIC-STRESS-DISORDER; EXPERIENTIAL AVOIDANCE; ALCOHOL-USE; VETERANS; IRAQ; AFGHANISTAN; COMBAT; ANGER; AGGRESSION; BEHAVIOR C1 [Raskind, Murray A.] Northwest Network VISN 20 Mental Illness Res Educ, Seattle, WA USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Raskind, MA (reprint author), Northwest Network VISN 20 Mental Illness Res Educ, Seattle, WA USA. EM murray.raskind@va.gov NR 15 TC 0 Z9 0 U1 3 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2014 VL 171 IS 7 BP 701 EP 704 DI 10.1176/appi.ajp.2014.14040528 PG 4 WC Psychiatry SC Psychiatry GA AJ9AD UT WOS:000337998300001 PM 24980162 ER PT J AU Freeman, MP AF Freeman, Marlene P. TI ADHD and Pregnancy SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; COCAINE EXPOSURE; FOLLOW-UP; METHYLPHENIDATE; ADULTS; BUPROPION; MEMORY; WOMEN; METAANALYSIS AB Attention deficit hyperactivity disorder (ADHD) has been increasingly recognized and treated in children and adults in recent years. As a result, a growing number of women enter their reproductive years treated with medication for ADHD or are diagnosed and start medication during their reproductive years. A common question in perinatal psychiatry regards the risk-benefit profile of pharmacotherapy for ADHD, particularly with stimulants. At this time, there are no guidelines to inform the treatment of ADHD across pregnancy and the postpartum period. Concerns about in utero exposure to stimulants are based primarily on the impact these medications might have on fetal growth. While stimulants do not appear to be associated with major congenital malformations, more human data regarding potential behavioral teratogenicity are needed in order to understand both the short- and long-term risks. Severity of illness, presence of comorbid disorders, and degree of impairment have an impact on treatment decisions. Crucial considerations include driving safety and ability to function in occupational roles. While most women can successfully avoid the use of stimulant medication during pregnancy, there are cases in which the benefits of stimulant treatment outweigh known and putative risks of in utero medication exposure. C1 [Freeman, Marlene P.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Freeman, Marlene P.] Massachusetts Gen Hosp, Perinatal & Reprod Psychiat Program, Boston, MA 02114 USA. RP Freeman, MP (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. EM mfreeman@partners.org FU Forest; GlaxoSmithKline; Lilly; Otsuka/Lundbeck; Pamlab; Takeda FX Dr. Freeman has received research support from or served on advisory boards or as a consultant for Forest, GlaxoSmithKline, Lilly, Otsuka/Lundbeck, Pamlab, and Takeda and has served as a medical editor for DSM Nutritional Products. NR 45 TC 1 Z9 1 U1 4 U2 22 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2014 VL 171 IS 7 BP 723 EP 728 DI 10.1176/appi.ajp.2013.13050680 PG 6 WC Psychiatry SC Psychiatry GA AJ9AD UT WOS:000337998300007 PM 24980168 ER PT J AU Pollack, MH Stein, M Simon, N Van Ameringen, M AF Pollack, Mark H. Stein, Murray Simon, Naomi Van Ameringen, Michael TI The Role of Benzodiazepines in Treating Social Anxiety Disorder Response SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Letter C1 [Pollack, Mark H.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. McMaster Univ, Hamilton, ON, Canada. RP Pollack, MH (reprint author), Rush Univ, Med Ctr, Chicago, IL 60612 USA. NR 3 TC 0 Z9 0 U1 0 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2014 VL 171 IS 7 BP 795 EP 796 DI 10.1176/appi.ajp.2014.14010048r PG 2 WC Psychiatry SC Psychiatry GA AJ9AD UT WOS:000337998300020 PM 24980175 ER PT J AU Alessandrini, A Bromberg, J AF Alessandrini, Alessandro Bromberg, Jonathan TI Foxp(3+) Cells by Any Other Name? SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material C1 [Alessandrini, Alessandro] Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02114 USA. [Alessandrini, Alessandro] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Bromberg, Jonathan] Univ Maryland, Sch Med, Div Transplantat, Baltimore, MD 21201 USA. RP Alessandrini, A (reprint author), Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2014 VL 14 IS 7 BP 1471 EP 1471 DI 10.1111/ajt.12840 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA AJ9JE UT WOS:000338024700002 ER PT J AU Koulmanda, M Sampathkumar, RS Bhasin, M Qipo, A Fan, Z Singh, G Movahedi, B Duggan, M Chipashvili, V Strom, TB AF Koulmanda, M. Sampathkumar, R. S. Bhasin, M. Qipo, A. Fan, Z. Singh, G. Movahedi, B. Duggan, M. Chipashvili, V. Strom, T. B. TI Prevention of Nonimmunologic Loss of Transplanted Islets in Monkeys SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Alpha-1-antitrypsin (AAT); inflammation bioinformatics; islet transplantation; monkey ID CYNOMOLGUS MONKEYS; ALPHA-1-ANTITRYPSIN; SURVIVAL; CELLS; MICE AB The nonimmunologic loss of islets in the pre-, peri-, and early post-islet transplant periods is profound. To determine the potential role that transplantation of only a marginal mass of functioning beta cells may play in triggering late nonimmunologic graft loss, we studied the effect of treatment with alpha-1-antitrypsin (AAT) in the autologous cynomolgus islet transplant model. A marginal mass of autologous islets, that is islets prepared from 70% to 80% of the pancreas, was transplanted at 1600-4100IEQ/kg into subtotal pancreatectomized, streptozotocin-treated and insulin-deficient diabetic hosts. In this marginal mass islet transplant model, islet function is insidiously lost over time and diabetes recurs in all untreated monkeys by 180 days posttransplantation. Short-term treatment with AAT, an acute phase reactant, in the peri-transplant period serves to terminate inflammation through effects upon expression of TGF, NFB and AKT and favorably altering expression of cell death and survival pathways, as detected by a system biology approach and histology. These effects enabled functional expansion of the islet mass in transplanted hosts such that graft function improves rather than deteriorating over time. C1 [Koulmanda, M.; Sampathkumar, R. S.; Qipo, A.; Fan, Z.; Singh, G.; Movahedi, B.; Chipashvili, V.; Strom, T. B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Transplant Inst, Boston, MA 02215 USA. [Koulmanda, M.; Sampathkumar, R. S.; Qipo, A.; Fan, Z.; Singh, G.; Movahedi, B.; Chipashvili, V.; Strom, T. B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Transplant Inst, Boston, MA 02215 USA. [Bhasin, M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Genom & Prote Core Ctr, Boston, MA 02215 USA. [Duggan, M.] Massachusetts Gen Hosp, Dept Surg, Ctr Comparat Med, Boston, MA 02114 USA. RP Strom, TB (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Transplant Inst, Boston, MA 02215 USA. EM mkoulman@bidmc.harvard.edu; tstrom@bidmc.harvard.edu FU NIH [5 RO1 AI50987, 1-U19 DK080652]; JDRF [7-2005-1329]; JDRF postdoctoral fellowship grant FX We thank Neal R. Smith, from the Massachusetts General Hospital, for his expert pathologic studies. This work was funded in part by NIH 5 RO1 AI50987, NIH 1-U19 DK080652, JDRF 7-2005-1329 (TBS and MK) and a JDRF postdoctoral fellowship grant (MB). NR 20 TC 6 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2014 VL 14 IS 7 BP 1543 EP 1551 DI 10.1111/ajt.12723 PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA AJ9JE UT WOS:000338024700014 PM 24913821 ER PT J AU Gao, B Moore, C Porcheray, F Rong, C Abidoglu, C DeVito, J Paine, R Girouard, TC Saidman, SL Schoenfeld, D Levin, B Wong, W Elias, N Schuetz, C Rosales, I Fu, Y Zorn, E AF Gao, B. Moore, C. Porcheray, F. Rong, C. Abidoglu, C. DeVito, J. Paine, R. Girouard, T. C. Saidman, S. L. Schoenfeld, D. Levin, B. Wong, W. Elias, N. Schuetz, C. Rosales, I. Fu, Y. Zorn, E. TI Pretransplant IgG Reactivity to Apoptotic Cells Correlates With Late kidney Allograft Loss SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Anti-apoptotic cell antibodies; apoptotic cells; complement; graft loss; kidney transplantation; sensitization ID CAPILLARY C4D DEPOSITION; CORONARY-ARTERY-DISEASE; HLA CLASS-I; TRANSPLANT RECIPIENTS; CLINICAL-RELEVANCE; HUMORAL REJECTION; IMMUNE-COMPLEXES; GRAFT FAILURE; B-CELLS; ANTIBODIES AB Preexisting serum antibodies have long been associated with graft loss in transplant recipients. While most studies have focused on HLA-specific antibodies, the contribution of non-HLA-reactive antibodies has been largely overlooked. We have recently characterized mAbs secreted by B cell clones derived from kidney allograft recipients with rejection that bind to apoptotic cells. Here, we assessed the presence of such antibodies in pretransplant serum from 300 kidney transplant recipients and examined their contribution to the graft outcomes. Kaplan-Meier survival analysis revealed that patients with high pretransplant IgG reactivity to apoptotic cells had a significantly increased rate of late graft loss. The effect was only apparent after approximately 1 year posttransplant. Moreover, the association between pretransplant IgG reactivity to apoptotic cells and graft loss was still significant after excluding patients with high reactivity to HLA. This reactivity was almost exclusively mediated by IgG1 and IgG3 with complement fixing and activating properties. Overall, our findings support the view that IgG reactive to apoptotic cells contribute to presensitization. Taking these antibodies into consideration alongside anti-HLA antibodies during candidate evaluation would likely improve the transplant risk assessment. C1 [Gao, B.; Fu, Y.] Jilin Univ, Hosp 1, Transplant Ctr, Changchun 130023, Peoples R China. [Gao, B.; Moore, C.; Porcheray, F.; Rong, C.; Abidoglu, C.; DeVito, J.; Paine, R.; Elias, N.; Schuetz, C.; Zorn, E.] Harvard Univ, Sch Med, Dept Surg, Transplant Ctr,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rong, C.] Changchun Univ Chinese Med, Affiliated Hosp, Changchun, Peoples R China. [Girouard, T. C.; Saidman, S. L.; Rosales, I.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Schoenfeld, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Ctr, Boston, MA USA. [Levin, B.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Wong, W.] Columbia Univ, New York Presbyterian Hosp, Med Ctr, Div Nephrol, New York, NY USA. RP Zorn, E (reprint author), Columbia Univ, New York Presbyterian Hosp, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10027 USA. EM ez2184@cumc.columbia.edu RI Schuetz, Christian/K-5234-2013 OI Schuetz, Christian/0000-0002-6828-4543 FU Fahd and Nadia Alireza's Research Fund; Roche Organ Transplantation Research Foundation (ROTRF); National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [DK083352] FX We thank Dr. Roberto Bellucci for the packaged lentiviral vector containing a beta 2-microglobulin shRNA. This work was supported by the Fahd and Nadia Alireza's Research Fund, the Roche Organ Transplantation Research Foundation (ROTRF), the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases (Grant No. DK083352). NR 47 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2014 VL 14 IS 7 BP 1581 EP 1591 DI 10.1111/ajt.12763 PG 11 WC Surgery; Transplantation SC Surgery; Transplantation GA AJ9JE UT WOS:000338024700018 PM 24935695 ER PT J AU Kawai, T Sachs, DH Sprangers, B Spitzer, TR Saidman, SL Zorn, E Tolkoff-Rubin, N Preffer, F Crisalli, K Gao, B Wong, W Morris, H LoCascio, SA Sayre, P Shonts, B Williams, WW Smith, RN Colvin, RB Sykes, M Cosimi, AB AF Kawai, T. Sachs, D. H. Sprangers, B. Spitzer, T. R. Saidman, S. L. Zorn, E. Tolkoff-Rubin, N. Preffer, F. Crisalli, K. Gao, B. Wong, W. Morris, H. LoCascio, S. A. Sayre, P. Shonts, B. Williams, W. W., Jr. Smith, R. -N. Colvin, R. B. Sykes, M. Cosimi, A. B. TI Long-Term Results in Recipients of Combined HLA-Mismatched Kidney and Bone Marrow Transplantation Without Maintenance Immunosuppression SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Chimerism; immunobiology; kidney transplantation; living donors; tolerance ID HEMATOPOIETIC-CELL TRANSPLANTATION; RENAL-ALLOGRAFT TOLERANCE; DONOR-SPECIFIC TOLERANCE; MIXED CHIMERISM; CYNOMOLGUS MONKEYS; NONHUMAN-PRIMATES; INDUCTION; REGIMEN; RESPONSES; RECOVERY AB We report here the long-term results of HLA-mismatched kidney transplantation without maintenance immunosuppression (IS) in 10 subjects following combined kidney and bone marrow transplantation. All subjects were treated with nonmyeloablative conditioning and an 8- to 14-month course of calcineurin inhibitor with or without rituximab. All 10 subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. Currently, four subjects remain IS free for periods of 4.5-11.4 years, while three required reinstitution of IS after 5-8 years due to recurrence of original disease or chronic antibody-mediated rejection. Of the 10 renal allografts, three failed due to thrombotic microangiopathy or rejection. When compared with 21 immunologically similar living donor kidney recipients treated with conventional IS, the long-term IS-free survivors developed significantly fewer posttransplant complications. Although most recipients treated with none or two doses of rituximab developed donor-specific antibody (DSA), no DSA was detected in recipients treated with four doses of rituximab. Although further revisions of the current conditioning regimen are planned in order to improve consistency of the results, this study shows that long-term stable kidney allograft survival without maintenance IS can be achieved following transient mixed chimerism induction. C1 [Kawai, T.; Zorn, E.; Tolkoff-Rubin, N.; Crisalli, K.; Gao, B.; Williams, W. W., Jr.; Cosimi, A. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Ctr, Boston, MA 02163 USA. [Sachs, D. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. [Sprangers, B.; Wong, W.; Morris, H.; LoCascio, S. A.; Shonts, B.; Sykes, M.] Columbia Univ, Columbia Ctr Translat Immunol, New York, NY USA. [Spitzer, T. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bone Marrow Transplant Unit, Boston, MA USA. [Saidman, S. L.; Preffer, F.; Smith, R. -N.; Colvin, R. B.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Sayre, P.] Immune Tolerance Network, San Francisco, CA USA. RP Kawai, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Ctr, Boston, MA 02163 USA. EM tkawai@partners.org FU ITN, an international clinical research consortium [N01-AI-15416]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; NIH [RO1 AI084074] FX This research was performed as a project of the ITN (N01-AI-15416), an international clinical research consortium and supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation. Mechanistic studies were supported by NIH grant RO1 AI084074. We thank the Clinical Trials Group of the ITN and Eleanor Ramos, MD, for their participation in the planning and conduct of these studies; the ITN Drug Withdrawal Committee for their help in determining appropriate conditions and means for withdrawal of immunosuppressive therapy. We thank Drs. James Markmann, Dicken Ko, Martin Hertl, Nahel Elias (transplant surgery), Steve McAfee, Bimalangshu Dey (hematology) and Ms. Sandy Debronkart, NP, for clinical management. We also appreciate Drs. Stanley Jordan and Joseph Kahwaji (Cedars-Sinai) for the clinical management of Subject 4. We acknowledge Drs. Joren Madsen and James Markmann (both MGH) for critical review of the manuscript. We also acknowledge Dr. David Schoenfeld for statistical analysis. This manuscript was not prepared or funded by any commercial organization. NR 39 TC 67 Z9 72 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2014 VL 14 IS 7 BP 1599 EP 1611 DI 10.1111/ajt.12731 PG 13 WC Surgery; Transplantation SC Surgery; Transplantation GA AJ9JE UT WOS:000338024700020 PM 24903438 ER PT J AU Tastesen, HS Keenan, AH Madsen, L Kristiansen, K Liaset, B AF Tastesen, Hanne Sorup Keenan, Alison H. Madsen, Lise Kristiansen, Karsten Liaset, Bjorn TI Scallop protein with endogenous high taurine and glycine content prevents high-fat, high-sucrose-induced obesity and improves plasma lipid profile in male C57BL/6J mice SO AMINO ACIDS LA English DT Article DE Cholesterol; Diet-induced obesity; Plasma lipid profile; Protein; Seafood; Taurine ID DIETARY COD PROTEIN; INSULIN-RESISTANT MEN; HIGH-CHOLESTEROL DIET; BODY-WEIGHT; METHIONINE RESTRICTION; SERUM-LIPIDS; AMINO-ACID; FISH-OIL; FED RATS; METABOLISM AB High-protein diets induce alterations in metabolism that may prevent diet-induced obesity. However, little is known as to whether different protein sources consumed at normal levels may affect diet-induced obesity and associated co-morbidities. We fed obesity-prone male C57BL/6J mice high-fat, high-sucrose diets with protein sources of increasing endogenous taurine content, i.e., chicken, cod, crab and scallop, for 6 weeks. The energy intake was lower in crab and scallop-fed mice than in chicken and cod-fed mice, but only scallop-fed mice gained less body and fat mass. Liver mass was reduced in scallop-fed mice, but otherwise no changes in lean body mass were observed between the groups. Feed efficiency and apparent nitrogen digestibility were reduced in scallop-fed mice suggesting alterations in energy utilization and metabolism. Overnight fasted plasma triacylglyceride, non-esterified fatty acids, glycerol and hydroxy-butyrate levels were significantly reduced, indicating reduced lipid mobilization in scallop-fed mice. The plasma HDL-to-total-cholesterol ratio was higher, suggesting increased reverse cholesterol transport or cholesterol clearance in scallop-fed mice in both fasted and non-fasted states. Dietary intake of taurine and glycine correlated negatively with body mass gain and total fat mass, while intake of all other amino acids correlated positively. Furthermore taurine and glycine intake correlated positively with improved plasma lipid profile, i.e., lower levels of plasma lipids and higher HDL-to-total-cholesterol ratio. In conclusion, dietary scallop protein completely prevents high-fat, high-sucrose-induced obesity whilst maintaining lean body mass and improving the plasma lipid profile in male C57BL/6J mice. C1 [Tastesen, Hanne Sorup; Madsen, Lise; Kristiansen, Karsten] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark. [Tastesen, Hanne Sorup; Madsen, Lise; Liaset, Bjorn] Natl Inst Nutr & Seafood Res, N-5817 Bergen, Norway. [Keenan, Alison H.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Kristiansen, K (reprint author), Univ Copenhagen, Dept Biol, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. EM Karsten.Kristiansen@bio.ku.dk; Bjorn.Liaset@nifes.no RI Madsen, Lise/C-6246-2012; Kristiansen, Karsten/J-5148-2014 OI Madsen, Lise/0000-0003-4468-1947; Kristiansen, Karsten/0000-0002-6024-0917 FU Norwegian Research Council [200515/I30]; National Institute of Nutrition and Seafood Research; Danish Natural Science Research Council; Novo Nordisk Foundation; Carlsberg Foundation FX The authors are grateful to Aase Heltveit, Oyvind Reinshol and Jacob Wessels for technical assistance. This study was conducted as a part of the 'Lean seafood in the prevention of the metabolic syndrome' project financially supported by the Norwegian Research Council (200515/I30) and the National Institute of Nutrition and Seafood Research. Parts of this work were also financially supported by the Danish Natural Science Research Council, the Novo Nordisk Foundation and the Carlsberg Foundation. NR 60 TC 17 Z9 17 U1 1 U2 32 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD JUL PY 2014 VL 46 IS 7 BP 1659 EP 1671 DI 10.1007/s00726-014-1715-1 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9JT UT WOS:000338026700006 PM 24658997 ER PT J AU Della-Torre, E Mattoo, H Mahajan, VS Deshpande, V Krause, D Song, P Pillai, S Stone, JH AF Della-Torre, Emanuel Mattoo, Hamid Mahajan, Vinay S. Deshpande, Vikram Krause, Donald Song, Philip Pillai, Shiv Stone, John H. TI IgG4-related midline destructive lesion SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Letter ID DISEASE C1 [Della-Torre, Emanuel; Mattoo, Hamid; Mahajan, Vinay S.; Pillai, Shiv] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Della-Torre, Emanuel] Univ Vita Salute San Raffaele, Unit Med & Clin Immunol, Milan, Italy. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Krause, Donald] St Joseph Healthcare, Rheumatol Serv, Bangor, ME USA. [Song, Philip] Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Stone, John H.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Clin, Yawkey 2,55 Fruit St, Boston, MA 02114 USA. EM jhstone@mgh.harvard.edu OI Della Torre, Emanuel/0000-0002-9192-4270 FU NHLBI NIH HHS [T32 HL007627]; NIAID NIH HHS [R01 AI076505, AI 064930, AI 076505, R01 AI064930] NR 7 TC 7 Z9 7 U1 0 U2 1 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 2014 VL 73 IS 7 BP 1434 EP U193 DI 10.1136/annrheumdis-2014-205187 PG 3 WC Rheumatology SC Rheumatology GA AJ7XK UT WOS:000337914300040 PM 24651619 ER PT J AU Rocha, VZ Folco, EJ Ozdemir, C Sheikine, Y Christen, T Sukhova, GK Tang, EHC Bittencourt, MS Santos, RD Luster, AD Cohen, DE Libby, P AF Rocha, Viviane Zorzanelli Folco, Eduardo J. Ozdemir, Cafer Sheikine, Yuri Christen, Thomas Sukhova, Galina K. Tang, Eva H. C. Bittencourt, Marcio Sommer Santos, Raul D. Luster, Andrew D. Cohen, David E. Libby, Peter TI CXCR3 Controls T-Cell Accumulation in Fat Inflammation SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE adipose tissue; CXCR3, receptors; inflammation; lymphocytes; macrophages; obesity ID ADIPOSE-TISSUE INFLAMMATION; CHEMOKINE RECEPTOR CXCR3; INSULIN-RESISTANCE; OBESITY; MICE; ATHEROSCLEROSIS; ATHEROGENESIS; INFILTRATION; RECRUITMENT; MACROPHAGES AB Objective-Obesity associates with increased numbers of inflammatory cells in adipose tissue (AT), including T cells, but the mechanism of T-cell recruitment remains unknown. This study tested the hypothesis that the chemokine (C-X-C motif) receptor 3 (CXCR3) participates in T-cell accumulation in AT of obese mice and thus in the regulation of local inflammation and systemic metabolism. Approach and Results-Obese wild-type mice exhibited higher mRNA expression of CXCR3 in periepididymal AT-derived stromal vascular cells compared with lean mice. We evaluated the function of CXCR3 in AT inflammation in vivo using CXCR3-deficient and wild-type control mice that consumed a high-fat diet. Periepididymal AT from obese CXCR3-deficient mice contained fewer T cells than obese controls after 8 and 16 weeks on high-fat diet, as assessed by flow cytometry. Obese CXCR3-deficient mice had greater glucose tolerance than obese controls after 8 weeks, but not after 16 weeks. CXCR3-deficient mice fed high-fat diet had reduced mRNA expression of proinflammatory mediators, such as monocyte chemoattractant protein-1 and regulated on activation, normal T cell expressed and secreted, and anti-inflammatory genes, such as Foxp3, IL-10, and arginase-1 in periepididymal AT, compared with obese controls. Conclusions-These results demonstrate that CXCR3 contributes to T-cell accumulation in periepididymal AT of obese mice. Our results also suggest that CXCR3 regulates the accumulation of distinct subsets of T cells and that the ratio between these functional subsets across time likely modulates local inflammation and systemic metabolism. C1 [Rocha, Viviane Zorzanelli; Folco, Eduardo J.; Christen, Thomas; Sukhova, Galina K.; Tang, Eva H. C.; Libby, Peter] Harvard Univ, Sch Med, Div Cardiovasc Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Ozdemir, Cafer; Cohen, David E.] Harvard Univ, Sch Med, Div Gastroenterol, Brigham & Womens Hosp,Dept Med, Boston, MA 02115 USA. [Sheikine, Yuri] Harvard Univ, Sch Med, Div Nucl Med & Mol Imaging, Brigham & Womens Hosp,Dept Radiol, Boston, MA 02115 USA. [Rocha, Viviane Zorzanelli; Santos, Raul D.] Univ Sao Paulo, Sch Med, Lipid Clin Cardiopulm Div, Heart Inst InCor, Sao Paulo, Brazil. [Tang, Eva H. C.] Univ Hong Kong, Dept Pharmacol & Pharm, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Bittencourt, Marcio Sommer] Univ Sao Paulo, Sch Med, Ctr Clin & Epidemiol Res, Div Internal Med,Univ Hosp, Sao Paulo, Brazil. [Luster, Andrew D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. RP Libby, P (reprint author), Harvard Univ, Sch Med, Div Cardiovasc Med, Brigham & Womens Hosp, 77 Ave Louis Pasteur,NRB-741, Boston, MA 02115 USA. EM plibby@rics.bwh.harvard.edu RI Santos, Raul/A-1170-2010; Bittencourt, Marcio/C-1444-2011 OI Santos, Raul/0000-0002-9860-6582; Bittencourt, Marcio/0000-0002-3711-1754 FU Donald W. Reynolds Foundation; National Institutes of Health [R01 HL080472, CA-069212, DK-48873, DK-56626]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior [BEX 1594 04/4]; Harvard Digestive Diseases Center [P30 DK034854]; J.P. Lemann Foundation FX This work was supported by the Donald W. Reynolds Foundation; by grants from the National Institutes of Health (R01 HL080472 to P. Libby, CA-069212 to A.D. Luster, and DK-48873 and DK-56626 to D.E. Cohen); by a grant from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (BEX 1594 04/4 to V.Z. Rocha); and by the Harvard Digestive Diseases Center (P30 DK034854). M.S. Bittencourt was supported by the J.P. Lemann Foundation as a Jorge Paulo Lemann Harvard Medical School Cardiovascular Fellow at Brigham & Women's Hospital. NR 32 TC 12 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2014 VL 34 IS 7 BP 1374 EP + DI 10.1161/ATVBAHA.113.303133 PG 24 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AJ5OC UT WOS:000337732900012 PM 24812325 ER PT J AU Bowling, MR Xing, DQ Kapadia, A Chen, YF Szalai, AJ Oparil, S Hage, FG AF Bowling, Meaghan R. Xing, Dongqi Kapadia, Akash Chen, Yiu-Fai Szalai, Alexander J. Oparil, Suzanne Hage, Fadi G. TI Estrogen Effects on Vascular Inflammation Are Age Dependent Role of Estrogen Receptors SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE aging; c-reactive protein; estrogen; vascular system injuries ID POSTMENOPAUSAL HORMONE-THERAPY; RANDOMIZED CONTROLLED-TRIAL; C-REACTIVE PROTEIN; SMOOTH-MUSCLE-CELLS; CARDIOVASCULAR-DISEASE; NEOINTIMA FORMATION; REPLACEMENT THERAPY; INJURED ARTERIES; TRANSGENIC MICE; CAROTID-ARTERY AB Objective-17 beta-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones performed in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age dependent. Approach and Results-Young (10 weeks) and aged (52 weeks) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pretreatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pretreatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER) knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ER alpha and in VSMCs via ER beta. BMMs derived from aged (versus young) mice expressed significantly less ERa mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice. Conclusions-E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ER alpha expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women. C1 [Bowling, Meaghan R.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Birmingham, AL 35294 USA. [Xing, Dongqi; Chen, Yiu-Fai; Oparil, Suzanne; Hage, Fadi G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Vasc Biol & Hypertens Program, Birmingham, AL 35294 USA. [Szalai, Alexander J.] Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Kapadia, Akash] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Birmingham Vet Adm Med Ctr, Cardiol Sect, Zeigler Res Bldg 1024,703 19th St South, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 FU Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award; American Heart Association NCRP Scientist Development Grant [0930098]; Greater Southeast Affiliate grant [09BGIA2250367]; National Heart, Lung, and Blood Institute [R01 HL087980, HL080017, HL044195] FX This work was supported, in part, by a Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award (to Dr Hage), American Heart Association NCRP Scientist Development Grant (0930098 N to Dr Hage) and a Greater Southeast Affiliate grant (09BGIA2250367 to Dr Xing), National Heart, Lung, and Blood Institute grants (R01 HL087980 to Dr Oparil) and (HL080017, HL044195 to Dr Chen). NR 48 TC 16 Z9 16 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2014 VL 34 IS 7 BP 1477 EP 1485 DI 10.1161/ATVBAHA.114.303629 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AJ5OC UT WOS:000337732900023 PM 24876352 ER PT J AU Chuang, ML Gona, P Oyama-Manabe, N Manders, ES Salton, CJ Hoffmann, U Manning, WJ O'Donnell, CJ AF Chuang, Michael L. Gona, Philimon Oyama-Manabe, Noriko Manders, Emily S. Salton, Carol J. Hoffmann, Udo Manning, Warren J. O'Donnell, Christopher J. TI Risk Factor Differences in Calcified and Noncalcified Aortic Plaque The Framingham Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; epidemiology; magnetic resonance imaging; risk factors ID CORONARY-ARTERY CALCIUM; COMPUTED-TOMOGRAPHY; ABDOMINAL-AORTA; THORACIC AORTA; ATHEROSCLEROSIS; ASSOCIATION; CALCIFICATION; DEPOSITS; DISEASE; REPRODUCIBILITY AB Objective-The objective of this study was to determine the prevalence and risk factor (RF) correlates of aortic plaque (AP) detected by cardiovascular magnetic resonance (CMR), which mainly shows noncalcified plaques, and by noncontrast computed tomography (CT), which best depicts calcified plaques, in community-dwelling adults. Approach and Results-A total of 1016 Framingham Heart Study Offspring cohort members (64 +/- 9 years; 474 men) underwent CMR and CT of the aorta. Potential RFs for AP (age; sex; body mass index; blood pressure; low-density lipoprotein and high-density lipoprotein cholesterol; fasting glucose; C-reactive protein; prevalent hypertension, diabetes mellitus, smoking; use of antihypertensive, diabetes mellitus, or lipid-lowering drugs) were compared between participants, with zero versus nonzero AP by CMR and by CT. Candidate RFs attaining P<0.05 for difference with either imaging modality were entered into multivariable logistic regression models adjusting for age, sex, and other RFs. Odds ratios were calculated for modality-specific prevalence of AP. Associations between RFs and continuous measures of AP were assessed using Tobit regression. Prevalence of CMR and CT AP was 49% and 82%, respectively. AP burdens by CMR and CT were correlated, r=0.28, P<0.0001. Increasing age and smoking were associated with prevalent AP by both CMR and CT. Additionally, prevalent AP by CMR was associated with female sex and fasting glucose and prevalent AP by CT with hypertension treatment and adverse lipid profile. Conclusions-AP by CMR and CT are both associated with smoking and increasing age, but other RFs differ between calcified and noncalcified AP. The relative predictive value of AP detected by CMR versus by CT for incident cardiovascular events remains to be determined. C1 [Chuang, Michael L.; Gona, Philimon; Manders, Emily S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Boston, MA USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Biostat & Hlth Serv Res, Worcester, MA USA. [Oyama-Manabe, Noriko; Salton, Carol J.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo; Manning, Warren J.; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N01-HC-38038, R01 HL70279]; National Heart, Lung and Blood Institute Division of Intramural Research FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195 and N01-HC-38038 and by R01 HL70279). C.J. O'Donnell is supported by the National Heart, Lung and Blood Institute Division of Intramural Research. NR 23 TC 4 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2014 VL 34 IS 7 BP 1580 EP + DI 10.1161/ATVBAHA.114.303600 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AJ5OC UT WOS:000337732900035 PM 24833796 ER PT J AU Bunaciu, L Leen-Feldner, EW Blumenthal, H Knapp, AA Badour, CL Feldner, MT AF Bunaciu, Liviu Leen-Feldner, Ellen W. Blumenthal, Heidemarie Knapp, Ashley A. Badour, Christal L. Feldner, Matthew T. TI An Experimental Test of the Effects of Parental Modeling on Panic-Relevant Escape and Avoidance Among Early Adolescents SO BEHAVIOR THERAPY LA English DT Article DE escape; avoidance; modeling; panic; voluntary hyperventilation ID DIOXIDE-ENRICHED AIR; ANXIETY SENSITIVITY; BEHAVIORAL-INHIBITION; BODILY SENSATIONS; LEARNING HISTORY; VOLUNTARY HYPERVENTILATION; FEAR-ACQUISITION; SOCIAL ANXIETY; CHILD ANXIETY; DISORDER AB Escape and avoidance behaviors play a prominent role in the maintenance and possibly development of panic disorder, yet the literature regarding the etiology of these emotion-regulation strategies is relatively underdeveloped. The current study experimentally tests hypotheses that parental modeling of escape during a well-established panic-relevant biological challenge increases panic-relevant escape and avoidance among offspring. Fifty physically and psychologically healthy early adolescents (28 females; M-age = 11.58; 86% Caucasian), stratified by gender, were randomly assigned to observe one of their parents (39 females; M-age = 40.04): either (a) model completing a 3-min voluntary hyperventilation exercise (no escape modeling group) or (b) model premature termination of a similar procedure (escape modeling group). Offspring in the escape modeling group demonstrated a stronger escape response by discontinuing their own challenge sooner than those in the no-escape modeling group (r = .70). No group differences emerged in terms of avoidance responding, as indexed by nearly identical responding in terms of delay time before initiating the challenge, respiration rate, and self-reported willingness to engage in a second proposed challenge. Results suggest that parental behaviors may play an important role in the development of some forms of panic-relevant responding. These preliminary findings may have important implications for future prevention programs targeting parents and at-risk youth. C1 [Bunaciu, Liviu; Leen-Feldner, Ellen W.; Knapp, Ashley A.; Badour, Christal L.; Feldner, Matthew T.] Univ Arkansas, Fayetteville, AR 72701 USA. [Bunaciu, Liviu] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Blumenthal, Heidemarie] Univ N Texas, Denton, TX 76203 USA. [Badour, Christal L.] Med Univ S Carolina, Charleston, SC USA. [Badour, Christal L.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Feldner, Matthew T.] Laureate Inst Brain Res, Tulsa, OK USA. RP Bunaciu, L (reprint author), Univ Arkansas, Dept Psychol Sci, Intervent Sci Lab, 216 Mem Hall, Fayetteville, AR 72701 USA. EM liviu_bunaciu@brown.edu; mfeldne@uark.edu NR 69 TC 1 Z9 1 U1 5 U2 16 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD JUL PY 2014 VL 45 IS 4 BP 517 EP 529 PG 13 WC Psychology, Clinical SC Psychology GA AJ7EQ UT WOS:000337860400006 PM 24912464 ER PT J AU Artherholt, SB Hong, FX Berry, DL Fann, JR AF Artherholt, Samantha B. Hong, Fangxin Berry, Donna L. Fann, Jesse R. TI Risk Factors for Depression in Patients Undergoing Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hematopoietic stem cell transplantation; Depression; Hematopoietic cell transplantation; Bone marrow transplantation; Quality of life ID QUALITY-OF-LIFE; HEALTH QUESTIONNAIRE-9; EUROPEAN-ORGANIZATION; MAJOR DEPRESSION; THE-LITERATURE; PRIMARY-CARE; CANCER; MORTALITY; SURVIVORS; PHQ-9 AB Despite the prevalence and known adverse impacts of depression after hematopoietic cell transplantation (HCT), little is known about the trajectory of depression occurring after HCT, or which pretransplantation risk factors might help predict new or worsening post-HCT depression. This secondary analysis evaluated the relationships between pre-HCT patient-reported outcomes and demographic characteristics and post-HCT depression. A total of 228 adult HCT patients were evaluated pre-HCT (T1) and again at 6 to 7 weeks post-HCT (T2), using touch-screen computers in the transplantation clinic during participation in a larger trial. Measures evaluated included the Symptom Distress Scale, the EORTC QLQ-C30 for quality of life, a single-item pain intensity question, and the Patient Health Questionnaire 9 for measurement of depression. At T1, rates of depression were quite low, with only 6% of participants reporting moderate or higher depression. At T2, however, the prevalence of moderate or higher depression was 31%. We observed a strong linear relationship in PHQ-9 scores between T1 and T2 (P < .0001). Depression score at T1 was a significant predictor of depression score at T2 (P = .03), as was poorer emotional function at T1 (P < .01). Our results indicate that post-HCT depression is common, even in patients with a low pre-HCT depression score. Frequent screening for symptoms of depression at critical time points, including 6 to 7 weeks post-HCT, are needed in this population, followed by referrals to supportive care as appropriate. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Artherholt, Samantha B.; Fann, Jesse R.] Univ Washington, Dept Psychiat & Behav Sci, Sch Med, Seattle, WA 98195 USA. [Artherholt, Samantha B.; Fann, Jesse R.] Seattle Canc Care Alliance, Seattle, WA USA. [Hong, Fangxin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Berry, Donna L.] Dana Farber Canc Inst, Dept Nursing, Boston, MA 02115 USA. [Berry, Donna L.] Dana Farber Canc Inst, Patient Care Sevices, Boston, MA 02115 USA. [Berry, Donna L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Fann, Jesse R.] Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. [Fann, Jesse R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Fann, JR (reprint author), Univ Washington, Box 356560,1959 NE Pacific St, Seattle, WA 98195 USA. EM fann@uw.edu FU National Institute of Nursing Research [R01 NR008726] FX This work was funded by the National Institute of Nursing Research (Grant R01 NR008726). NR 38 TC 7 Z9 7 U1 2 U2 3 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 2014 VL 20 IS 7 BP 946 EP 950 DI 10.1016/j.bbmt.2014.03.010 PG 5 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500007 PM 24650679 ER PT J AU Wirk, B Fenske, TS Hamadani, M Zhang, MJ Hu, ZH Akpek, G Aljurf, MD Armand, P Ayala, E Bachanova, V Bolwell, B Cairo, MS Cashen, A Chen, YB Costa, LJ Farhan, S Freytes, CO Gajewski, JL Gibson, J Hale, GA Holmberg, LA Hsu, JW Inwards, DJ Kamble, RT Maharaj, D Maziarz, RT Munker, R Nath, R Reddy, NM Reeder, CB Rizzieri, DA Sauter, CS Savani, BN Schouten, HC Sureda, A Vose, JM Waller, EK Wiernik, PH Gale, RP Burns, LJ Saber, W AF Wirk, Baldeep Fenske, Timothy S. Hamadani, Mehdi Zhang, Mei-Jie Hu, Zhen-Huan Akpek, Goerguen Aljurf, Mahmoud D. Armand, Philippe Ayala, Ernesto Bachanova, Veronika Bolwell, Brian Cairo, Mitchell S. Cashen, Amanda Chen, Yi-Bin Costa, Luciano J. Farhan, Shatha Freytes, Cesar O. Gajewski, James L. Gibson, John Hale, Gregory A. Holmberg, Leona A. Hsu, Jack W. Inwards, David J. Kamble, Rummurti T. Maharaj, Dipnarine Maziarz, Richard T. Munker, Reinhold Nath, Rajneesh Reddy, Nishitha M. Reeder, Craig B. Rizzieri, David A. Sauter, Craig S. Savani, Bipin N. Schouten, Harry C. Sureda, Anna Vose, Julie M. Waller, Edmund K. Wiernik, Peter H. Gale, Robert Peter Burns, Linda J. Saber, Wael TI Outcomes of Hematopoietic Cell Transplantation for Diffuse Large B Cell Lymphoma Transformed from Follicular Lymphoma SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Transformed follicular; lymphoma; Transplant ID NON-HODGKINS-LYMPHOMA; HIGH-DOSE THERAPY; LOW-GRADE; HISTOLOGICAL TRANSFORMATION; RITUXIMAB; FLUDARABINE; SURVIVAL; SUBTYPE; SUPPORT; BLOOD AB There are limited data on the outcomes of autologous or allogeneic hematopoietic cell transplantation (HCT) in diffuse large B cell lymphoma transformed from follicular lymphoma. We analyzed transplantation outcomes in 141 subjects with biopsy-proven diffuse large B-cell lymphoma transformed from follicular lymphoma reported to the Center for International Blood and Marrow Transplant Research between 1990 and 2009. Two groups were identified: autologous HCT (auto-Ha; n = 108) and allogeneic HCT (allo-HCT; n = 33). Fewer auto-Has were done for transformed follicular lymphoma in 2003 to 2009, with a shift favoring allo-HCT. Auto-HCT was associated with a 1-year nonrelapse mortality (NRM) of 8% (95% confidence interval [CI], 4% to 14%), 5-year progression-free survival of 35% (95% CI, 26% to 45%), and 5-year overall survival of 50% (95% CI, 40% to 59%). In contrast, allo-HCT was associated with a 1-year NRM of 41% (95% CI, 23% to 58%), 5-year progression-free survival of 18% (95% CI, 6% to 35%), and 5-year overall survival of 22% (95% CI, 8% to 41%). Auto-HCT for transformed follicular lymphoma achieves sustained remission in a high proportion of subjects. The high NRM of allo-HCT offset any benefit that might be associated with this transplantation modality. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Wirk, Baldeep] SUNY Stony Brook, Hlth Sci Ctr, Med Ctr, Stony Brook, NY 11794 USA. [Fenske, Timothy S.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Milwaukee, WI 53226 USA. [Hamadani, Mehdi] West Virginia Univ Hosp, Morgantown, WV USA. [Zhang, Mei-Jie; Hu, Zhen-Huan; Saber, Wael] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Gilbert, AZ USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. [Armand, Philippe] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ayala, Ernesto] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Bachanova, Veronika; Burns, Linda J.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Bolwell, Brian] Cleveland Clin, Cleveland, OH 44106 USA. [Cairo, Mitchell S.] New York Med Coll, Valhalla, NY 10595 USA. [Cashen, Amanda] Barnes Jewish Hosp, St Louis, MO 63110 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Costa, Luciano J.] Med Univ S Carolina, Charleston, SC 29425 USA. [Farhan, Shatha] Henry Ford Hosp, Bone Marrow Transplant Program, Detroit, MI 48202 USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Gajewski, James L.; Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Gibson, John] Royal Prince Alfred Hosp, Inst Haematol, Camperdown, NSW 2050, Australia. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Holmberg, Leona A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hsu, Jack W.] Shands HealthCare, Gainesville, FL USA. [Hsu, Jack W.] Univ Florida, Gainesville, FL USA. [Inwards, David J.] Mayo Clin Rochester, Rochester, MN USA. [Kamble, Rummurti T.] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Maharaj, Dipnarine] Bethesda Hlth City, Boynton Beach, FL USA. [Munker, Reinhold] Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Nath, Rajneesh] UMass Mem Med Ctr, Worcester, MA USA. [Reddy, Nishitha M.; Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Sauter, Craig S.] Mayo Clin Arizona, Phoenix, AZ USA. [Reeder, Craig B.] Phoenix Childrens Hosp, Phoenix, AZ USA. [Rizzieri, David A.] Duke Univ, Med Ctr, Durham, NC USA. [Sauter, Craig S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Schouten, Harry C.] Acad Ziekenhuis Maastricht, Maastricht, Netherlands. [Sureda, Anna] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Vose, Julie M.] Univ Nebraska Med Ctr, Omaha, NE USA. [Waller, Edmund K.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Wiernik, Peter H.] Our Lady Mercy Med Ctr, Bronx, NY USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Sect Hematol, Div Expt Med, London, England. RP Wirk, B (reprint author), SUNY Stony Brook, Hlth Sci Ctr, Div Hematol Oncol, T15-053,101 Nicolls Rd, Stony Brook, NY 11794 USA. EM bmwirk@gmail.com OI farhan, shatha/0000-0002-5723-7442 FU Public Health Service Grant/Cooperative Agreement from the National Cancer Institute (NCI) [U24 CA076518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI and NCI [U10 HL069294]; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-131-0039]; Allos Therapeutics, Amgen FX The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24 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 U10 HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with Health Resources and Services Administration; Grants N00014-12-1-0142 and N00014-131-0039 from the Office of Naval Research; and grants from Allos Therapeutics, Amgen, anonymous donation to the Medical College of Wisconsin, Ariad, Be the Match Foundation, Blue Cross and Blue Shield Association, Celgene, Fresenius-Biotech North America, Gamida Cell Teva Joint Venture, Genentech, Gentium, Genzyme, GlaxoSmithKline, HistoGenetics, Kiadis Pharma, Leukemia 82 Lymphoma Society, Medical College of Wisconsin, Merck & Co, Millennium: Takeda Oncology, Milliman USA, Miltenyi Biotec, National Marrow Donor Program, Onyx Pharmaceuticals, Optum Healthcare Solutions, Osiris Therapeutics, Otsuka America Pharmaceutical, Remedy Informatics, Sanofi US, Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix, StemCyte, Stemsoft Software, Swedish Orphan Biovitrum, Tarix Pharmaceuticals, TerumoBCT, Teva Neuroscience, Therakos, and Wellpoint. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, or any other agency of the US Government. NR 38 TC 12 Z9 13 U1 0 U2 5 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 2014 VL 20 IS 7 BP 951 EP 959 DI 10.1016/j.bbmt.2014.03.014 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500008 PM 24641828 ER PT J AU McClune, BL Ahn, KW Wang, HL Antin, JH Artz, AS Cahn, JY Deol, A Freytes, CO Hamadani, M Holmberg, LA Jagasia, MH Jakubowski, AA Kharfan-Dabaja, MA Lazarus, HM Miller, AM Olsson, R Pedersen, TL Pidala, J Pulsipher, MA Rowe, JM Saber, W van Besien, KW Waller, EK Aljurf, MD Akpek, G Bacher, U Chao, NJ Chen, YB Cooper, BW Dehn, J de Lima, MJ Hsu, JW Lewis, ID Marks, DI McGuirk, J Cairo, MS Schouten, HC Szer, J Ramanathan, M Savani, BN Seftel, M Socie, G Vij, R Warlick, ED Weisdorf, DJ AF McClune, Brian L. Ahn, Kwang Woo Wang, Hai-Lin Antin, Joseph H. Artz, Andrew S. Cahn, Jean-Yves Deol, Abhinav Freytes, Cesar O. Hamadani, Mehdi Holmberg, Leona A. Jagasia, Madan H. Jakubowski, Ann A. Kharfan-Dabaja, Mohamed A. Lazarus, Hillard M. Miller, Alan M. Olsson, Richard Pedersen, Tanya L. Pidala, Joseph Pulsipher, Michael A. Rowe, Jacob M. Saber, Wael van Besien, Koen W. Waller, Edmund K. Aljurf, Mahmoud D. Akpek, Goergun Bacher, Ulrike Chao, Nelson J. Chen, Yi-Bin Cooper, Brenda W. Dehn, Jason de Lima, Marcos J. Hsu, Jack W. Lewis, Ian D. Marks, David I. McGuirk, Joseph Cairo, Mitchell S. Schouten, Harry C. Szer, Jeffrey Ramanathan, Muthalagu Savani, Bipin N. Seftel, Matthew Socie, Gerard Vij, Ravi Warlick, Erica D. Weisdorf, Daniel J. TI Allotransplantation for Patients Age >= 40 Years with Non-Hodgkin Lymphoma: Encouraging Progression-Free Survival SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Reduced intensity; Nonmyeloablative; Allogeneic; Hematopoietic cell transplantation; Elderly; Lymphoma ID HEMATOPOIETIC-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; LONG-TERM OUTCOMES; REDUCED-INTENSITY; ALLOGENEIC TRANSPLANTATION; AUTOLOGOUS TRANSPLANTATION; OLDER PATIENTS; MYELODYSPLASTIC SYNDROME; FOLLICULAR LYMPHOMA AB Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age >= 40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age >= 65; P = .0008). Fewer patients aged >= 65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age >= 65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age >= 65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age >= 55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age >= 55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [McClune, Brian L.; Warlick, Erica D.; Weisdorf, Daniel J.] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo; Wang, Hai-Lin; Hamadani, Mehdi; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Antin, Joseph H.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Artz, Andrew S.] Univ Chicago, Sch Med, Sect Hematol Oncol, Chicago, IL 60637 USA. [Cahn, Jean-Yves] Univ Hosp, Dept Hematol, Grenoble, France. [Deol, Abhinav] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, Dept Hematol, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Holmberg, Leona A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Jagasia, Madan H.; Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN 37235 USA. [Jakubowski, Ann A.] Mem Sloan Kettering Canc Ctr, Dept Med, Bone Marrow Transplant Serv, New York, NY 10021 USA. [Kharfan-Dabaja, Mohamed A.; Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Seidman Canc Ctr, Cleveland, OH 44106 USA. [Miller, Alan M.] Baylor Univ, Med Ctr, Dept Oncol, Dallas, TX USA. [Olsson, Richard] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Pedersen, Tanya L.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Pulsipher, Michael A.] Univ Utah, Huntsman Canc Inst, Primary Childrens Hosp, Div Hematol Hematol Malignancies, Salt Lake City, UT USA. [Rowe, Jacob M.] Rambam Med Ctr, Dept Hematol, Haifa, Israel. [van Besien, Koen W.] Weill Cornell Med Coll, New York, NY USA. [Waller, Edmund K.] Emory Univ Hosp, Winship Canc Inst, Bone Marrow & Stem Cell Transplant Ctr, Atlanta, GA 30322 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Akpek, Goergun] Banner MD Anderson Canc Ctr, Gilbert, AZ USA. [Bacher, Ulrike] Univ Hamburg, Dept Stem Cell Transplantat, Hamburg, Germany. [Bacher, Ulrike] MLL Munich Leukemia Lab, Munich, Germany. [Chao, Nelson J.] Duke Univ, Med Ctr, Div Cell Therapy, Durham, NC USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Cooper, Brenda W.; de Lima, Marcos J.] Univ Hosp Cleveland, Case Med Ctr, Div Hematol Oncol, Cleveland, OH 44106 USA. [Dehn, Jason] Natl Marrow Donor Program, Minneapolis, MN USA. [Hsu, Jack W.] Univ Florida, Shands HealthCare, Div Hematol Oncol, Gainesville, FL USA. [Lewis, Ian D.] Royal Adelaide Hosp SA Pathol, Haematol Clin Trial Off, Adelaide, SA, Australia. [Marks, David I.] Bristol Childrens Hosp, Avon Haematol Unit, Bristol, Avon, England. [Marks, David I.] Bristol Childrens Hosp, BCH BMT Unit, Bristol, Avon, England. [McGuirk, Joseph] Univ Kansas, Div Hematol & Oncol, Westwood, KS USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Valhalla, NY 10595 USA. [Schouten, Harry C.] Acad Ziekenhuis, Div Hematol, Maastricht, Netherlands. [Szer, Jeffrey] Royal Melbourne Hosp, Dept Clin Haematol & Bone Marrow Transplantat, Melbourne, Vic, Australia. [Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Hematol Malignancies Bone Marrow Transplant, Worcester, MA USA. [Seftel, Matthew] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Socie, Gerard] Hop St Louis, Dept Hematol, Paris, France. [Vij, Ravi] Washington Univ, St Louis Childrens Hosp, Barnes Jewish Hosp, Div Med Oncol, St Louis, MO 63110 USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Div Hematol Oncol & Transplantat, MMC 480,420 Delaware St SE, Minneapolis, MN 55455 USA. EM weisd001@umn.edu RI Cahn, Jean-Yves/M-6493-2014; OI Olsson, Richard/0000-0001-5970-2128 FU Public Health Service from the National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI and NCI [5U01HL069294]; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; American Association of Blood Banks, Aetna; American Society for Blood and Marrow Transplantation, Amgen; National Marrow Donor Program and Health Resources and Services Administration [HHSH234200637020C] FX The Center for International Blood and Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 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 5U01HL069294 from the NHLBI and NCI; Contract HHSH234200637015C with the Health Resources and Services Administration; Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from the American Association of Blood Banks, Aetna, American Society for Blood and Marrow Transplantation, Amgen, anonymous donation to the Medical College of Wisconsin, Association of Medical Microbiology and Infectious Disease Canada, Astellas Pharma US, Baxter International, Bayer HealthCare Pharmaceuticals, Blood Center of Wisconsin, Blue Cross and Blue Shield Association, Bone Marrow Foundation, Canadian Blood and Marrow Transplant Group, Celgene, CellGenix, Centers for Disease Control and Prevention, ClinImmune Labs, CTI Clinical Trial and Consulting Services, Cubist Pharmaceuticals, Cylex, CytoTherm, DOR BioPharma, Dynal Biotech, Enzon Pharmaceuticals, European Group for Blood and Marrow Transplantation, Gambro BCT, Gamida Cell, Genzyme, Histogenetics, HKS Medical Information Systems, Hospira, Infectious Diseases Society of America, Kiadis Pharma, Kirin Brewery, Merck & Company, Medical College of Wisconsin, MGI Pharma, Michigan Community Blood Centers, Millennium Pharmaceuticals, Miller Pharmacal Group, Milliman USA, Miltenyi Biotec, National Marrow Donor Program, Nature Publishing Group, New York Blood Center, Novartis Oncology, Oncology Nursing Society, Osiris Therapeutics, Otsuka Pharmaceutical Development & Commercialization, Pall Life Sciences, PDL BioPharma, Pfizer, Pharmion, Saladax Biomedical, Schering Plough, Society for Healthcare Epidemiology of America, StemCyte, StemSoft Software, Sysmex, Teva Pharmaceutical Industries, The Marrow Foundation, Therako, Vidacare, Vion Pharmaceuticals,ViraCor Laboratories, ViroPharma, and Wellpoint. The views expressed in this article do not reflect the official polity or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. This project was supported in part by funding from the National Marrow Donor Program and Health Resources and Services Administration Contract HHSH234200637020C to the National Marrow Donor Program. The views expressed in this article do not reflect the official policy or position of the Health Resources and Services Administration or the National Marrow Donor Program. NR 37 TC 10 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2014 VL 20 IS 7 BP 960 EP 968 DI 10.1016/j.bbmt.2014.03.013 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500009 PM 24641829 ER PT J AU Giglia, JL White, MJ Hart, AJ Toro, JJ Freytes, CO Holt, CC Cai, Y Williams, SM Brandt, SJ AF Giglia, Jennifer L. White, Marquitta J. Hart, Andrew J. Toro, Juan J. Freytes, Cesar O. Holt, Cherish C. Cai, Ying Williams, Scott M. Brandt, Stephen J. TI A Single Nucleotide Polymorphism in SLC7A5 Is Associated with Gastrointestinal Toxicity after High-Dose Melphalan and Autologous Stem Cell Transplantation for Multiple Myeloma SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Pharmacogenetics; Multiple myeloma; High-dose melphalan; Autologous hematopoietic stem; cell transplantation; Gastrointestinal toxicity; Drug transporter ID ACID TRANSPORTER-1 LAT1; ORAL MUCOSITIS; SYSTEM L; AMINO; PHARMACOKINETICS AB Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant nonhematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to interindividual differences in the development of gastrointestinal complications of HDM, we analyzed single nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and correlated these with the need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and 20 in SLC7A8 were genotyped. Multiple analyses indicated that 1 SNP in the first intron of SLC7A5, rs4240803, was significantly associated with TPN use (odds ratio = .45, 95% confidence interval, .25 to .79; P = .007). Further, every haplotype that correlated with TPN requirement included this SNP. These results suggest that variability in melphalan transport affects mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Giglia, Jennifer L.; Hart, Andrew J.; Cai, Ying; Brandt, Stephen J.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [White, Marquitta J.; Holt, Cherish C.; Williams, Scott M.] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [White, Marquitta J.; Holt, Cherish C.; Williams, Scott M.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37232 USA. [Toro, Juan J.; Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Toro, Juan J.; Freytes, Cesar O.] Audie L Murphy VA Hosp, South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. [Williams, Scott M.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Brandt, Stephen J.] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Brandt, Stephen J.] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN 37232 USA. [Brandt, Stephen J.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Brandt, Stephen J.] Nashville VA Hosp, Tennessee Valley Healthcare Syst, Dept Vet Affairs, Nashville, TN USA. RP Brandt, SJ (reprint author), Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Room 777,Preston Res Bldg, Nashville, TN 37232 USA. EM stephen.brandt@vanderbilt.edu FU Clinical and Translational Science Award - National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000445] FX This project was supported in part by a Clinical and Translational Science Award program grant originally designated UL1TR000445 from the National Center for Advancing Translational Sciences, National Institutes of Health. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health. NR 17 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2014 VL 20 IS 7 BP 1014 EP 1020 DI 10.1016/j.bbmt.2014.03.022 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500016 PM 24704384 ER PT J AU Murphy, DG Loeb, S Basto, MY Challacombe, B Trinh, QD Leveridge, M Morgan, T Dasgupta, P Bultitude, M AF Murphy, Declan G. Loeb, Stacy Basto, Marnique Y. Challacombe, Benjamin Quoc-Dien Trinh Leveridge, Mike Morgan, Todd Dasgupta, Prokar Bultitude, Matthew TI Engaging responsibly with social media: The British Journal of Urology International (BJUI) guidelines SO BJU INTERNATIONAL LA English DT Editorial Material C1 [Murphy, Declan G.; Basto, Marnique Y.] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Murphy, Declan G.] Epworth Healthcare Richmond, Epworth Prostate Ctr, Melbourne, Vic, Australia. [Loeb, Stacy] NYU, New York, NY USA. [Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Div Urol Surg, Boston, MA 02115 USA. [Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Morgan, Todd] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Challacombe, Benjamin; Dasgupta, Prokar; Bultitude, Matthew] Kings Coll London, Guys Hosp, London WC2R 2LS, England. [Leveridge, Mike] Queens Univ, Dept Urol, Kingston, ON, Canada. RP Murphy, DG (reprint author), Peter MacCallum Canc Ctr, Div Canc Surg, East Melbourne, Vic 3002, Australia. EM declan.murphy@petermac.org FU Department of Health; Medical Research Council NR 8 TC 21 Z9 21 U1 1 U2 4 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 2014 VL 114 IS 1 BP 9 EP 11 DI 10.1111/bju.12788 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AK0RE UT WOS:000338121500008 PM 24774415 ER PT J AU Maggard-Gibbons, M AF Maggard-Gibbons, Melinda TI The use of report cards and outcome measurements to improve the safety of surgical care: the American College of Surgeons National Surgical Quality Improvement Program SO BMJ QUALITY & SAFETY LA English DT Review ID RISK ADJUSTMENT; POSTOPERATIVE MORTALITY; BYPASS-SURGERY; PRIVATE-SECTOR; COMPLICATION; FEASIBILITY; HOSPITALS; INFECTION; NSQIP AB Postoperative adverse events occur all too commonly and contribute greatly to our large and increasing healthcare costs. Surgeons, as well as hospitals, need to know their own outcomes in order to recognise areas that need improvement before they can work towards reducing complications. In the USA, the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) collects clinical data that provide benchmarks for providers and hospitals. This review summarises the history of ACS NSQIP and its components, and describes the evidence that feeding outcomes back to providers, along with real-time comparisons with other hospital rates, leads to quality improvement, better patient outcomes, cost savings and overall improved patient safety. The potential harms and limitations of the program are discussed. C1 [Maggard-Gibbons, Melinda] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Maggard-Gibbons, Melinda] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Maggard-Gibbons, Melinda] Olive View UCLA Med Ctr, Dept Surg, Sylmar, CA 91342 USA. RP Maggard-Gibbons, M (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, CHS 72-215,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM mmaggard@mednet.ucla.edu FU Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services [HHSA-290-2007-100621] FX This study was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (contract no. HHSA-290-2007-100621). The Agency for Healthcare Research and Quality reviewed contract deliverables to ensure adherence to contract requirements and quality, and a copyright release was obtained from the Agency for Healthcare Research and Quality before submission of this manuscript. The author of this study is responsible for its content. Statements in the study should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. NR 37 TC 17 Z9 17 U1 2 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD JUL PY 2014 VL 23 IS 7 BP 589 EP 599 DI 10.1136/bmjqs-2013-002223 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AJ7ZB UT WOS:000337919700010 PM 24748371 ER PT J AU Dennis, NA Johnson, CE Peterson, KM AF Dennis, Nancy A. Johnson, Christina E. Peterson, Kristina M. TI Neural correlates underlying true and false associative memories SO BRAIN AND COGNITION LA English DT Article DE Associative memory; False memory; fMRI; MTL; Retrieval; PFC ID EVENT-RELATED FMRI; ILLUSORY RECOGNITION MEMORY; PREFRONTAL ACTIVITY; RELATIONAL MEMORY; HIPPOCAMPAL CONTRIBUTIONS; SENSORY SIGNATURE; ITEM RECOGNITION; BRAIN ACTIVITY; RETRIEVAL; RECOLLECTION AB Despite the fact that associative memory studies produce a large number of false memories, neuroimaging analyses utilizing this paradigm typically focus only on neural activity mediating successful retrieval. The current study sought to expand on this prior research by examining the neural basis of both true and false associative memories. Though associative false memories are substantially different than those found in semantic or perceptual false memory paradigms, results suggest that associative false memories are mediated by similar neural mechanisms. Specifically, we found increased frontal activity that likely represents enhanced monitoring and evaluation compared to that needed for true memories and correct rejections. Results also indicated that true, and not false associative memories, are mediated by neural activity in the MTL, specifically the hippocampus. Finally, while activity in early visual cortex distinguished true from false memories, a lack of neural differences between hits and correct rejections failed to support previous findings suggesting that activity in early visual cortex represents sensory reactivation of encoding-related processing. (C) 2014 Elsevier Inc. All rights reserved. C1 [Dennis, Nancy A.; Johnson, Christina E.; Peterson, Kristina M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Peterson, Kristina M.] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Jamaica Plain, MA USA. [Peterson, Kristina M.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Dennis, NA (reprint author), Penn State Univ, Dept Psychol, 520 Moore Bldg, University Pk, PA 16802 USA. EM nad12@psu.edu OI Webb, Christina/0000-0002-7005-1650 FU National Science Foundation [BCS1025709]; American Federation for Aging Research; Department of Defense Counterdrug Technology Development Program Office FX The authors wish to thank Caitlin Bowman, Indira Turney, and Avery Rizio for helpful comments during the preparation of this manuscript. This work was supported by a National Science Foundation grant BCS1025709 awarded to Dr. Nancy Dennis. This research was conducted while Dr. Dennis was an AFAR Research. Grant recipient from the American Federation for Aging Research. Portions of the research in this article used the Color FERET (Facial Recognition Technology) database of facial images collected under the FERET program, sponsored by, the Department of Defense Counterdrug Technology Development Program Office. NR 54 TC 6 Z9 6 U1 2 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD JUL PY 2014 VL 88 BP 65 EP 72 DI 10.1016/j.bandc.2014.04.009 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AJ6CQ UT WOS:000337777700009 PM 24859815 ER PT J AU Donthamsetty, S Brahmbhatt, M Pannu, V Rida, PCG Ramarathinam, S Ogden, A Cheng, A Singh, KK Aneja, R AF Donthamsetty, Shashikiran Brahmbhatt, Meera Pannu, Vaishali Rida, Padmashree C. G. Ramarathinam, Sujatha Ogden, Angela Cheng, Alice Singh, Keshav K. Aneja, Ritu TI Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis SO CELL CYCLE LA English DT Article DE mitochondrial genome; centrosome amplification; osteosarcoma; rho0; cybrid ID RENAL-CELL CARCINOMA; HUMAN BREAST-CANCER; DNA MUTATIONS; CHROMOSOMAL INSTABILITY; SPINDLE MULTIPOLARITY; AURORA-A; DEPLETION; AMPLIFICATION; TUMORIGENESIS; P53 AB Centrosomes direct spindle morphogenesis to assemble a bipolar mitotic apparatus to enable error-free chromosome segregation and preclude chromosomal instability (CIN). Amplified centrosomes, a hallmark of cancer cells, set the stage for CIN, which underlies malignant transformation and evolution of aggressive phenotypes. Several studies report CIN and a tumorigenic and/or aggressive transformation in mitochondrial DNA (mtDNA)-depleted cells. Although several nuclear-encoded proteins are implicated in centrosome duplication and spindle organization, the involvement of mtDNA encoded proteins in centrosome amplification (CA) remains elusive. Here we show that disruption of mitochondrial function by depletion of mtDNA induces robust CA and mitotic aberrations in osteosarcoma cells. We found that overexpression of Aurora A, Polo-like kinase 4 (PLK4), and Cyclin E was associated with emergence of amplified centrosomes. Supernumerary centrosomes in rho0 (mtDNA-depleted) cells resulted in multipolar mitoses bearing "real" centrosomes with paired centrioles at the multiple poles. This abnormal phenotype was recapitulated by inhibition of respiratory complex I in parental cells, suggesting a role for electron transport chain (ETETC) in maintaining numeral centrosomal homeostasis. Furthermore, rho0 cells displayed a decreased proliferative capacity owing to a G2/M arrest. Downregulation of nuclear-encoded p53 in rho0 cells underscores the importance of mitochondrial and nuclear genome crosstalk and may perhaps underlie the observed mitotic aberrations. By contrast, repletion of wild-type mtDNA in rho0 cells (cybrid) demonstrated a much lesser extent of CA and spindle multipolarity, suggesting partial restoration of centrosomal homeostasis. Our study provides compelling evidence to implicate the role of mitochondria in regulation of centrosome duplication, spindle architecture, and spindle pole integrity. C1 [Donthamsetty, Shashikiran; Brahmbhatt, Meera; Pannu, Vaishali; Rida, Padmashree C. G.; Ramarathinam, Sujatha; Ogden, Angela; Cheng, Alice; Aneja, Ritu] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Singh, Keshav K.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Dept Environm Hlth, Birmingham, AL USA. [Singh, Keshav K.] Univ Alabama Birmingham, Ctr Free Rad Biol, Ctr Aging, Birmingham, AL USA. [Singh, Keshav K.] Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL USA. [Singh, Keshav K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Aneja, R (reprint author), Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA. EM kksingh@uab.edu; raneja@gsu.edu FU National Cancer Institute at the National Institutes of Health [R00CA131489, R01 CA169127]; Veterans Administration [1I01BX001716]; National Institute of Health [R01CA121904] FX This study was supported by grants to R. A. from the National Cancer Institute at the National Institutes of Health (R00CA131489, R01 CA169127). Research in K. K. S. laboratory is supported by Veterans Administration grant 1I01BX001716 and National Institute of Health R01CA121904. We thank Dr Bhupendra Singh for helping us with Figure 4F. NR 45 TC 5 Z9 6 U1 0 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD JUL 1 PY 2014 VL 13 IS 13 BP 2056 EP 2063 DI 10.4161/cc.29061 PG 8 WC Cell Biology SC Cell Biology GA AJ9OJ UT WOS:000338041700012 PM 24799670 ER PT J AU Sami, N Bhol, KC Beutner, EH Plunkett, RW Leiferman, KM Foster, CS Ahmed, AR AF Sami, Naveed Bhol, Kailash C. Beutner, Ernst H. Plunkett, Richard W. Leiferman, Kristin M. Foster, C. Stephen Ahmed, A. Razzaque TI Simultaneous presence of mucous membrane pemphigoid and pemphigus vulgaris: molecular characterization of both autoantibodies (Retraction of vol 100, pg 219, 2001) SO CLINICAL IMMUNOLOGY LA English DT Correction C1 [Sami, Naveed; Bhol, Kailash C.; Ahmed, A. Razzaque] Harvard Univ, Sch Dent Med, Dept Oral Med, Boston, MA 02115 USA. [Beutner, Ernst H.; Plunkett, Richard W.] Beutner Labs, Buffalo, NY 14215 USA. [Leiferman, Kristin M.] Mayo Clin, Immunodermatol Lab, Rochester, MN 55905 USA. [Foster, C. Stephen] Mass Eye & Ear Infirm, Boston, MA 02114 USA. [Sami, Naveed; Bhol, Kailash C.; Ahmed, A. Razzaque] New England Baptist Hosp, Dept Med, Boston, MA 02115 USA. RP Sami, N (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med, 188 Longwood Ave, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2014 VL 153 IS 1 BP 241 EP 241 DI 10.1016/j.clim.2014.03.002 PG 1 WC Immunology SC Immunology GA AJ8EQ UT WOS:000337935900030 ER PT J AU Besheli, LD Aran, S Shaqdan, K Kay, J Abujudeh, H AF Besheli, L. Daftari Aran, S. Shaqdan, K. Kay, J. Abujudeh, H. TI Current status of nephrogenic systemic fibrosis SO CLINICAL RADIOLOGY LA English DT Review ID IMATINIB MESYLATE TREATMENT; RESONANCE CONTRAST AGENT; NORMAL HUMAN MACROPHAGES; OF-THE-LITERATURE; RENAL-FAILURE; RISK-FACTORS; GADOLINIUM; KIDNEY; TRANSPLANTATION; GADODIAMIDE AB Nephrogenic systemic fibrosis (NSF) occurs in patients with advanced chronic kidney disease (CKD) or acute renal failure, most commonly following exposure to gadolinium-based contrast agents (GBCAs). NSF can be debilitating and associated with increased mortality. The putative association of NSF with GBCAs prompted the development of guidelines to limit the use of these contrast agents in at-risk patients. Indeed, the incidence of NSF has decreased dramatically following application of these guidelines, which appears to be the only effective means of decreasing NSF incidence. Thus, increasing clinician awareness of these updated guidelines is important. The present review introduces and compares updated guidelines for GBCA use and discusses the latest advances in the understanding of the pathogenic mechanisms and treatment of NSF. (C) 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. C1 [Besheli, L. Daftari; Aran, S.; Shaqdan, K.; Abujudeh, H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Kay, J.] Univ Massachusetts, Sch Med, Dept Med, Div Rheumatol, Worcester, MA USA. [Kay, J.] UMass Mem Med Ctr, Worcester, MA USA. RP Abujudeh, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,FND 210, Boston, MA 02114 USA. EM habujudeh@partners.org OI Kay, Jonathan/0000-0002-8970-4260 NR 74 TC 22 Z9 23 U1 0 U2 10 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0009-9260 EI 1365-229X J9 CLIN RADIOL JI Clin. Radiol. PD JUL PY 2014 VL 69 IS 7 BP 661 EP 668 DI 10.1016/j.crad.2014.01.003 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ7LA UT WOS:000337877000001 ER PT J AU Araki, T Sholl, LM Gerbaudo, VH Hatabu, H Nishino, M AF Araki, T. Sholl, L. M. Gerbaudo, V. H. Hatabu, H. Nishino, M. TI Intrathymic cyst: Clinical and radiological features in surgically resected cases SO CLINICAL RADIOLOGY LA English DT Article ID MULTILOCULAR THYMIC CYST; COMPUTED-TOMOGRAPHY; EPITHELIAL TUMORS; MYASTHENIA-GRAVIS; HODGKIN DISEASE; CT; HYPERPLASIA; THYMOMA; MALIGNANCIES; THERAPY AB AIM: To investigate radiological and clinical characteristics of pathologically proven cases of intrathymic cysts. MATERIALS AND METHODS: The study population consisted of 18 patients (five males, 13 females; median age 56 years) with pathologically confirmed intrathymic cysts who underwent thymectomy and had preoperative chest computed tomography (CT) available for review. The patient demographics, clinical presentation, and preoperative radiological diagnoses were reviewed. CT images were evaluated for shape, contour, location of the cysts and the presence of adjacent thymic tissue, mass effect, calcifications, and septa. The size and CT attenuations of the cysts were measured. RESULTS: The most common CT features of intrathymic cysts included oval shape (9/18; 50%), smooth contour (12/18; 67%), midline location (11/18; 61%), the absence of visible adjacent thymic tissue (12/18; 67%), and the absence of calcification (16/18; 89%). The mean longest diameter and the longest perpendicular diameter were 25 mm (range 17-49 mm) and 19 mm (range 10-44 mm), respectively. The mean CT attenuation was 38 HU (range 6-62 HU) on contrast-enhanced CT, and was 45 HU (range 26-64 HU) on unenhanced CT (p = 0.41). The CT attenuation was >20 HU in 15 of 18 patients (83%). Preoperative radiological diagnosis included thymoma in 11 patients. CONCLUSION: In surgically removed, pathologically proven cases of intrathymic cyst, the CT attenuation was >20 HU in most cases, leading to the preoperative diagnosis of thymoma. Awareness of the spectrum of imaging findings of the entity is essential to improve the diagnostic accuracy and patient management. (C) 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. C1 [Araki, T.; Gerbaudo, V. H.; Hatabu, H.; Nishino, M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sholl, L. M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Nishino, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. RP Nishino, M (reprint author), Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. EM Mizuki_Nishino@DFCI.HARVARD.EDU FU [1K23CA157631 (NCI)] FX M.N. was supported by 1K23CA157631 (NCI). NR 32 TC 3 Z9 3 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0009-9260 EI 1365-229X J9 CLIN RADIOL JI Clin. Radiol. PD JUL PY 2014 VL 69 IS 7 BP 732 EP 738 DI 10.1016/j.crad.2014.03.002 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ7LA UT WOS:000337877000012 PM 24824976 ER PT J AU Viron, M Bello, I Freudenreich, O Shtasel, D AF Viron, Mark Bello, Iruma Freudenreich, Oliver Shtasel, Derri TI Characteristics of Homeless Adults with Serious Mental Illness Served by a State Mental Health Transitional Shelter SO COMMUNITY MENTAL HEALTH JOURNAL LA English DT Article ID ASSERTIVE COMMUNITY TREATMENT; NEW-YORK-CITY; PSYCHIATRIC-DISORDERS; RISK-FACTORS; FOLLOW-UP; ILL; MORTALITY; CARE; POPULATION; PREVALENCE AB Specialized transitional shelters are available in various cities to provide assistance to homeless individuals with serious mental illness. Little is known about the population using such shelters. The authors conducted a retrospective chart review to collect demographic, social, and clinical data of residents in a state-operated mental health transitional shelter in Massachusetts. A total of 74 subjects were included. Schizophrenia-spectrum disorders were present in 67.6 % of the sample and mood disorders in 35.1 %. Substance use disorders were documented in 44.6 %. Chronic medical illness (mostly hypertension, dyslipidemia, asthma, and diabetes) was found in 82.4 %. The co-occurrence of a psychiatric and substance use disorder and chronic medical illness was found in 36.5 %. The majority (75.7 %) of patients had a history of legal charges. Homeless individuals with serious mental illness served by specialized transitional shelters represent a population with complex psychiatric, medical and social needs. C1 [Viron, Mark] Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. [Viron, Mark; Freudenreich, Oliver; Shtasel, Derri] Harvard Univ, Sch Med, Boston, MA USA. [Bello, Iruma] NYU, Langone Med Ctr, Bellevue Hosp, New York, NY USA. [Bello, Iruma] NYU, Sch Med, New York, NY USA. [Freudenreich, Oliver] Massachusetts Gen Hosp, Schizophrenia Res Program, Boston, MA 02114 USA. [Shtasel, Derri] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Viron, M (reprint author), Massachusetts Mental Hlth Ctr, 75 Fenwood Rd, Boston, MA 02115 USA. EM mark.viron@state.ma.us NR 37 TC 2 Z9 2 U1 4 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0010-3853 EI 1573-2789 J9 COMMUNITY MENT HLT J JI Community Ment. Health J. PD JUL PY 2014 VL 50 IS 5 BP 560 EP 565 DI 10.1007/s10597-013-9607-5 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AJ6HB UT WOS:000337790700008 PM 23703373 ER PT J AU Rasmussen, JL Steketee, G Frost, RO Tolin, DF Brown, TA AF Rasmussen, Jessica L. Steketee, Gail Frost, Randy O. Tolin, David F. Brown, Timothy A. TI Assessing Squalor in Hoarding: The Home Environment Index SO COMMUNITY MENTAL HEALTH JOURNAL LA English DT Article DE Hoarding; Self-neglect; Squalor; Poor housekeeping ID SEVERE DOMESTIC SQUALOR; STRESS SCALES DASS; SELF-NEGLECT; DIOGENES SYNDROME; OLD-AGE; COMMUNITY; CLEANLINESS; DEPRESSION AB The current study examined a new measure of squalor associated with hoarding, the Home Environment Index (HEI). Participants (N = 793) were recruited from a large database of individuals who sought information about hoarding following national media appearances and consented to an internet study. Participants completed measures of hoarding and related psychopathology, including the HEI. The HEI showed good internal consistency and construct validity and reflected a single factor of home squalor (15 items). The HEI correlated positively with measures of hoarding and mood psychopathology. Recommendations for future modifications and further study are provided. C1 [Rasmussen, Jessica L.; Brown, Timothy A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Steketee, Gail] Boston Univ, Sch Social Work, Boston, MA 02215 USA. [Frost, Randy O.] Smith Coll, Dept Psychol, Northampton, MA 01063 USA. [Tolin, David F.] Inst Living, Hartford, CT 06106 USA. RP Rasmussen, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Simches Res Bldg,185 Cambridge St,Suite 2000, Boston, MA 02114 USA. EM jrasmussen@mgh.harvard.edu NR 23 TC 3 Z9 3 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0010-3853 EI 1573-2789 J9 COMMUNITY MENT HLT J JI Community Ment. Health J. PD JUL PY 2014 VL 50 IS 5 BP 591 EP 596 DI 10.1007/s10597-013-9665-8 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AJ6HB UT WOS:000337790700012 PM 24292497 ER PT J AU Sampaio, AS McCarthy, KD Mancuso, E Stewart, SE Geller, DA AF Sampaio, Aline S. McCarthy, Katherine D. Mancuso, Elizabeth Stewart, S. Evelyn Geller, Daniel A. TI Validation of the University of Sao Paulo's Sensory Phenomena Scale - English version SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; TOURETTES-SYNDROME; REPETITIVE BEHAVIORS; RELIABILITY; ADOLESCENTS; CHILDREN; GILLES AB Introduction: Sensory phenomena (SP) are disturbing sensations, feelings or urges. Although such feelings are often found in obsessive compulsive disorder (OCD) and Tourette's Syndrome (TS) patients, sensory phenomena are usually not addressed in assessment measures. The University of Sao Paulo's Sensory Phenomena Scale (USP-SPS) was designed to measure sensory phenomena among all ages of patients with OCD and TS, and it was validated in Portuguese. Objectives: The aim of this study is to validate the English version of the USP-SPS and to examine its psychometric properties. Material and Methods: Sixty subjects, between the ages of 7 and 60 years, completed the USP-SPS, Y-BOCS or CY-BOCS and YGTSS. An expert clinician also performed a Clinical Inquiry about SP. Inter-rater reliability, sensitivity, specificity, convergent and divergent validity were evaluated. Results: The USP-SPS symptom checklist showed good sensitivity in all ages, however its severity scale did not show good validity results for the pediatric population. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sampaio, Aline S.] Univ Fed Bahia, Sch Med, Univ Hlth Serv, BR-40110170 Salvador, BA, Brazil. [McCarthy, Katherine D.] Alliant Int Univ, Calif Sch Profess Psychol, San Francisco, CA 94133 USA. [Mancuso, Elizabeth] Belmont Publ Sch, Belmont, MA 02478 USA. [Stewart, S. Evelyn] British Columbia Mental Hlth & Addict Res Unit, Vancouver, BC V5Z 4H4, Canada. [Geller, Daniel A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sampaio, AS (reprint author), Rua Altino Serbeto de Barros 241,Sala 404, BR-41810010 Salvador, BA, Brazil. EM aline.sampaio@ufba.br; mccarthy.katherine@gmail.com; eamancuso@partners.org; evelyn.stewart@ubc.ca; dan@gellers.org RI Stewart, Evelyn/K-6961-2014; OI Stewart, S. Evelyn/0000-0002-0994-6383 FU Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES; Coordination for Education of Graduated People), Brazil; Fundo de Aprimoramento Academico (FUAA; Grant for Academic Improvement); Department & Institute of Psychiatry-University of Sao Paulo Medical School FX This study received financial support in the form of grants provided by the following Brazilian governmental agencies to Dr Sampaio: by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES; Coordination for Education of Graduated People), Brazil, Fundo de Aprimoramento Academico (FUAA; Grant for Academic Improvement), Department & Institute of Psychiatry-University of Sao Paulo Medical School. NR 26 TC 2 Z9 2 U1 1 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 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JUL PY 2014 VL 55 IS 5 BP 1330 EP 1336 DI 10.1016/j.comppsych.2014.02.008 PG 7 WC Psychiatry SC Psychiatry GA AJ7AV UT WOS:000337850300036 PM 24666717 ER PT J AU Lin, YJB Gardiner, MF AF Lin, Yijie B. Gardiner, Matthew F. TI Fingernail-Induced Corneal Abrasions: Case Series From an Ophthalmology Emergency Department SO CORNEA LA English DT Article DE corneal abrasion; recurrent erosion syndrome; corneal infection; fingernail injury ID DICLOFENAC; MANAGEMENT; EFFICACY AB Purpose:Fingernail-induced corneal abrasions are one of the most common eye injuries that present to the emergency department, and yet there is little literature available to offer guidelines for management. We analyzed the treatment used in cases of fingernail-induced corneal abrasions that presented to the Massachusetts Eye and Ear Infirmary Emergency Department and studied its relationship to the development of complications such as recurrent erosion syndrome and infection.Methods:We performed a retrospective review of 99 patients who presented to the Massachusetts Eye and Ear Infirmary Emergency Department with fingernail-induced corneal abrasions between January 1, 2009 and December 31, 2009. We followed the patients for 12 months and documented demographics, nature of the injury, treatment, and complications.Results:The average age was 29.4 (range, 2-89) years. Forty-four percent (n = 44) were female and 56% (n = 55) were male. Of the 99 subjects, 39 had a full 12 month follow-up, and 7 developed a complication from the injury. Compared with the 32 subjects without complications, there was no difference in age or gender. However, there was a significant difference in that adults scratched by another adult were more highly represented in the group with complications (43%, n = 3/7 vs. 3%, n = 1/32; P = 0.0017). There was no significant difference in outcome by treatment used.Conclusions:This is the largest fingernail-induced corneal abrasion study completed to date. Patients are at risk of developing complications, but there is scant evidenced-based literature available for treating this common injury. Prospective trials should be performed to better optimize and standardize treatments. C1 [Lin, Yijie B.; Gardiner, Matthew F.] Harvard Univ, Sch Med, Boston, MA USA. [Gardiner, Matthew F.] Massachusetts Eye & Ear Infirm, Dept Emergency Ophthalmol, Boston, MA 02114 USA. RP Gardiner, MF (reprint author), Massachusetts Eye & Ear Infirm, Dept Emergency Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM Matthew_Gardiner@meei.harvard.edu OI Gardiner, Matthew/0000-0002-8864-2379 NR 10 TC 2 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2014 VL 33 IS 7 BP 691 EP 695 DI 10.1097/ICO.0000000000000133 PG 5 WC Ophthalmology SC Ophthalmology GA AJ5SP UT WOS:000337748400009 PM 24831196 ER PT J AU Arnoldner, MA Kheirkhah, A Jakobiec, FA Durand, ML Hamrah, P AF Arnoldner, Michael A. Kheirkhah, Ahmad Jakobiec, Frederick A. Durand, Marlene L. Hamrah, Pedram TI Successful Treatment of Paecilomyces lilacinus Keratitis With Oral Posaconazole SO CORNEA LA English DT Article DE Paecilomyces lilacinus; fungal keratitis; posaconazole; in vivo confocal microscopy ID SUCCESSFUL MEDICAL-TREATMENT AB Purpose:To report a case of successful medical treatment with oral posaconazole in refractory fungal keratitis caused by Paecilomyces lilacinus.Methods:Case report.Results:A 57-year-old male, soft contact lens wearer presented with irritation, pain, photophobia, and reduced vision. Slit-lamp examination showed a large corneal epithelial defect with a peripheral infiltrate. The patient did not improve on fortified topical antibiotics. After the diagnosis of P. lilacinus fungal keratitis, oral voriconazole and topical antifungal therapy were started. Despite antifungal therapy, progressive disease required therapeutic penetrating keratoplasty. Postoperatively, because of clinical signs of recurrence and in vivo confocal microscopy findings of presumed hyphae in the cornea, intracameral miconazole was injected and oral posaconazole was started. The patient improved and demonstrated no hyphae 6 weeks after starting posaconazole. When posaconazole was stopped, the cornea remained clear with excellent acuity. However, because of acute graft rejection 2 months after stopping posaconazole, keratoprosthesis was implanted, with no evidence of infection at surgery or during the 3.5-year follow-up.Conclusions:To the best of our knowledge, this is the first report on the use of oral posaconazole for Paecilomyces keratitis. Posaconazole might be indicated in the treatment of refractory Paecilomyces keratitis that is resistant to conventional therapy. C1 [Arnoldner, Michael A.; Kheirkhah, Ahmad; Hamrah, Pedram] Massachusetts Eye & Ear Infirm, Ocular Surface Imaging Ctr, Boston, MA 02114 USA. [Kheirkhah, Ahmad; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Corneal & Refract Surg Serv,Dept Ophthalmol, Boston, MA 02114 USA. [Jakobiec, Frederick A.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cogan Pathol Lab, Boston, MA 02114 USA. [Durand, Marlene L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Infect Dis, Boston, MA 02114 USA. RP Hamrah, P (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu FU NIH [K08-EY020575, K12-EY016335]; New England corneal transplant research fund; Falk Medical Research Foundation FX Supported by NIH K08-EY020575, NIH K12-EY016335, New England corneal transplant research fund, and Falk Medical Research Foundation (P.H.). NR 12 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2014 VL 33 IS 7 BP 747 EP 749 DI 10.1097/ICO.0000000000000143 PG 3 WC Ophthalmology SC Ophthalmology GA AJ5SP UT WOS:000337748400020 PM 24858020 ER PT J AU Elmets, CA Cala, CM Xu, H AF Elmets, Craig A. Cala, Cather M. Xu, Hui TI Photoimmunology SO DERMATOLOGIC CLINICS LA English DT Article DE Photoimmunology; Nonmelanoma skin cancer; Ultraviolet radiation; Polymorphous light eruption; Chronic actinic dermatitis; Cutaneous lupus erythematosus; Phototherapy; Photosensitivity ID CUTANEOUS LUPUS-ERYTHEMATOSUS; RADIATION-INDUCED IMMUNOSUPPRESSION; POLYMORPHIC LIGHT ERUPTION; CHRONIC ACTINIC DERMATITIS; INDUCED IMMUNE SUPPRESSION; HIGH-DOSE UVA1; ULTRAVIOLET-B PHOTOTHERAPY; NECROSIS-FACTOR-ALPHA; GENE-RELATED PEPTIDE; REGULATORY-T-CELLS AB The discipline that investigates the biologic effects of ultraviolet radiation on the immune system is called photoimmunology. Photoimmunology evolved from an interest in understanding the role of the immune system in skin cancer development and why immunosuppressed organ transplant recipients are at a greatly increased risk for cutaneous neoplasms. In addition to contributing to an understanding of the pathogenesis of nonmelanoma skin cancer, the knowledge acquired about the immunologic effects of ultraviolet radiation exposure has provided an understanding of its role in the pathogenesis of other photodermatologic diseases. C1 [Elmets, Craig A.; Xu, Hui] Univ Alabama Birmingham, Birmingham VA Med Ctr, UAB Comprehens Canc Ctr, Dept Dermatol,UAB Skin Dis Res Ctr, Birmingham, AL 35294 USA. [Cala, Cather M.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. RP Elmets, CA (reprint author), Univ Alabama Birmingham, Birmingham VA Med Ctr, UAB Comprehens Canc Ctr, Dept Dermatol,UAB Skin Dis Res Ctr, EFH 414,1720 2nd Ave South, Birmingham, AL 35294 USA. EM celmets@uab.edu FU NIH [P30 AR050948, P30 CA013148, N01 CN05014-69]; VA Merit Review [18-103-02] FX Funded by NIH grants and contracts: P30 AR050948, P30 CA013148, N01 CN05014-69 and by VA Merit Review 18-103-02. NR 112 TC 5 Z9 5 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8635 EI 1558-0520 J9 DERMATOL CLIN JI Dermatol. Clin. PD JUL PY 2014 VL 32 IS 3 BP 277 EP + DI 10.1016/j.det.2014.03.005 PG 15 WC Dermatology SC Dermatology GA AJ7AL UT WOS:000337849300004 PM 24891051 ER PT J AU Kleinridders, A Ferris, HA Cai, WK Kahn, CR AF Kleinridders, Andre Ferris, Heather A. Cai, Weikang Kahn, C. Ronald TI Insulin Action in Brain Regulates Systemic Metabolism and Brain Function SO DIABETES LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; LONG-TERM DEPRESSION; DIET-INDUCED OBESITY; GROWTH-FACTOR-I; HIPPOCAMPAL SYNAPTIC PLASTICITY; HEPATIC GLUCOSE-PRODUCTION; DB/DB DIABETIC MICE; A-BETA OLIGOMERS; ALZHEIMERS-DISEASE; INTRANASAL INSULIN AB Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases. C1 [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institutes of Health [DK-31036, DK-33201, DK-55545, 5K08-DK-097293-02]; Mary K. Iacocca Professorship; Deutsche Forschungsgemeinschaft [KL-2399/1-1] FX This research was supported by National Institutes of Health grants DK-31036, DK-33201, DK-55545, and 5K08-DK-097293-02; a Mary K. Iacocca Professorship; and Deutsche Forschungsgemeinschaft grant project KL-2399/1-1. NR 126 TC 77 Z9 80 U1 1 U2 28 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 2014 VL 63 IS 7 BP 2232 EP 2243 DI 10.2337/db14-0568 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ7YO UT WOS:000337918200014 PM 24931034 ER PT J AU Biessels, GJ Reijmer, YD AF Biessels, Geert Jan Reijmer, Yael D. TI Brain Changes Underlying Cognitive Dysfunction in Diabetes: What Can We Learn From MRI? SO DIABETES LA English DT Article ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; WHITE-MATTER ABNORMALITIES; SMALL VESSEL DISEASE; MIDDLE-AGED ADULTS; CORTICAL THICKNESS; FUNCTIONAL MRI; TYPE-1; MELLITUS; ATROPHY; PROGRESSION AB Diabetes is associated with cognitive dysfunction and an increased risk of dementia. This article addresses findings with brain MRI that may underlie cognitive dysfunction in diabetes. Studies in adults with type 1 diabetes show regional reductions in brain volume. In those with a diabetes onset in childhood, these volume reductions are likely to reflect the sum of changes that occur during brain development and changes that occur later in life due to exposure to diabetes-related factors. Type 2 diabetes is associated with global brain atrophy and an increased burden of small-vessel disease. These brain changes occur in the context of aging and often also in relation to an adverse vascular risk factor profile. Advanced imaging techniques detect microstructural lesions in the cerebral gray and white matter of patients with diabetes that affect structural and functional connectivity. Challenges are to further unravel the etiology of these cerebral complications by integrating findings from different imaging modalities and detailed clinical phenotyping and by linking structural MRI abnormalities to histology. A better understanding of the underlying mechanisms is necessary to establish interventions that will improve long-term cognitive outcomes for patients with type 1 and type 2 diabetes. C1 [Biessels, Geert Jan; Reijmer, Yael D.] Univ Med Ctr, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Reijmer, Yael D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, J Philip Kistler Stroke Res Ctr, Boston, MA USA. RP Biessels, GJ (reprint author), Univ Med Ctr, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. EM g.j.biessels@umcutrecht.nl FU ZonMw [91711384]; Netherlands Organisation for Health Research and Development; Netherlands Heart Foundation [2010T073] FX The research of G.J.B. is supported by Vidi grant 91711384 from ZonMw, The Netherlands Organisation for Health Research and Development, and grant 2010T073 from the Netherlands Heart Foundation. NR 51 TC 42 Z9 46 U1 1 U2 18 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 2014 VL 63 IS 7 BP 2244 EP 2252 DI 10.2337/db14-0348 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ7YO UT WOS:000337918200015 PM 24931032 ER PT J AU Taborsky, GJ Mei, Q Bornfeldt, KE Hackney, DJ Mundinger, TO AF Taborsky, Gerald J., Jr. Mei, Qi Bornfeldt, Karin E. Hackney, Daryl J. Mundinger, Thomas O. TI The p75 Neurotrophin Receptor Is Required for the Major Loss of Sympathetic Nerves From Islets Under Autoimmune Attack SO DIABETES LA English DT Article ID DEPENDENT DIABETES-MELLITUS; AUTONOMIC NEUROPATHY; IMPAIRED GLUCAGON; TRANSGENIC MODEL; NERVOUS-SYSTEM; GROWTH-FACTOR; INNERVATION; INSULIN; SECRETION; RAT AB Our goal was to determine the role of the p75 neurotrophin receptor (p75NTR) in the loss of islet sympathetic nerves that occurs during the autoimmune attack of the islet. The islets of transgenic (Tg) mice in which beta-cells express a viral glycoprotein (GP) under the control of the insulin promotor (Ins2) were stained for neuropeptide Y before, during, and after virally induced autoimmune attack of the islet. Ins2-GP(Tg) mice injected with lymphocytic choriomeningitis virus (LCMV) lost islet sympathetic nerves before diabetes development but coincident with the lymphocytic infiltration of the islet. The nerve loss wasmarked and islet-selective. Similar nerve loss, chemically induced, was sufficient to impair sympathetically mediated glucagon secretion. In contrast, LCMV-injected Ins2-GP(Tg) mice lacking the p75NTR retained most of their islet sympathetic nerves, despite both lymphocytic infiltration and development of diabetes indistinguishable from that of p75NTR wild-type mice. We conclude that an nducible autoimmune attack of the islet causes a marked and islet-selective loss of sympathetic nerves that precedes islet collapse and hyperglycemia. The p75NTR mediates this nerve loss but plays no role in mediating the loss of islet b-cells or the subsequent diabetes. p75NTR-mediated nerve loss may contribute to the impaired glucose counterregulation seen in type 1 diabetes. C1 [Taborsky, Gerald J., Jr.] Vet Affairs Puget Sound Hlth Care Syst, Div Endocrinol Metab, Seattle, WA 98108 USA. [Taborsky, Gerald J., Jr.; Mei, Qi; Bornfeldt, Karin E.; Mundinger, Thomas O.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Bornfeldt, Karin E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Bornfeldt, Karin E.] Univ Washington, Diabet Obes Ctr Excellence, Seattle, WA 98195 USA. [Hackney, Daryl J.] Seattle Inst Biomed & Clin Res, Seattle, WA USA. RP Taborsky, GJ (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Div Endocrinol Metab, Seattle, WA 98108 USA. EM taborsky@u.washington.edu FU Medical Research Service of the Department of Veterans Affairs; National Institutes of Health [R01-DK-50154, P30-DK-17047, R01-HL-097365, R01-HL-062887, P01-HL-092969] FX This work was supported by the Medical Research Service of the Department of Veterans Affairs (to G.J.T.) and National Institutes of Health grants R01-DK-50154 (to G.J.T.), P30-DK-17047, R01-HL-097365, R01-HL-062887, and P01-HL-092969 (to K.E.B.). NR 38 TC 5 Z9 5 U1 0 U2 1 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 2014 VL 63 IS 7 BP 2369 EP 2379 DI 10.2337/db13-0778 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ7YO UT WOS:000337918200026 PM 24608438 ER PT J AU Liu, RJ Zhong, YF Li, XZ Chen, HB Jim, B Zhou, MM Chuang, PY He, JC AF Liu, Ruijie Zhong, Yifei Li, Xuezhu Chen, Haibing Jim, Belinda Zhou, Ming-Ming Chuang, Peter Y. He, John Cijiang TI Role of Transcription Factor Acetylation in Diabetic Kidney Disease SO DIABETES LA English DT Article ID GLYCATION END-PRODUCTS; IN-VIVO; SIRT1; NEPHROPATHY; INHIBITION; EXPRESSION; ACTIVATION; RESVERATROL; BROMODOMAIN; PODOCYTES AB Nuclear factor (NF)-kappa B and signal transducer and activator of transcription 3 (STAT3) play a critical role in diabetic nephropathy (DN). Sirtuin-1 (SIRT1) regulates transcriptional activation of target genes through protein deacetylation. Here, we determined the roles of Sirt1 and the effect of NF-kappa B (p65) and STAT3 acetylation in DN. We found that acetylation of p65 and STAT3 was increased in both mouse and human diabetic kidneys. In human podocytes, advanced glycation end products (AGEs) induced p65 and STAT3 acetylation and overexpression of acetylation-incompetent mutants of p65 and STAT3 abrogated AGE-induced expression of NF-kappa B and STAT3 target genes. Inhibition of AGE formation in db/db mice by pyridoxamine treatment attenuated proteinuria and podocyte injury, restored SIRT1 expression, and reduced p65 and STAT3 acetylation. Diabetic db/db mice with conditional deletion of SIRT1 in podocytes developed more proteinuria, kidney injury, and acetylation of p65 and STAT3 compared with db/db mice without SIRT1 deletion. Treatment of db/db mice with a bromodomain and extraterminal (BET)-specific bromodomain inhibitor (MS417) which blocks acetylation-mediated association of p65 and STAT3 with BET proteins, attenuated proteinuria, and kidney injury. Our findings strongly support a critical role for p65 and STAT3 acetylation in DN. Targeting protein acetylation could be a potential new therapy for DN. C1 [Liu, Ruijie; Chuang, Peter Y.; He, John Cijiang] Mt Sinai Sch Med, Dept Med Nephrol, New York, NY 10029 USA. [Zhong, Yifei] Shanghai Univ Tradit Chinese Med, Longhua Hosp, Dept Nephrol, Shanghai, Peoples R China. [Li, Xuezhu] Tongji Univ, Sch Med, Shanghai East Hosp, Dept Nephrol, Shanghai 200092, Peoples R China. [Chen, Haibing] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol, Shanghai 200030, Peoples R China. [Jim, Belinda] Jacobi Med Ctr, Div Nephrol, Bronx, NY USA. [Zhou, Ming-Ming] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY USA. [He, John Cijiang] James J Peters VA Med Ctr, Renal Sect, Bronx, NY USA. RP He, JC (reprint author), Mt Sinai Sch Med, Dept Med Nephrol, New York, NY 10029 USA. EM cijiang.he@mssm.edu FU VA Merit Award [1I01BX000345]; 973 fund [2012CB517601]; National Institutes of Health (NIH) [1R01-DK-078897, 1R01-DK-088541]; NIH [5K08-DK-082760, R01-HG-004508, R01-CA-87658]; National Natural Science Foundation of China for Young Investigators [1999-30901944]; Shanghai Bureau of Health for Young Investigators [2011-XYQ2011059] FX J.C.H. is supported by VA Merit Award (1I01BX000345), 973 fund (2012CB517601), and National Institutes of Health (NIH) grants 1R01-DK-078897 and 1R01-DK-088541. P.Y.C. is supported by NIH grant 5K08-DK-082760. Y.Z. is supported by the National Natural Science Foundation of China for Young Investigators (1999-30901944) and the Shanghai Bureau of Health for Young Investigators (2011-XYQ2011059). M.-M.Z. is supported by NIH grants R01-HG-004508 and R01-CA-87658. NR 54 TC 32 Z9 33 U1 2 U2 12 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 2014 VL 63 IS 7 BP 2440 EP 2453 DI 10.2337/db13-1810 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ7YO UT WOS:000337918200032 PM 24608443 ER PT J AU Vassy, JL Hivert, MF Dauriz, M Meigs, JB AF Vassy, Jason L. Hivert, Marie-France Dauriz, Marco Meigs, James B. TI Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection. Diabetes 2014;63:2172-2182 RESPONSE SO DIABETES LA English DT Editorial Material C1 [Vassy, Jason L.; Hivert, Marie-France; Dauriz, Marco; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Vassy, Jason L.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. [Vassy, Jason L.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Boston, MA 02115 USA. [Hivert, Marie-France] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Hivert, Marie-France] Univ Sherbrooke, Div Endocrinol, Dept Med, Sherbrooke, PQ J1K 2R1, Canada. [Dauriz, Marco; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dauriz, Marco] Univ Verona, Div Endocrinol & Metab Dis, Dept Med, Sch Med, I-37100 Verona, Italy. [Dauriz, Marco] Hosp Trust Verona, Verona, Italy. RP Meigs, JB (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM jmeigs@partners.org RI Dauriz, Marco/S-5843-2016 OI Dauriz, Marco/0000-0002-5542-5941 NR 2 TC 0 Z9 0 U1 0 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 2014 VL 63 IS 7 BP E13 EP E13 DI 10.2337/db14-0449 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ7YO UT WOS:000337918200002 PM 24962928 ER PT J AU Negrier, S Bushmakin, AG Cappelleri, JC Korytowsky, B Sandin, R Charbonneau, C Michaelson, MD Figlin, RA Motzer, RJ AF Negrier, S. Bushmakin, A. G. Cappelleri, J. C. Korytowsky, B. Sandin, R. Charbonneau, C. Michaelson, M. D. Figlin, R. A. Motzer, R. J. TI Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Sunitinib; Overall survival; Progression-free survival; Surrogate end-point; Renal cell carcinoma ID PHASE-III TRIAL; INTERFERON-ALPHA; COLORECTAL-CANCER; CLINICAL-TRIALS; TUMOR RESPONSE; BREAST-CANCER; DOUBLE-BLIND; ASSOCIATION; SUNITINIB; ONCOLOGY AB Background: To determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naive metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-alpha) in a phase III study. Methods: The relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan-Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test. Results: In the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P < 0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan-Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P < 0.0001). Conclusions: A positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-alpha. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Negrier, S.] Univ Lyon, Ctr Leon Berard, F-69373 Lyon 08, France. [Bushmakin, A. G.; Cappelleri, J. C.] Pfizer Inc, Stat, Groton, CT 06340 USA. [Korytowsky, B.] Pfizer Oncol, Global Hlth Econ & Outcomes Res, New York, NY 10017 USA. [Sandin, R.] Pfizer Oncol, Global Hlth Econ & Outcomes Res, S-10191 Sollentuna, Sweden. [Charbonneau, C.] Pfizer PIO, Specialty Care BU, Global Outcomes Res, F-75014 Paris, France. [Michaelson, M. D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Figlin, R. A.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Negrier, S (reprint author), Univ Lyon, Ctr Leon Berard, 28 Rue Laennec, F-69373 Lyon 08, France. EM sylvie.negrier@lyon.unicancer.fr OI Michaelson, Dror/0000-0001-9249-6338 FU Pfizer.Inc. FX We would like to thank all of the participating patients and their families, as well as the network of investigators, research nurses, study coordinators and operations staff. Medical writing support was provided by Andy Gannon and Felicity Leigh at ACUMED (c) (New York, NY, USA; Tytherington, UK) and was funded by Pfizer.Inc. NR 30 TC 5 Z9 5 U1 2 U2 5 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 2014 VL 50 IS 10 BP 1766 EP 1771 DI 10.1016/j.ejca.2014.03.012 PG 6 WC Oncology SC Oncology GA AJ7KO UT WOS:000337875800009 PM 24768571 ER PT J AU Sanchez-Mas, J Lax, A Asensio-Lopez, MD Fernandez-Del Palacio, MJ Caballero, L Santarelli, G Januzzi, JL Pascual-Figal, DA AF Sanchez-Mas, Jesus Lax, Antonio del Carmen Asensio-Lopez, Maria Fernandez-Del Palacio, Maria J. Caballero, Luis Santarelli, Giorgia Januzzi, James L. Pascual-Figal, Domingo A. TI Modulation of IL-33/ST2 system in postinfarction heart failure: correlation with cardiac remodelling markers SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE Acute myocardial infarction; cardiac remodelling; interleukin; ST2 ID FAMILY-MEMBER ST2; ACUTE MYOCARDIAL-INFARCTION; SOLUBLE CONCENTRATIONS; IL-1 RECEPTOR; THERAPY; BIOMARKERS; MORTALITY; ROLES AB Background Interleukin (IL)-33 and sST2 are molecules with an opposite pathophysiologic implications in the myocardial response after acute myocardial infarction (AMI). Both may be a target for therapeutic interventions. The kinetics of IL-33 and sST2 expression in infarcted myocardium and their correlation with the ongoing processes of fibrosis, inflammation and apoptosis remains poorly defined. Materials and methods Fifty Wistar rats underwent left anterior descending coronary artery surgical ligation and were sacrificed at 1, 2, 4, 12 or 24weeks post-AMI. A sham-operated group was also included. The mRNA cardiac expression levels of IL-33, sST2, fibrosis markers, inflammatory markers and apoptosis markers were assessed by RT-PCR. The protein expression of IL-33 was also measured by Western blotting. Results The mRNA levels of IL-33 and sST2 were upregulated in the infarcted myocardium during the first week after AMI. However, while IL-33 levels remained elevated during the first 12weeks post-AMI, sST2 levels showed a marked drop at 4weeks. IL-33 protein expression showed a similar kinetic than mRNA expression. The expression of sST2 positively correlated with cardiac gene expression of inflammatory and fibrosis markers. However, the IL-33 level did not correlate with these cardiac remodelling markers. No correlation of sST2 with apoptosis markers was observed. Conclusion After AMI, expression of sST2 is rapidly upregulated during the first 4weeks and, in contrast to IL-33, its levels correlated with the ongoing processes of fibrosis and inflammation. These findings suggest differential regulation of IL33 and sST2. Therapeutic modulation of early sST2 expression may be of greater importance to prevent adverse remodelling after AMI. C1 [Sanchez-Mas, Jesus; Lax, Antonio; del Carmen Asensio-Lopez, Maria; Caballero, Luis; Pascual-Figal, Domingo A.] Univ Hosp Virgen de la Arrixaca, Dept Cardiol, Murcia 30120, Spain. [Sanchez-Mas, Jesus; Lax, Antonio; del Carmen Asensio-Lopez, Maria; Pascual-Figal, Domingo A.] Univ Murcia, Dept Internal Med, Sch Med, Murcia, Spain. [Fernandez-Del Palacio, Maria J.; Santarelli, Giorgia] Univ Murcia, Vet Teaching Hosp, Dept Vet Med & Surg, Murcia, Spain. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Lax, A (reprint author), Univ Hosp Virgen de la Arrixaca, Dept Cardiol, Heart Failure Unit, Ctra Madrid Cartagena S-N, Murcia 30120, Spain. EM alax@um.es OI Pascual Figal, Domingo A./0000-0002-4993-9540 FU Fundacion Seneca, Murcia, Spain [11857/PI/09]; Ministerio de Sanidad, Madrid, Spain [PS09/02106]; national network of investigation in cardiovascular diseases [RD12/0042/0049] FX This study was supported in part by Grant 11857/PI/09 from Fundacion Seneca, Murcia, Spain; by Grant PS09/02106 from the Ministerio de Sanidad, Madrid, Spain; and by the national network of investigation in cardiovascular diseases RD12/0042/0049. We thank Sergio Abenza Camacho for their technical support. NR 24 TC 7 Z9 7 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 EI 1365-2362 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD JUL PY 2014 VL 44 IS 7 BP 643 EP 651 DI 10.1111/eci.12282 PG 9 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AJ9FB UT WOS:000338011900005 PM 24837094 ER PT J AU Paquin, AM Zimmerman, K Rudolph, JL AF Paquin, Allison M. Zimmerman, Kristin Rudolph, James L. TI Risk versus risk: a review of benzodiazepine reduction in older adults SO EXPERT OPINION ON DRUG SAFETY LA English DT Review DE aged; benzodiazepine; patient safety; polypharmacy ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; WITHDRAWAL SYMPTOM QUESTIONNAIRE; LONG-TERM USE; GENERAL-PRACTICE; DISCONTINUATION PROGRAM; PSYCHOMETRIC EVALUATION; CHRONIC INSOMNIA; ANXIOUS PATIENTS; TAPER AB Introduction: Benzodiazepines (BZD) are potentially inappropriate for older adults, yet their use persists. Patients and providers may hesitate to discontinue BZDs due to concerns for withdrawal or relapse. We reviewed the literature for BZD reduction protocols to examine common elements, safety and efficacy. A framework is proposed for clinicians to address BZD reduction challenges. Areas covered: Following a systematic literature review, this analysis included 28 studies of older out-patients tapering chronic BZDs. Populations included insomnia, depression and anxiety. Protocols included taper alone (32%), taper plus cognitive behavioral therapy (32%) and taper plus medication substitution (36%). Success rates were favorable for all modalities (mean 60%, median 67%, range 25 - 85%) and independent of dose or duration of use. Common schedules included a 25% dose reduction over 1 - 2 weeks until drug-free. Withdrawal symptoms included mainly mild psychological and somatic concerns. No serious safety events were reported. Expert opinion: BZD reduction protocols among older adults are feasible and successful. Given unique cognitive and functional abilities and comorbidities of older adults, a patient-centered approach to reduction is needed. Our framework guides clinicians in planning and persisting with BZD reduction, while our checklist addresses tailored tapers. Monitoring and support is emphasized, and taper modifications are proposed for struggling patients. C1 [Paquin, Allison M.] VABHS, Boston, MA 02130 USA. [Zimmerman, Kristin] Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. [Rudolph, James L.] VABHS, GRECC, Boston, MA USA. [Rudolph, James L.] VABHS, Sect Geriatr & Palliat Care, Boston, MA USA. [Rudolph, James L.] Harvard Univ, Sch Med, Boston, MA USA. RP Paquin, AM (reprint author), VABHS, Boston, MA 02130 USA. EM allison.paquin@va.gov FU Veterans Affairs (VA) Transformational grant; VA Rehabilitation Research Career Development Award FX AM Paquin has been supported by a Veterans Affairs (VA) Transformational grant to develop non-institutional alternatives to long-term care - the PILL Project. JL Rudolph is supported by a VA Rehabilitation Research Career Development Award and has been supported by a VA Transformational grant to develop non-institutional alternatives to long-term care - the PILL Project. 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. Doctors Paquin and Rudolph are the US Government employees. NR 53 TC 10 Z9 10 U1 1 U2 17 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1474-0338 EI 1744-764X J9 EXPERT OPIN DRUG SAF JI Expert Opin. Drug Saf. PD JUL PY 2014 VL 13 IS 7 BP 919 EP 934 DI 10.1517/14740338.2014.925444 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ7TS UT WOS:000337901100007 PM 24905348 ER PT J AU Clancy, CJ Nguyen, MH AF Clancy, Cornelius J. Minh Hong Nguyen TI Undiagnosed invasive candidiasis: incorporating non-culture diagnostics into rational prophylactic and preemptive antifungal strategies SO EXPERT REVIEW OF ANTI-INFECTIVE THERAPY LA English DT Editorial Material DE anti-mannan antibody; Candida; candidemia; candidiasis; deep-seated candidiasis; Fungitell; intra-abdominal candidiasis; mannan; beta-D-glucan ID PLACEBO-CONTROLLED TRIAL; ILL SURGICAL-PATIENTS; D-GLUCAN ASSAY; REAL-TIME PCR; CRITICALLY-ILL; INTRAABDOMINAL CANDIDIASIS; DOUBLE-BLIND; HIGH-RISK; FLUCONAZOLE PROPHYLAXIS; FUNGAL-INFECTIONS AB The insensitivity of blood cultures for diagnosing invasive candidiasis fuels prophylactic and preemptive antifungal treatment. Assays like serum beta-D-glucan or mannan/anti-mannan detection can identify blood culture-negative invasive candidiasis, but their roles in guiding antifungal therapy are undefined. We propose that non-culture tests can be incorporated into rational management strategies, based on clinical setting. As an example, beta-D-glucan sensitivity/specificity for blood culture-negative, deep-seated candidiasis is approximately 60/75%. In intensive care units with <1 or 3% invasive candidiasis rates, positive/negative predictive values are <2/>99% and 6/98%, respectively. With pre-test likelihoods of 10 and 33%, positive/negative predictive values are 20/94% and 54/79%, respectively. Based on these data, negative and positive beta-D-glucan results likely will be most useful for discontinuing prophylaxis among low-risk to moderate-risk patients (pre-test likelihoods similar to 3-10%), and triggering preemptive therapy among moderate-risk to high-risk patients (pre-test likelihoods similar to 10-25%), respectively. In extremely high-risk patients, universal prophylaxis is likely to be the best strategy. C1 [Clancy, Cornelius J.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Div Infect Dis, Pittsburgh, PA 15261 USA. [Clancy, Cornelius J.; Minh Hong Nguyen] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. RP Clancy, CJ (reprint author), Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Div Infect Dis, Scaife 867,3550 Terrace St, Pittsburgh, PA 15261 USA. EM cjc76@pitt.edu NR 23 TC 11 Z9 11 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-7210 EI 1744-8336 J9 EXPERT REV ANTI-INFE JI Expert Rev. Anti-Infect. Ther. PD JUL PY 2014 VL 12 IS 7 BP 731 EP 734 DI 10.1586/14787210.2014.919853 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ5VO UT WOS:000337758300003 PM 24850393 ER PT J AU Hasegawa, K Mansbach, JM Camargo, CA AF Hasegawa, Kohei Mansbach, Jonathan M. Camargo, Carlos A., Jr. TI Infectious pathogens and bronchiolitis outcomes SO EXPERT REVIEW OF ANTI-INFECTIVE THERAPY LA English DT Review DE acute respiratory infection; asthma; atopy; bronchiolitis; IgE; recurrent wheeze; respiratory syncytial virus; rhinovirus ID RESPIRATORY SYNCYTIAL VIRUS; HUMAN RHINOVIRUS C; HIGH-RISK CHILDREN; CHILDHOOD ASTHMA; YOUNG-CHILDREN; EARLY-LIFE; FOLLOW-UP; VIRAL-INFECTIONS; HOSPITALIZED INFANTS; RSV BRONCHIOLITIS AB Bronchiolitis is a common early childhood illness and an important cause of morbidity, it is the number one cause of hospitalization among US infants. Bronchiolitis is also an active area of research, and recent studies have advanced our understanding of this illness. Although it has long been the conventional wisdom that the infectious etiology of bronchiolitis does not affect outcomes, a growing number of studies have linked specific pathogens of bronchiolitis (e.g., rhinovirus) to short- and long-term outcomes, such as future risk of developing asthma. The authors review the advent of molecular diagnostic techniques that have demonstrated diverse pathogens in bronchiolitis, and they review recent studies on the complex link between infectious pathogens of bronchiolitis and the development of childhood asthma. C1 [Hasegawa, Kohei; Camargo, Carlos A., Jr.] Dept Emergency Med, Boston, MA 02111 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Rheumatol Allergy & Immunol, Boston, MA USA. [Mansbach, Jonathan M.] Harvard Univ, Sch Med, Dept Med, Boston Childrens Hosp, Boston, MA USA. RP Hasegawa, K (reprint author), Dept Emergency Med, Boston, MA 02111 USA. EM khasegawa1@partners.org FU National Institutes of Health (Bethesda, MD, USA) [U01 AI-67693] FX Camargo CA was supported by grant U01 AI-67693 from the National Institutes of Health (Bethesda, MD, USA). 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 141 TC 12 Z9 12 U1 1 U2 7 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-7210 EI 1744-8336 J9 EXPERT REV ANTI-INFE JI Expert Rev. Anti-Infect. Ther. PD JUL PY 2014 VL 12 IS 7 BP 817 EP 828 DI 10.1586/14787210.2014.906901 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ5VO UT WOS:000337758300012 PM 24702592 ER PT J AU Pfab, F Schalock, PC Napadow, V Athanasiadis, GI Huss-Marp, J Ring, J AF Pfab, Florian Schalock, Peter C. Napadow, Vitaly Athanasiadis, Georgios I. Huss-Marp, Johannes Ring, Johannes TI Acupuncture for allergic disease therapy - the current state of evidence SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Article DE acupuncture; allergic rhinitis; allergy; asthma; atopic dermatitis ID HISTAMINE-INDUCED ITCH; CONTROLLED CLINICAL-TRIAL; ALTERNATIVE MEDICINE CAM; I HYPERSENSITIVITY ITCH; ATOPIC-DERMATITIS; BRONCHIAL-ASTHMA; CROSSOVER TRIAL; COST-EFFECTIVENESS; LASER ACUPUNCTURE; RANDOMIZED-TRIAL AB This review summarizes current evidence for acupuncture treatment of allergies. Several randomized controlled trials have demonstrated a specific effect of acupuncture for allergic rhinitis; while a few studies have shown positive effects for atopic dermatitis, asthma and itch. Specifically for allergic rhinitis and asthma, acupuncture may be cost-effective in terms of money spent per quality-of-life gained. Acupuncture plays an increasingly important role as an evidence-based therapy for allergy relief and can be recommended as adjunct therapy for allergic rhinitis. Future randomized controlled trials need to further explore acupuncture efficacy for the treatment of itch, atopic dermatitis and asthma. More experimental research is also needed to investigate mechanisms of action underlying acupuncture for allergy relief. C1 [Pfab, Florian; Athanasiadis, Georgios I.] Tech Univ Munich, Dept Dermatol & Allergy, D-80290 Munich, Germany. [Pfab, Florian] Tech Univ Munich, Dept Prevent & Sports Med, D-80290 Munich, Germany. [Pfab, Florian; Napadow, Vitaly] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Schalock, Peter C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA USA. [Napadow, Vitaly] Logan Coll Chiropract, Dept Radiol, Chesterfield, MO USA. [Napadow, Vitaly] Kyung Hee Univ, Dept Biomed Engn, Yongin, South Korea. [Huss-Marp, Johannes] Univ Freiburg, Med Ctr, Dept Exercise Med & Sport, Freiburg, Germany. [Huss-Marp, Johannes] Phadia GmbH, Thermo Fisher Sci, Freiburg, Germany. [Ring, Johannes] Tech Univ Munich, Dept Dermatol & Allergy, CK CARE, Klinikum Rechts Isar, D-80290 Munich, Germany. RP Pfab, F (reprint author), Tech Univ Munich, Dept Dermatol & Allergy, D-80290 Munich, Germany. EM florian.pfab@lrz.tum.de OI Schalock, Peter/0000-0001-8953-4639 FU Christine Kuhne Foundation for Allergy; Ministry of Germany; NIH; CK-CARE FX This work has been supported by Christine Kuhne Foundation for Allergy. F Pfab has received grants from the Ministry of Germany. V Napadow has received multiple NIH grants. J Ring has received multiple grants from the Ministry of Germany and CK-CARE, where he is director of the research area 'Innovative Diagnostics and Therapy'. J Huss-Marp is an employee of Thermo-Fischer Company. 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 76 TC 5 Z9 5 U1 3 U2 18 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X EI 1744-8409 J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD JUL PY 2014 VL 10 IS 7 BP 831 EP 841 DI 10.1586/1744666X.2014.924855 PG 11 WC Immunology SC Immunology GA AJ8AE UT WOS:000337923500004 PM 24881629 ER PT J AU Mannello, F Ligi, D Canale, M Raffetto, JD AF Mannello, Ferdinando Ligi, Daniela Canale, Matteo Raffetto, Joseph D. TI Omics profiles in chronic venous ulcer wound fluid: innovative applications for translational medicine SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE biomarker; chronic venous disease; cytokine; genomic; inflammation; metabolomic; proteinase; proteomic; venous leg ulcer; wound fluid ID CHRONIC LEG ULCERS; ENDOTHELIAL GROWTH-FACTOR; VARICOSE-VEIN FORMATION; MATRIX-METALLOPROTEINASE ACTIVITY; ADHESION MOLECULES ICAM-1; COLLAGEN TYPE-I; EXTRACELLULAR-MATRIX; PRESSURE ULCERS; OXIDATIVE STRESS; TISSUE INHIBITOR AB Chronic venous disease represents a healthcare problem due to high prevalence and recurrence rates. Studies on chronic venous ulcer wound fluid (CVUWF) have demonstrated increased inflammation and proteolysis which can cause tissue destruction and delayed healing. This review discusses: nearly all known metabolites discovered in the past 25 years in CVUWF studies; the omics approaches characterizing the microenvironment of human venous leg ulcers; and the use of biocompounds as prognostic biomarkers and as possible targets for therapeutic approaches. A biomarker is a biological compound that can be functional or non-functional, specific or non-specific in the diagnosis/prognosis to a disease state and may be quantified to determine progression or regression of disease. Omics studies in CVUWF provide the impetus for future identification of biomarkers within the intricate network in chronic venous disease and set the basis for determining the appropriate combination of molecules that are expressed with the healing status of venous leg ulcers. C1 [Mannello, Ferdinando; Ligi, Daniela; Canale, Matteo] Univ Carlo Bo, Dept Biomol Sci, Sect Clin Biochem & Cell Biol, I-61029 Urbino, PU, Italy. [Raffetto, Joseph D.] VA Boston Healthcare Syst, Div Vasc Surg, West Roxbury, MA USA. [Raffetto, Joseph D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Mannello, F (reprint author), Univ Carlo Bo, Dept Biomol Sci, Sect Clin Biochem & Cell Biol, Via O Ubaldini 7, I-61029 Urbino, PU, Italy. EM ferdinando.mannello@uniurb.it NR 223 TC 8 Z9 11 U1 1 U2 21 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2014 VL 14 IS 6 BP 737 EP 762 DI 10.1586/14737159.2014.927312 PG 26 WC Pathology SC Pathology GA AJ8AW UT WOS:000337925600011 PM 24918119 ER PT J AU Sweigard, JH Yanai, R Gaissert, P Saint-Geniez, M Kataoka, K Thanos, A Stahl, GL Lambris, JD Connor, KM AF Sweigard, J. Harry Yanai, Ryoji Gaissert, Philipp Saint-Geniez, Magali Kataoka, Keiko Thanos, Aristomenis Stahl, Gregory L. Lambris, John D. Connor, Kip M. TI The alternative complement pathway regulates pathological angiogenesis in the retina SO FASEB JOURNAL LA English DT Article DE neovascularization; innate immune system; factor b; Cd55; oxygen-induced retinopathy ID ENDOTHELIAL GROWTH-FACTOR; DECAY-ACCELERATING FACTOR; CHOROIDAL NEOVASCULARIZATION; ISCHEMIC RETINOPATHY; FACTOR CD55; 2 PARTS; INHIBITION; EXPRESSION; MODEL; PROTEINS AB A defining feature in proliferative retinopathies is the formation of pathological neovessels. In these diseases, the balance between neovessel formation and regression determines blindness, making the modulation of neovessel growth highly desirable. The role of the immune system in these retinopathies is of increasing interest, but it is not completely understood. We investigated the role of the alternative complement pathway during the formation and resolution of aberrant neovascularization. We used alternative complement pathway-deficient (Fb(-/-)) mice and age- and strain-matched control mice to assess neovessel development and regression in an oxygen-induced retinopathy (OIR) mouse model. In the control mice, we found increased transcription of Fb after OIR treatment. In the Fb(-/-) mice, we prepared retinal flat-mounts and identified an increased number of neovessels, peaking at postnatal day 17 (P17; P = 0.001). Subjecting human umbilical vein endothelial cells (HUVECs) to low oxygen, mimicking a characteristic of neovessels, decreased the expression of the complement inhibitor Cd55. Finally, using laser capture microdissection (LCM) to isolate the neovessels after OIR, we found decreased expression of Cd55 (P = 0.005). Together, our data implicate the alternative complement pathway in facilitating neovessel clearance by down-regulating the complement inhibitor Cd55 specifically on neovessels, allowing for their targeted removal while leaving the established vasculature intact. C1 [Sweigard, J. Harry; Yanai, Ryoji; Gaissert, Philipp; Kataoka, Keiko; Thanos, Aristomenis; Connor, Kip M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Saint-Geniez, Magali] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Stahl, Gregory L.] Harvard Univ, Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Sch Med,Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02114 USA. [Lambris, John D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Connor, KM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM kip_connor@meei.harvard.edu RI Kataoka, Keiko/B-2806-2016; OI Kataoka, Keiko/0000-0002-8795-6536; Lambris, John/0000-0002-9370-5776; Connor, Kip/0000-0002-2048-9080 FU National Eye Institute of the U.S. National Institutes of Health (NIH) [R01EY022084-01/S1, EY020633-02, AI068730, T32EY007145, P30EY014104]; Howe Laboratory endowment of the Massachusetts Eye and Ear Infirmary; March of Dimes Foundation [5-FY09-535]; Research to Prevent Blindness; Massachusetts Lions Eye Research Fund, Inc.; Japan Eye Bank Association FX Research reported in this publication was supported by the National Eye Institute of the U.S. National Institutes of Health (NIH) under award numbers R01EY022084-01/S1 (K.M.C.), EY020633-02 and AI068730 (J.D.L.), T32EY007145 (J.H.S.), and P30EY014104. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was provided by the Howe Laboratory endowment of the Massachusetts Eye and Ear Infirmary; March of Dimes Foundation (5-FY09-535); a Research to Prevent Blindness unrestricted grant; Massachusetts Lions Eye Research Fund, Inc. (K.M.C.); and an award from the Japan Eye Bank Association (to R.Y.). NR 50 TC 9 Z9 10 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2014 VL 28 IS 7 BP 3171 EP 3182 DI 10.1096/fj.14-251041 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AJ8JN UT WOS:000337949400037 PM 24668752 ER PT J AU Bassett, IV Regan, S Luthuli, P Mbonambi, H Bearnot, B Pendleton, A Robine, M Mukuvisi, D Thulare, H Walensky, RP Freedberg, KA Losina, E Mhlongo, B AF Bassett, I. V. Regan, S. Luthuli, P. Mbonambi, H. Bearnot, B. Pendleton, A. Robine, M. Mukuvisi, D. Thulare, H. Walensky, R. P. Freedberg, K. A. Losina, E. Mhlongo, B. TI Linkage to care following community-based mobile HIV testing compared with clinic-based testing in Umlazi Township, Durban, South Africa SO HIV MEDICINE LA English DT Article DE HIV; AIDS; linkage to care; mobile HIV testing; South Africa ID SERVICES; PROGRAM AB Objectives The aim of the study was to assess HIV prevalence, disease stage and linkage to HIV care following diagnosis at a mobile HIV testing unit, compared with results for clinic-based testing, in a Durban township. Methods This was a prospective cohort study. We enrolled adults presenting for HIV testing at a community-based mobile testing unit (mobile testers) and at an HIV clinic (clinic testers) serving the same area. Testers diagnosed with HIV infection, regardless of testing site, were offered immediate CD4 testing and instructed to retrieve results at the clinic. We assessed rates of linkage to care, defined as CD4 result retrieval within 90 days of HIV diagnosis and/or completion of antiretroviral therapy (ART) literacy training, for mobile vs. clinic testers. Results From July to November 2011, 6957 subjects were HIV tested (4703 mobile and 2254 clinic); 55% were female. Mobile testers had a lower HIV prevalence than clinic testers (10% vs. 36%, respectively), were younger (median 23 vs. 27 years, respectively) and were more likely to live >5km or >30min from the clinic (64% vs. 40%, respectively; all P<0.001). Mobile testers were less likely to undergo CD4 testing (33% vs. 83%, respectively) but more likely to have higher CD4 counts [median (interquartile range) 416 (287-587) cells/L vs. 285 (136-482) cells/L, respectively] than clinic testers (both P<0.001). Of those who tested HIV positive, 10% of mobile testers linked to care, vs. 72% of clinic testers (P<0.001). Conclusions Mobile HIV testing reaches people who are younger, who are more geographically remote, and who have earlier disease compared with clinic-based testing. Fewer mobile testers underwent CD4 testing and linked to HIV care. Enhancing linkage efforts may improve the impact of mobile testing for those with early HIV disease. C1 [Bassett, I. V.; Regan, S.; Robine, M.; Walensky, R. P.; Freedberg, K. A.; Losina, E.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Bassett, I. V.; Walensky, R. P.; Freedberg, K. A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bassett, I. V.; Regan, S.; Robine, M.; Walensky, R. P.; Freedberg, K. A.; Losina, E.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Bassett, I. V.; Pendleton, A.; Walensky, R. P.; Freedberg, K. A.; Losina, E.] Harvard Univ, Sch Med, Boston, MA USA. [Bassett, I. V.; Walensky, R. P.; Freedberg, K. A.; Losina, E.] Harvard Univ, Harvard Ctr AIDS Res, Boston, MA 02115 USA. [Luthuli, P.; Mbonambi, H.; Mukuvisi, D.; Thulare, H.; Mhlongo, B.] AIDS Healthcare Fdn, Ithembalabantu Clin, Durban, South Africa. [Bearnot, B.] NYU, Sch Med, New York, NY USA. [Walensky, R. P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Freedberg, K. A.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA USA. [Freedberg, K. A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Losina, E.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, E.] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. RP Bassett, IV (reprint author), 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ibassett@partners.org FU AIDS Healthcare Foundation; National Institutes of Health [R01 MH090326, R01 AI058736, R01 MH073445]; Harvard Center for AIDS Research [P30 AI060354] FX Sources of funding: The work was supported by the AIDS Healthcare Foundation, the National Institutes of Health (R01 MH090326, R01 AI058736 and R01 MH073445) and the Harvard Center for AIDS Research (P30 AI060354). NR 20 TC 14 Z9 14 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD JUL PY 2014 VL 15 IS 6 BP 367 EP 372 DI 10.1111/hiv.12115 PG 6 WC Infectious Diseases SC Infectious Diseases GA AJ5PW UT WOS:000337738700007 PM 24251725 ER PT J AU de Bruin, M Simoni, J Amico, KR Parsons, JT Fisher, J Safren, SA AF de Bruin, M. Simoni, J. Amico, K. R. Parsons, J. T. Fisher, J. Safren, S. A. TI Poor citation, coding and reporting: a review of adherence-enhancing interventions for highly active antiretroviral therapy creates an inaccurate picture of the state of the field SO HIV MEDICINE LA English DT Letter ID RANDOMIZED-CONTROLLED-TRIALS; HIV-INFECTED PATIENTS; EFFICACY C1 [de Bruin, M.] Univ Aberdeen, Inst Appl Hlth Sci, Aberdeen AB25 2ZD, Scotland. [de Bruin, M.] Univ Amsterdam, Amsterdam Sch Commun Res, Amsterdam, Netherlands. [Simoni, J.] Univ Washington, Dept Psychol, Seatle, WA USA. [Amico, K. R.; Fisher, J.] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT USA. [Parsons, J. T.] CUNY Hunter Coll, Dept Psychol, New York, NY 10021 USA. [Safren, S. A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP de Bruin, M (reprint author), Univ Aberdeen, Inst Appl Hlth Sci, Hlth Sci Bldg,Foresterhill, Aberdeen AB25 2ZD, Scotland. EM m.debruin@abdn.ac.uk OI Simoni, Jane/0000-0002-8711-1576 FU NICHD NIH HHS [R21 HD074141]; NIMH NIH HHS [K24 MH093243] NR 8 TC 1 Z9 1 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD JUL PY 2014 VL 15 IS 6 BP 381 EP 382 DI 10.1111/hiv.12139 PG 2 WC Infectious Diseases SC Infectious Diseases GA AJ5PW UT WOS:000337738700009 PM 24916574 ER PT J AU Cipriani, NA Kurzawa, P Ahmad, RA Deshpande, V Hornicek, FJ Mullen, JT Nielsen, GP AF Cipriani, Nicole A. Kurzawa, Pawel Ahmad, Rima A. Deshpande, Vikram Hornicek, Francis J. Mullen, John T. Nielsen, G. Petur TI Prognostic value of myogenic differentiation in undifferentiated pleomorphic sarcomas of soft tissue SO HUMAN PATHOLOGY LA English DT Article DE Myogenic differentiation; Myoid differentiation; Undifferentiated pleomorphic sarcoma; UPS; Soft tissue sarcoma ID MALIGNANT FIBROUS HISTIOCYTOMA; EXTREMITY; REAPPRAISAL; RELEVANCE AB Patients with pleomorphic soft tissue sarcomas with myogenic differentiation (MD) are thought to have a worse prognosis than those without MD. In this study, we sought to determine the prognostic significance of MD in a restricted cohort of patients with high-grade undifferentiated pleomorphic sarcoma (UPS) of the extremities or trunk that were uniformly treated at a single institution. Thirty-eight patients met the inclusion criteria: (1) extremity or truncal soft tissue UPS, (2) histologic high grade, (3) size of 8 cm or more, (4) received protocol treatment. Immunohistochemical stains were performed on each tumor for 3 muscle markers: muscle-specific actin, smooth muscle actin, and desmin. A tumor was classified as having MD if it showed positive staining for at least 1 muscle marker. We correlated the line of differentiation with outcome using chi(2) and Kaplan-Meier analysis. MD was identified in 15 tumors and non-MD in 23 tumors. There were no significant differences between the myogenic and nonmyogenic groups in terms of age, sex, tumor size, tumor grade, or follow-up. The overall survival (OS) and disease-specific survival (DSS) were both 86.7% for patients with myogenic sarcomas. The OS and DSS were both 91.3% for those with nonmyogenic sarcomas. There was no significant difference between groups for OS or DSS in chi(2) testing (P = .649) or on Kaplan-Meier curve/log-rank testing (P = .541). In this homogenous group of patients with large, high-grade, extremity or truncal UPS who received neoadjuvant chemoradiotherapy, MD did not predict a worse survival than non-MD. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cipriani, Nicole A.; Deshpande, Vikram; Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cipriani, Nicole A.; Ahmad, Rima A.; Deshpande, Vikram; Hornicek, Francis J.; Mullen, John T.; Nielsen, G. Petur] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kurzawa, Pawel] Poznan Univ Med Sci, Dept Pathol, PL-61701 Poznan, Poland. [Ahmad, Rima A.; Mullen, John T.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Hornicek, Francis J.] Massachusetts Gen Hosp, Dept Orthoped Oncol, Boston, MA 02114 USA. RP Cipriani, NA (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM ncipriani@gmail.com NR 10 TC 3 Z9 3 U1 1 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 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD JUL PY 2014 VL 45 IS 7 BP 1504 EP 1508 DI 10.1016/j.humpath.2014.03.002 PG 5 WC Pathology SC Pathology GA AJ8UV UT WOS:000337984300024 PM 24780826 ER PT J AU Faje, AT Fazeli, PK Miller, KK Katzman, DK Ebrahimi, S Lee, H Mendes, N Snelgrove, D Meenaghan, E Misra, M Klibanski, A AF Faje, Alexander T. Fazeli, Pouneh K. Miller, Karen K. Katzman, Debra K. Ebrahimi, Seda Lee, Hang Mendes, Nara Snelgrove, Deirdre Meenaghan, Erinne Misra, Madhusmita Klibanski, Anne TI Fracture Risk and Areal Bone Mineral Density in Adolescent Females with Anorexia Nervosa SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE bone mineral density; anorexia nervosa; fracture risk ID DISTAL FOREARM FRACTURES; SECRETORY DYNAMICS; EATING-DISORDERS; GIRLS; CHILDREN; WOMEN; MICROARCHITECTURE; EPIDEMIOLOGY; OSTEOPOROSIS; METABOLISM AB Objective: To (i) compare fracture prevalence in adolescent females with anorexia nervosa (AN) versus normal-weight controls and (ii) examine whether reductions in areal bone mineral density (aBMD) predict fracture risk in females with AN. Method: Four-hundred eighteen females (310 with active AN and 108 normal-weight controls) 12- to 22-years-old were studied cross-sectionally. Lifetime fracture history was recorded by a physician during participant interviews. Body composition and aBMD measurements of the whole body, whole body less head, lumbar spine, and hip were assessed by dual-energy X-ray absorptiometry, and bone mineral apparent density (BMAD) was calculated for the lumbar spine. Results: Participants with AN and normal-weight controls did not differ for chronological age, sexual maturity, or height. The lifetime prevalence of prior fracture was 59.8% higher in those with AN as compared to controls (31.0% vs. 19.4%, p = 0.02), and the fracture incidence rate peaked in our cohort after the diagnosis of AN. Lower aBMD and lumbar BMAD were not associated with a higher prevalence of fracture in the AN or control group on univariate or multi-variate analyses. Compared to controls, fracture prevalence was significantly higher in the subgroup of girls with AN who had normal aBMD or only modest reductions of aBMD (Z-scores > -1 or -1.5). Discussion: This is the first study to show that the risk of fracture during childhood and adolescence is significantly higher in patients with AN than in normal-weight controls. Fracture prevalence is increased in this cohort of participants with AN even without significant reductions in aBMD. (C) 2014 Wiley Periodicals, Inc. C1 [Faje, Alexander T.; Fazeli, Pouneh K.; Miller, Karen K.; Mendes, Nara; Meenaghan, Erinne; Misra, Madhusmita; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Faje, Alexander T.; Fazeli, Pouneh K.; Miller, Karen K.; Mendes, Nara; Meenaghan, Erinne; Misra, Madhusmita; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA USA. [Katzman, Debra K.; Snelgrove, Deirdre] Hosp Sick Children, Dept Pediat, Div Adolescent Med, Toronto, ON M5G 1X8, Canada. [Katzman, Debra K.; Snelgrove, Deirdre] Univ Toronto, Toronto, ON, Canada. [Ebrahimi, Seda] Cambridge Eating Disorders Ctr, Cambridge, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org RI Mendes Estella, Nara/A-1469-2015 FU NIH [1 UL1 RR025758-01, 2 R01 DK062249-07, 1 R01 HD060827, 5R01 MH083657-04, 2R01 DK052625-11, 1 K24 HD071843] FX Supported by grant 1 UL1 RR025758-01, 2 R01 DK062249-07, 1 R01 HD060827, 5R01 MH083657-04, 2R01 DK052625-11, 1 K24 HD071843 from NIH. NR 35 TC 32 Z9 33 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD JUL PY 2014 VL 47 IS 5 BP 458 EP 466 DI 10.1002/eat.22248 PG 9 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AJ5CX UT WOS:000337700300003 PM 24430890 ER PT J AU Swanson, SA Aloisio, KM Horton, NJ Sonneville, KR Crosby, RD Eddy, KT Field, AE Micali, N AF Swanson, Sonja A. Aloisio, Kate M. Horton, Nicholas J. Sonneville, Kendrin R. Crosby, Ross D. Eddy, Kamryn T. Field, Alison E. Micali, Nadia TI Assessing Eating Disorder Symptoms in Adolescence: Is There a Role for Multiple Informants? SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE eating disorder; adolescence; multiple informants; ALSPAC ID COMORBIDITY-SURVEY-REPLICATION; WELL-BEING ASSESSMENT; SUPPLEMENT NCS-A; REGRESSION-ANALYSIS; ADVERSE OUTCOMES; PSYCHOPATHOLOGY; PREVALENCE; CHILD; PERSPECTIVES; ASSOCIATIONS AB Objectives: Studies of adolescent psychiatric disorders often collect information from adolescents and parents, yet most eating disorder epidemiologic studies only rely on adolescent report. Method: We studied the eating disorder symptom reports, from questionnaires sent at participants' ages 14 and 16 years, provided by 7,968 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC), and their parents. Adolescents and parents were asked questions about the adolescent's eating disorder symptoms (binge eating, vomiting, laxative use, fasting, and thinness). We assessed cross-sectional concordance and prevalence using kappa coefficients and generalized estimating equations. Generalized estimating equations were used to assess prospective associations between symptom reports and adolescent weight outcomes measured at a face-to-face assessment at 17.5 years. Results: Parents and adolescents were largely discordant on symptom reports cross-sectionally (kappas < 0.3), with the parent generally less likely to report bulimic symptoms than the adolescent but more likely to report thinness. Female adolescents were more likely to report bulimic symptoms than males (e. g., two to four times more likely to report binge eating), while prevalence estimates according to parent reports of female vs. male adolescents were similar. Both informants' symptom reports were predictive of body mass and composition measures at 17.5 years; compared to adolescent report, parentally reported binge eating was more strongly predictive of body mass index. Discussion: Parent report of eating disorder symptoms seemed to measure different, but potentially important, aspects of these symptoms during adolescence. Epidemiologic eating disorder studies should consider the potential value added from incorporating parental reports, particularly in studies of males. (C) 2014 Wiley Periodicals, Inc. C1 [Swanson, Sonja A.; Field, Alison E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Aloisio, Kate M.] Smith Coll, Dept Math, Northampton, MA 01063 USA. [Horton, Nicholas J.] Amherst Coll, Dept Math, Amherst, MA 01002 USA. [Sonneville, Kendrin R.; Field, Alison E.] Boston Childrens Hosp, Dept Med, Div Adolescent Med, Boston, MA USA. [Sonneville, Kendrin R.; Field, Alison E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Crosby, Ross D.] Univ N Dakota, Sch Med & Hlth Sci, Neuropsychiat Res Inst, Dept Clin Neurosci, Fargo, ND USA. [Eddy, Kamryn T.] Massachusetts Gen Hosp, Dept Psychiat, Harris Ctr Educ & Advocacy Eating Disorders, Boston, MA 02114 USA. [Eddy, Kamryn T.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Field, Alison E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Field, Alison E.] Harvard Univ, Sch Med, Boston, MA USA. [Micali, Nadia] UCL, Inst Child Hlth, Behav & Brain Sci Unit, London, England. RP Swanson, SA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,Kresge 9th Floor, Boston, MA 02115 USA. EM sswanson@hsph.harvard.edu RI Micali, nadia/E-6829-2010; OI Micali, nadia/0000-0001-5571-2273; Crosby, Ross/0000-0001-9131-1629; Horton, Nicholas/0000-0003-3332-4311 FU Wellcome Trust [092731]; National Institute of Health Research (NIHR) [DHCS/08/08/012]; NIH [MN087786-01] FX The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731), and the University of Bristol provide core support for ALSPAC. This specific study further received funding from the National Institute of Health Research (NIHR)-clinician scientist award to Dr. N Micali (DHCS/08/08/012) and the NIH (Grant ref: MN087786-01). NR 30 TC 8 Z9 8 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD JUL PY 2014 VL 47 IS 5 BP 475 EP 482 DI 10.1002/eat.22250 PG 8 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AJ5CX UT WOS:000337700300006 PM 24436213 ER PT J AU Huik, K Avi, R Uibopuu, H Pauskar, M Margus, T Karki, T Krispin, T Kool, P Ruutel, K Talu, A Abel-Ollo, K Uuskula, A Carrillo, A He, WJ Ahuja, SK Lutsar, I AF Huik, Kristi Avi, Radko Uibopuu, Helen Pauskar, Merit Margus, Tonu Karki, Tonis Krispin, Tonu Kool, Piret Rueuetel, Kristi Talu, Ave Abel-Ollo, Katri Uuskuela, Anneli Carrillo, Andrew He, Weijing Ahuja, Sunil K. Lutsar, Irja TI Association Between HIV-1 Tropism and CCR5 Human Haplotype E in a Caucasian Population SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CCR5; X4 tropic viruses; intravenous drug users ID HUMAN-IMMUNODEFICIENCY-VIRUS; TREATMENT-NAIVE PATIENTS; INJECTION-DRUG USERS; CELL-SURFACE CCR5; DISEASE PROGRESSION; PROMOTER POLYMORPHISM; TYPE-1 VARIANTS; INFECTION; EXPRESSION; DENSITY AB Background:The influence of the diversity of CCR5 on HIV susceptibility and disease progression has been clearly demonstrated but how the variability of this gene influences the HIV tropism is poorly understood. We investigated whether CCR5 haplotypes are associated with HIV tropism in a Caucasian population.Methods:We evaluated 161 HIV-positive subjects in a cross-sectional study. CCR5 haplotypes were derived after genotyping 9 CCR2-CCR5 polymorphisms. The HIV subtype was determined by phylogenetic analysis using the maximum likelihood method and viral tropism by the genotypic tropism assay (geno2pheno). Associations between CCR5 haplotypes and viral tropism were determined using logistic regression analyses. Samples from 500 blood donors were used to evaluate the representativeness of HIV-positives in terms of CCR5 haplotype distribution.Results:The distribution of CCR5 haplotypes was similar in HIV-positive subjects and blood donors. The majority of viruses (93.8%) belonged to HIV-1 CRF06_cpx; 7.5% were X4, and the remaining were R5 tropic. X4 tropic viruses were over represented among people with CCR5 human haplotype E (HHE) compared with those without this haplotype (13.0% vs 1.4%; P = 0.006). People possessing CCR5 HHE had 11 times increased odds (odds ratio = 11.00; 95% confidence interval: 1.38 to 87.38) of having X4 tropic viruses than those with non-HHE. After adjusting for antiretroviral (ARV) therapy, neither the presence of HHE nor the use of ARV was associated with X4 tropic viruses.Conclusions:Our results suggest that CCR5 HHE and ARV treatment might be associated with the presence of HIV-1 X4 tropic viruses. C1 [Huik, Kristi; Avi, Radko; Pauskar, Merit; Karki, Tonis; Krispin, Tonu; Lutsar, Irja] Univ Tartu, Fac Med, Dept Microbiol, EE-50411 Tartu, Estonia. [Uibopuu, Helen] West Tallinn Hosp Labs, Tallinn, Estonia. [Margus, Tonu] Univ Tartu, Inst Mol & Cell Biol, Dept Bioinformat, EE-50411 Tartu, Estonia. [Margus, Tonu] Estonian Bioctr, Tartu, Estonia. [Kool, Piret] Tartu Prison Hosp, Tartu, Estonia. [Rueuetel, Kristi; Abel-Ollo, Katri] Natl Inst Hlth Dev, Tallinn, Estonia. [Talu, Ave; Uuskuela, Anneli] Univ Tartu, Fac Med, Dept Publ Hlth, EE-50411 Tartu, Estonia. [Carrillo, Andrew; He, Weijing; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Carrillo, Andrew; He, Weijing; Ahuja, Sunil K.] South Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV Infect 1, San Antonio, TX USA. [Carrillo, Andrew; He, Weijing; Ahuja, Sunil K.] South Texas Vet Hlth Care Syst, Ctr Personalized Med, San Antonio, TX USA. RP Huik, K (reprint author), Univ Tartu, Dept Microbiol, Ravila 19, EE-50411 Tartu, Estonia. EM kristi.huik@ut.ee RI lutsar, irja/H-3177-2015; Uuskula, Anneli/H-3303-2015 FU European Union through European Regional Development Fund; Estonian Science Foundation [8415, 8856]; Basic Financing and the Target Financing of Estonian Ministry of Education and Research [SF0180004s12, SF0180026s09]; European Commission [2005305]; Global Fund to Fight HIV, Tuberculosis and Malaria Program "Scaling up the response to HIV in Estonia"; National HIV/AIDS Strategy; US Civilian Research Development Foundation [ESX0-2722-TA-06]; US National Institutes of Health, National Institute on Drug Abuse [R01DA03574]; Archimedes Foundation; Norwegian Financial Mechanism/EEA [EE0016]; Veterans Affairs (VA) Center for AIDS and HIV Infection; VA Center for Personalized Medicine of the South Texas Veterans Health Care System, a National Institutes of Health MERIT Grant [R37AI046326]; Doris Duke Distinguished Clinical Scientist Award; VA MERIT award; Elizabeth Glaser Pediatric AIDS Foundation; Burroughs Welcome Clinical Scientist Award in Translational Research; Max and Minnie Tomerlin Voelcker Fund FX Supported by European Union through the European Regional Development Fund, Estonian Science Foundation (Grants 8415 and 8856), Basic Financing and the Target Financing of Estonian Ministry of Education and Research (SF0180004s12 and SF0180026s09), European Commission funded project Expanding Network for Comprehensive and Coordinated Action on HIV/AIDS prevention among IDUs and Bridging Population Nr. 2005305 (ENCAP), Global Fund to Fight HIV, Tuberculosis and Malaria Program "Scaling up the response to HIV in Estonia" for 2003-2007, National HIV/AIDS Strategy for 2006-2015, US Civilian Research Development Foundation (Grant ESX0-2722-TA-06), US National Institutes of Health, National Institute on Drug Abuse (Grant R01DA03574), the Archimedes Foundation and Norwegian Financial Mechanism/EEA (Grant EE0016), the Veterans Affairs (VA) Center for AIDS and HIV Infection and VA Center for Personalized Medicine of the South Texas Veterans Health Care System, a National Institutes of Health MERIT Grant (R37AI046326), and the Doris Duke Distinguished Clinical Scientist Award to S.K.A. S.K.A. is also supported by a VA MERIT award, the Elizabeth Glaser Pediatric AIDS Foundation, the Burroughs Welcome Clinical Scientist Award in Translational Research, and the Senior Scholar Award from the Max and Minnie Tomerlin Voelcker Fund. NR 37 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 IS 3 BP 239 EP 244 DI 10.1097/QAI.0000000000000127 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AJ9JL UT WOS:000338025800005 PM 24508837 ER PT J AU Woody, GE Bruce, D Korthuis, PT Chhatre, S Poole, S Hillhouse, M Jacobs, P Sorensen, J Saxon, AJ Metzger, D Ling, W AF Woody, George E. Bruce, Douglas Korthuis, P. Todd Chhatre, Sumedha Poole, Sabrina Hillhouse, Maureen Jacobs, Petra Sorensen, James Saxon, Andrew J. Metzger, David Ling, Walter TI HIV Risk Reduction With Buprenorphine-Naloxone or Methadone: Findings From a Randomized Trial SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; risk reduction; buprenorphine; methadone ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUBSTANCE-ABUSE TREATMENT; INTRAVENOUS-DRUG-USERS; OUT-OF-TREATMENT; OPIOID DEPENDENCE; MAINTENANCE TREATMENT; PRIMARY-CARE; FOLLOW-UP; BEHAVIORS; PREVENTION AB Objectives:Compare HIV injecting and sex risk in patients being treated with methadone (MET) or buprenorphine-naloxone (BUP).Methods:Secondary analysis from a study of liver enzyme changes in patients randomized to MET or BUP who completed 24 weeks of treatment and had 4 or more blood draws. The initial 1:1 randomization was changed to 2:1 (BUP:MET) after 18 months due to higher dropout in BUP. The Risk Behavior Survey measured HIV risk before 30 days at baseline and weeks 12 and 24.Results:Among 529 patients randomized to MET, 391 (74%) were completers; among 740 randomized to BUP, 340 (46%) were completers; 700 completed the Risk Behavior Survey. There were significant reductions in injecting risk (P < 0.0008) with no differences between groups in mean number of times reported injecting heroin, speedball, other opiates, and number of injections; or percent who shared needles; did not clean shared needles with bleach; shared cookers; or engaged in front/back loading of syringes. The percent having multiple sex partners decreased equally in both groups (P < 0.03). For males on BUP, the sex risk composite increased; for males on MET, the sex risk decreased resulting in significant group differences over time (P < 0.03). For females, there was a significant reduction in sex risk (P < 0.02) with no group differences.Conclusions:Among MET and BUP patients who remained in treatment, HIV injecting risk was equally and markedly reduced; however, MET retained more patients. Sex risk was equally and significantly reduced among females in both treatment conditions, but it increased for males on BUP and decreased for males on MET. C1 [Woody, George E.; Chhatre, Sumedha; Poole, Sabrina; Metzger, David] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Woody, George E.; Chhatre, Sumedha; Poole, Sabrina; Metzger, David] Treatment Res Inst, Philadelphia, PA 19106 USA. [Bruce, Douglas] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Hillhouse, Maureen; Ling, Walter] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Jacobs, Petra] NIDA, Bethesda, MD 20892 USA. [Sorensen, James] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Dept Psychiat, Seattle, WA USA. RP Woody, GE (reprint author), Treatment Res Inst, 150 South Independence Mall W, Philadelphia, PA 19106 USA. EM woody@tresearch.org FU NIDA [U10-DA 13045, U10-DA013714, U10 DA-13043, KO5 DA-17009] FX Supported by NIDA grants: U10-DA 13045 (W.L.); U10-DA013714 (D.D.); U10 DA-13043, KO5 DA-17009 (G.W.). NR 46 TC 12 Z9 12 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 IS 3 BP 288 EP 293 DI 10.1097/QAI.0000000000000165 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AJ9JL UT WOS:000338025800011 PM 24751432 ER PT J AU Ouattara, EN Ross, EL Yazdanpanah, Y Wong, AY Robine, M Losina, E Moh, R Walensky, RP Danel, C Paltiel, AD Eholie, SP Freedberg, KA Anglaret, X AF Ouattara, Eric N. Ross, Eric L. Yazdanpanah, Yazdan Wong, Angela Y. Robine, Marion Losina, Elena Moh, Raoul Walensky, Rochelle P. Danel, Christine Paltiel, A. David Eholie, Serge P. Freedberg, Kenneth A. Anglaret, Xavier TI Clinical Impact and Cost-Effectiveness of Making Third-Line Antiretroviral Therapy Available in Sub-Saharan Africa: A Model-Based Analysis in Cote d'Ivoire SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE antiretroviral therapy; second-line ART failure; third-line ART; adherence reinforcement; HIV in sub-Saharan Africa ID RESOURCE-LIMITED SETTINGS; HIV-INFECTED ADULTS; DRUG-RESISTANCE; VIRAL LOAD; TRIAL; MORTALITY; OUTCOMES; INITIATION; STRATEGY; BENEFITS AB Objective:In sub-Saharan Africa, HIV-infected adults who fail second-line antiretroviral therapy (ART) often do not have access to third-line ART. We examined the clinical impact and cost-effectiveness of making third-line ART available in Cote d'Ivoire.Methods:We used a simulation model to compare 4 strategies after second-line ART failure: continue second-line ART (C-ART2), continue second-line ART with an adherence reinforcement intervention (AR-ART2), immediate switch to third-line ART (IS-ART3), and continue second-line ART with adherence reinforcement, switching patients with persistent failure to third-line ART (AR-ART3). Third-line ART consisted of a boosted-darunavir plus raltegravir-based regimen. Primary outcomes were 10-year survival and lifetime incremental cost-effectiveness ratios (ICERs), in $/year of life saved (YLS). ICERs below $3585 (3 times the country per capita gross domestic product) were considered cost-effective.Results:Ten-year survival was 6.0% with C-ART2, 17.0% with AR-ART2, 35.4% with IS-ART3, and 37.2% with AR-ART3. AR-ART2 was cost-effective ($1100/YLS). AR-ART3 had an ICER of $3600/YLS and became cost-effective if the cost of third-line ART decreased by <1%. IS-ART3 was less effective and more costly than AR-ART3. Results were robust to wide variations in the efficacy of third-line ART and of the adherence reinforcement, as well as in the cost of second-line ART.Conclusions:Access to third-line ART combined with an intense adherence reinforcement phase, used as a tool to distinguish between patients who can still benefit from their current second-line regimen and those who truly need third-line ART would provide substantial survival benefits. With minor decreases in drug costs, this strategy would be cost-effective. C1 [Ouattara, Eric N.; Danel, Christine; Anglaret, Xavier] Univ Bordeaux, Ctr Inserm 897, Bordeaux, France. [Ouattara, Eric N.; Danel, Christine; Anglaret, Xavier] Univ Bordeaux, ISPED, Bordeaux, France. [Ouattara, Eric N.; Moh, Raoul; Danel, Christine; Eholie, Serge P.; Anglaret, Xavier] CHU Treichville, Programme PACCI ANRS Res Site, Abidjan 18, Cote Ivoire. [Ross, Eric L.; Wong, Angela Y.; Robine, Marion; Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Ross, Eric L.; Wong, Angela Y.; Robine, Marion; Losina, Elena; Moh, Raoul; Walensky, Rochelle P.; Eholie, Serge P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Yazdanpanah, Yazdan] Bichat Claude Bernard Univ Hosp, Dept Infect & Trop Dis, Paris, France. [Yazdanpanah, Yazdan] Univ Paris Diderot, INSERM, U738, Equipe Atip Avenir, Paris, France. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped, Boston, MA 02115 USA. [Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Boston, MA USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Moh, Raoul; Eholie, Serge P.] Treichville Univ Hosp, Dept Infect & Trop Dis, Abidjan, Cote Ivoire. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Paltiel, A. David] Yale Univ, Sch Publ Hlth, Dept Epidemiol & Publ Hlth, New Haven, CT USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Ouattara, EN (reprint author), CHU Treichville, Programme PACCI, 18 BP 1954, Abidjan 18, Cote Ivoire. EM eric.ouattara@isped.u-bordeaux2.fr RI Anglaret, Xavier/F-7333-2013 FU Agence Nationale de Recherches sur le SIDA et les hepatites virales (ANRS, Paris, France), within the framework of the Thilao (Third-Line Antiretroviral Optimization) cohort study [ANRS 12269]; National Institute of Allergy and Infectious Diseases [R01 AI058736]; Doris Duke Charitable Foundation FX Supported by the Agence Nationale de Recherches sur le SIDA et les hepatites virales (ANRS, Paris, France), within the framework of the Thilao (Third-Line Antiretroviral Optimization) cohort study (grant: ANRS 12269); the National Institute of Allergy and Infectious Diseases (R01 AI058736); and the Doris Duke Charitable Foundation. NR 40 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 IS 3 BP 294 EP 302 DI 10.1097/QAI.0000000000000166 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AJ9JL UT WOS:000338025800012 PM 24732870 ER PT J AU Donnell, D Baeten, JM Bumpus, NN Brantley, J Bangsberg, DR Haberer, JE Mujugira, A Mugo, N Ndase, P Hendrix, C Celum, C AF Donnell, Deborah Baeten, Jared M. Bumpus, Namandje N. Brantley, Justin Bangsberg, David R. Haberer, Jessica E. Mujugira, Andrew Mugo, Nelly Ndase, Patrick Hendrix, Craig Celum, Connie TI HIV Protective Efficacy and Correlates of Tenofovir Blood Concentrations in a Clinical Trial of PrEP for HIV Prevention SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Africa; HIV prevention; pre-exposure prophylaxis; serodiscordant couples; adherence; drug concentrations ID ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS; DISOPROXIL FUMARATE; HEALTHY-VOLUNTEERS; COST-EFFECTIVENESS; AFRICAN WOMEN; PILL COUNTS; ADHERENCE; INFECTION; PHARMACOKINETICS; NONADHERENCE AB Background:Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence.Methods:In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected.Results:Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P < 0.001) for individuals receiving TDF and 91% (95% confidence interval: 47 to 98, P = 0.008) for individuals receiving FTC/TDF. Controls had consistent patterns of PrEP concentrations during follow-up; among the 81% with concentrations >40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations 40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner.Conclusions:Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence. C1 [Donnell, Deborah; Baeten, Jared M.; Brantley, Justin; Mujugira, Andrew; Mugo, Nelly; Ndase, Patrick; Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Seattle, WA 98019 USA. [Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Med, Seattle, WA USA. [Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bumpus, Namandje N.; Hendrix, Craig] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Baltimore, MD USA. [Bumpus, Namandje N.; Hendrix, Craig] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Bangsberg, David R.; Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.; Haberer, Jessica E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Mugo, Nelly] Univ Nairobi, Dept Obstet & Gynecol, Nairobi, Kenya. [Mugo, Nelly] Kenyatta Natl Hosp, Nairobi, Kenya. [Hendrix, Craig] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Donnell, D (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1100 Fairview Ave N, Seattle, WA 98019 USA. EM Deborah@fhcrc.org OI Donnell, Deborah/0000-0002-0587-7480 FU The Bill and Melinda Gates Foundation [47,674, OOPS52516] FX The Bill and Melinda Gates Foundation (grants 47,674 and OOPS52516) provided financial support for this study. NR 32 TC 56 Z9 56 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 IS 3 BP 340 EP 348 DI 10.1097/QAI.0000000000000172 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AJ9JL UT WOS:000338025800018 PM 24784763 ER PT J AU Evers, K de-Wit, L Van der Hallen, R Haesen, B Steyaert, J Noens, I Wagemans, J AF Evers, Kris de-Wit, Lee Van der Hallen, Ruth Haesen, Birgitt Steyaert, Jean Noens, Ilse Wagemans, Johan TI Brief Report: Reduced Grouping Interference in Children with ASD: Evidence from a Multiple Object Tracking Task SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Attention; Autism spectrum disorder (ASD); Global interference; Grouping; Multiple object tracking; Weak central coherence ID AUTISM SPECTRUM DISORDERS; PERCEPTUAL ORGANIZATION; VISUAL-PERCEPTION; SPATIAL PROXIMITY; WEAK COHERENCE; MOTION; ATTENTION; INDIVIDUALS; INTEGRATION; COLLINEARITY AB This study was inspired by the more locally oriented processing style in autism spectrum disorders (ASD). A modified multiple object tracking (MOT) task was administered to a group of children with and without ASD. Participants not only had to distinguish moving targets from distracters, but they also had to track targets when they were visually grouped to distracters, a manipulation which has a detrimental effect on tracking performance in adults. MOT performance in the ASD group was also affected by grouping, but this effect was significantly reduced. This result highlights how the reduced bias towards more global processing in ASD could influence further stages of cognition by altering the way in which attention selects information for further processing. C1 [Evers, Kris; de-Wit, Lee; Van der Hallen, Ruth; Haesen, Birgitt; Wagemans, Johan] Katholieke Univ Leuven, Expt Psychol Lab, B-3000 Leuven, Belgium. [Evers, Kris; Steyaert, Jean] UPC KU Leuven, Dept Child Psychiat, Leuven, Belgium. [Evers, Kris; Van der Hallen, Ruth; Haesen, Birgitt; Steyaert, Jean; Noens, Ilse; Wagemans, Johan] Katholieke Univ Leuven, Leuven Autism Res LAuRes, B-3000 Leuven, Belgium. [Steyaert, Jean] Univ Hosp Maastricht, Dept Clin Genet, Maastricht, Netherlands. [Noens, Ilse] Katholieke Univ Leuven, Parenting & Special Educ Res Unit, B-3000 Leuven, Belgium. [Noens, Ilse] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Evers, K (reprint author), Katholieke Univ Leuven, Expt Psychol Lab, Tiensestr 102,Box 3711, B-3000 Leuven, Belgium. EM kris.evers@psy.kuleuven.be RI Steyaert, Jean/B-5326-2015 OI Steyaert, Jean/0000-0003-2512-4694 NR 56 TC 2 Z9 2 U1 4 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JUL PY 2014 VL 44 IS 7 BP 1779 EP 1787 DI 10.1007/s10803-013-2031-4 PG 9 WC Psychology, Developmental SC Psychology GA AJ5TY UT WOS:000337752800026 PM 24398878 ER PT J AU Sledge, GW Mamounas, EP Hortobagyi, GN Burstein, HJ Goodwin, PJ Wolff, AC AF Sledge, George W. Mamounas, Eleftherios P. Hortobagyi, Gabriel N. Burstein, Harold J. Goodwin, Pamela J. Wolff, Antonio C. TI Past, Present, and Future Challenges in Breast Cancer Treatment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; PROJECT PROTOCOL B-27; CARCINOMA IN-SITU; STAR P-2 TRIAL; BOWEL PROJECT; FOLLOW-UP; RANDOMIZED-TRIALS; ESTROGEN-RECEPTOR; TUMOR RECURRENCE; COMBINATION CHEMOTHERAPY C1 [Sledge, George W.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Mamounas, Eleftherios P.] Univ Florida, Hlth Canc Ctr, Orlando, FL USA. [Hortobagyi, Gabriel N.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goodwin, Pamela J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Wolff, Antonio C.] Johns Hopkins Canc Ctr, Baltimore, MD USA. RP Sledge, GW (reprint author), Stanford Univ, Sch Med, Stanford, CA 94305 USA. OI Wolff, Antonio/0000-0003-3734-1063 FU Novartis; Genentech; AstraZeneca FX Gabriel N. Hortobagyi, Novartis; Antonio C. Wolff, Genentech, AstraZeneca NR 94 TC 26 Z9 26 U1 0 U2 13 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 2014 VL 32 IS 19 BP 1979 EP 1986 DI 10.1200/JCO.2014.55.4139 PG 8 WC Oncology SC Oncology GA AJ8AV UT WOS:000337925500002 PM 24888802 ER PT J AU Aizer, AA Falit, B Mendu, ML Chen, MH Choueiri, TK Hoffman, KE Hu, JC Martin, NE Trinh, QD Alexander, BM Nguyen, PL AF Aizer, Ayal A. Falit, Benjamin Mendu, Mallika L. Chen, Ming-Hui Choueiri, Toni K. Hoffman, Karen E. Hu, Jim C. Martin, Neil E. Quoc-Dien Trinh Alexander, Brian M. Nguyen, Paul L. TI Cancer-Specific Outcomes Among Young Adults Without Health Insurance SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CARE; DISPARITIES; STATES; WOMEN AB Purpose The Patient Protection and Affordable Care Act (ACA) will likely improve insurance coverage for most young adults, but subsets of young adults in the United States will face significant premium increases in the individual market. We examined the association between insurance status and cancer-specific outcomes among young adults. Methods We used the SEER program to identify 39,447 patients age 20 to 40 years diagnosed with a malignant neoplasm between 2007 and 2009. The association between insurance status and stage at presentation, employment of definitive therapy, and all-cause mortality was assessed using multivariable logistic or Cox regression, as appropriate. Results Patients who were uninsured were more likely to be younger, male, nonwhite, and unmarried than patients who were insured and were also more likely to be from regions of lower income, education, and population density ( P <.001 in all cases). After adjustment for pertinent confounding variables, an association between insurance coverage and decreased likelihood of presentation with metastatic disease (odds ratio [OR], 0.84; 95% CI, 0.75 to 0.94; P = .003), increased receipt of definitive treatment (OR, 1.95; 95% CI, 1.52 to 2.50; P = .001), and decreased death resulting from any cause (hazard ratio, 0.77; 95% CI, 0.65 to 0.91; P = .002) was noted. Conclusion The improved coverage fostered by the ACA may translate into better outcomes among most young adults with cancer. Extra consideration will need to be given to ensure that patients who will face premium increases in the individual market can obtain insurance coverage under the ACA. (C) 2014 by American Society of Clinical Oncology C1 [Aizer, Ayal A.; Falit, Benjamin] Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Mendu, Mallika L.; Quoc-Dien Trinh] Brigham & Womens Hosp, Boston, MA 02115 USA. [Choueiri, Toni K.; Martin, Neil E.; Alexander, Brian M.; Nguyen, Paul L.] Brigham & Womens Hosp, Dana Farber Canc Inst Boston, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Storrs, CT USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hu, Jim C.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Aizer, AA (reprint author), Harvard Radiat Oncol Program, 75 Francis St,Level L2-ASB 1, Boston, MA 02115 USA. EM aaaizer@partners.org RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Varian Medical Systems FX Paul L. Nguyen, Varian Medical Systems NR 24 TC 35 Z9 36 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2014 VL 32 IS 19 BP 2025 EP U62 DI 10.1200/JCO.2013.54.2555 PG 7 WC Oncology SC Oncology GA AJ8AV UT WOS:000337925500010 PM 24888800 ER PT J AU James, DF Werner, L Brown, JR Wierda, WG Barrientos, JC Castro, JE Greaves, A Johnson, AJ Rassenti, LZ Rai, KR Neuberg, D Kipps, TJ AF James, Danelle F. Werner, Lillian Brown, Jennifer R. Wierda, William G. Barrientos, Jacqueline C. Castro, Januario E. Greaves, Andrew Johnson, Amy J. Rassenti, Laura Z. Rai, Kanti R. Neuberg, Donna Kipps, Thomas J. TI Lenalidomide and Rituximab for the Initial Treatment of Patients With Chronic Lymphocytic Leukemia: A Multicenter Clinical-Translational Study From the Chronic Lymphocytic Leukemia Research Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; NATURAL-KILLER-CELL; MUTATION STATUS; PHASE-II; THERAPY; ANTIBODY; DISEASE; CANCER; GENE; CYCLOPHOSPHAMIDE AB Purpose Lenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatmentnaive patients. Patients and Methods Lenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis. Results Sixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort. Conclusion Intrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ. (C) 2014 by American Society of Clinical Oncology C1 [James, Danelle F.; Castro, Januario E.; Greaves, Andrew; Rassenti, Laura Z.; Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Werner, Lillian; Brown, Jennifer R.; Neuberg, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wierda, William G.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Barrientos, Jacqueline C.; Rai, Kanti R.] North Shore Long Isl Jewish Hlth Syst, New Hyde Pk, NY USA. [Johnson, Amy J.] Ohio State Univ, Columbus, OH 43210 USA. RP Kipps, TJ (reprint author), Univ Calif San Diego, Moores Canc Ctr, 3855 Hlth Sci Dr 0820, La Jolla, CA 92093 USA. EM tkipps@ucsd.edu OI Barrientos, Jacqueline/0000-0001-6018-5535 FU National Institutes of Health [PO1-CA081534, R21-CA135681, K23 CA115682]; American Society of Clinical Oncology Young Investigator Award; Lymphoma Research Foundation Postdoctoral fellowship; Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator Award FX Supported in part by Grants No. PO1-CA081534 and R21-CA135681 (T.J.K.) from the National Institutes of Health, an American Society of Clinical Oncology Young Investigator Award (D.F.J.), and a Lymphoma Research Foundation Postdoctoral fellowship (DFJ), as well as by Grant No. NIH K23 CA115682 (J.R.B.) and a Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator Award. J.R.B. was also a scholar of the American Society of Hematology and a scholar in clinical research Leukemia Lymphoma Society. NR 26 TC 32 Z9 32 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2014 VL 32 IS 19 BP 2067 EP U120 DI 10.1200/JCO.2013.51.5890 PG 11 WC Oncology SC Oncology GA AJ8AV UT WOS:000337925500015 PM 24868031 ER PT J AU Giordano, SH Temin, S Kirshner, JJ Chandarlapaty, S Crews, JR Davidson, NE Esteva, FJ Gonzalez-Angulo, AM Krop, I Levinson, J Lin, NU Modi, S Patt, DA Perez, EA Perlmutter, J Ramakrishna, N Winer, EP AF Giordano, Sharon H. Temin, Sarah Kirshner, Jeffrey J. Chandarlapaty, Sarat Crews, Jennie R. Davidson, Nancy E. Esteva, Francisco J. Gonzalez-Angulo, Ana M. Krop, Ian Levinson, Jennifer Lin, Nancy U. Modi, Shanu Patt, Debra A. Perez, Edith A. Perlmutter, Jane Ramakrishna, Naren Winer, Eric P. TI Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LAPATINIB PLUS CAPECITABINE; PHASE-II; TRASTUZUMAB; WOMEN; COMBINATION; SURVIVAL; TRIAL; PROGNOSIS; COMMUNICATION; PROGRESSION AB Purpose To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. Methods The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events. Results A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer. Recommendations HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone. (c) 2014 by American Society of Clinical Oncology C1 [Giordano, Sharon H.; Gonzalez-Angulo, Ana M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Patt, Debra A.] Texas Oncol, Austin, TX USA. [Temin, Sarah] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Kirshner, Jeffrey J.] Hematol Oncol Associates Cent New York, East Syracuse, NY USA. [Chandarlapaty, Sarat; Modi, Shanu] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Esteva, Francisco J.] NYU, Inst Canc, New York, NY USA. [Crews, Jennie R.] PeaceHealth St Joseph Canc Ctr, Bellingham, WA USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davidson, Nancy E.] Univ Pittsburgh, Med Ctr, Ctr Canc, Pittsburgh, PA USA. [Lin, Nancy U.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL USA. [Ramakrishna, Naren] Univ Florida, Orlando Hlth, Hlth Canc Ctr, Orlando, FL USA. RP Giordano, SH (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI Modi, Shanu/0000-0001-6427-7373; Esteva, Francisco/0000-0003-2437-3920 FU Puma; Genentech; GlaxoSmithKline; Array Biopharma; Novartis; Synta; Synta Pharmaceuticals FX Sarat Chandarlapaty, Puma; Ian Krop, Genentech, Roche; Nancy U. Lin, Genentech, GlaxoSmithKline, Array Biopharma, Novartis, Synta; Shanu Modi, Genentech, Novartis, Synta Pharmaceuticals; Edith A. Perez, Genentech, GlaxoSmithKline; Eric P. Winer, Genentech NR 52 TC 85 Z9 89 U1 1 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2014 VL 32 IS 19 BP 2078 EP U148 DI 10.1200/JCO.2013.54.0948 PG 23 WC Oncology SC Oncology GA AJ8AV UT WOS:000337925500017 PM 24799465 ER PT J AU Ramakrishna, N Temin, S Chandarlapaty, S Crews, JR Davidson, NE Esteva, FJ Giordano, SH Gonzalez-Angulo, AM Kirshner, JJ Krop, I Levinson, J Modi, S Patt, DA Perez, EA Perlmutter, J Winer, EP Lin, NU AF Ramakrishna, Naren Temin, Sarah Chandarlapaty, Sarat Crews, Jennie R. Davidson, Nancy E. Esteva, Francisco J. Giordano, Sharon H. Gonzalez-Angulo, Ana M. Kirshner, Jeffrey J. Krop, Ian Levinson, Jennifer Modi, Shanu Patt, Debra A. Perez, Edith A. Perlmutter, Jane Winer, Eric P. Lin, Nancy U. TI Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NERVOUS-SYSTEM METASTASES; LAPATINIB PLUS CAPECITABINE; STEREOTACTIC RADIOSURGERY; SURGICAL RESECTION; RADIATION-THERAPY; ADJUVANT TRASTUZUMAB; TUMOR SUBTYPE; PHASE-II; SURVIVAL; RADIOTHERAPY AB Purpose To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. Methods The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. Results No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process. Recommendations Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer. (c) 2014 by American Society of Clinical Oncology C1 [Ramakrishna, Naren] Univ Florida Hlth, Orlando Hlth, Ctr Canc, Orlando, FL USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL USA. [Temin, Sarah] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Chandarlapaty, Sarat; Modi, Shanu] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Esteva, Francisco J.] NYU, Inst Canc, New York, NY USA. [Kirshner, Jeffrey J.] Hematol Oncol Associates Cent New York, East Syracuse, NY USA. [Crews, Jennie R.] PeaceHealth St Joseph Canc Ctr, Bellingham, WA USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davidson, Nancy E.] Univ Pittsburgh, Med Ctr, Ctr Canc, Pittsburgh, PA USA. [Giordano, Sharon H.; Gonzalez-Angulo, Ana M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Patt, Debra A.] Texas Oncol, Austin, TX USA. [Krop, Ian; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ramakrishna, N (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI Modi, Shanu/0000-0001-6427-7373; Esteva, Francisco/0000-0003-2437-3920 FU Puma; Bristol-Myers Squibb; Genentech; GlaxoSmithKline; Novartis; Roche; Synta Pharmaceuticals; Array Biopharma; Geron FX Sarat Chandarlapaty, Puma; Ana M. Gonzalez-Angulo, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Novartis; Ian Krop, Genentech, Roche; Shanu Modi, Genentech, Novartis, Synta Pharmaceuticals; Edith A. Perez, Genentech, GlaxoSmithKline; Eric P. Winer, Genentech; Nancy U. Lin, Genentech, GlaxoSmithKline, Novartis, Array Biopharma, Geron NR 56 TC 38 Z9 41 U1 1 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2014 VL 32 IS 19 BP 2100 EP U158 DI 10.1200/JCO.2013.54.0955 PG 10 WC Oncology SC Oncology GA AJ8AV UT WOS:000337925500018 PM 24799487 ER PT J AU Luo, CM Ren, HX Wan, JB Yao, XL Zhang, XJ He, CW So, KF Kang, JX Pei, Z Su, HX AF Luo, Chuanming Ren, Huixia Wan, Jian-Bo Yao, Xiaoli Zhang, Xiaojing He, Chengwei So, Kwok-Fai Kang, Jing X. Pei, Zhong Su, Huanxing TI Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury SO JOURNAL OF LIPID RESEARCH LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; SPINAL-CORD-INJURY; NF-KAPPA-B; DOCOSAHEXAENOIC ACID; CEREBRAL-ISCHEMIA; CELL-DEATH; TRANSGENIC MICE; BRAIN-INJURY; EICOSAPENTAENOIC ACID; OMEGA-6/OMEGA-3 RATIO AB Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (omega-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for omega-3 fatty acid desaturase, which leads to an increase in endogenous omega-3 PUFAs and a concomitant decrease in omega-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous omega-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model. C1 [Luo, Chuanming; Ren, Huixia; Wan, Jian-Bo; Zhang, Xiaojing; He, Chengwei; Su, Huanxing] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Taipa, Peoples R China. [Yao, Xiaoli; Pei, Zhong] Sun Yat Sen Univ, Affiliated Hosp 1, Natl Key Clin Dept, Dept Neurol, Guangzhou 510080, Guangdong, Peoples R China. [Yao, Xiaoli; Pei, Zhong] Sun Yat Sen Univ, Affiliated Hosp 1, Key Discipline Neurol, Guangzhou 510080, Guangdong, Peoples R China. [So, Kwok-Fai] Jinan Univ, Guangdong Hong Kong Macau Inst CNS Regenerat, Guangzhou 510632, 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. RP Pei, Z (reprint author), Sun Yat Sen Univ, Affiliated Hosp 1, Natl Key Clin Dept, Dept Neurol, Guangzhou 510080, Guangdong, Peoples R China. EM peizhong@mail.sysu.edu.cn; huanxingsu@umac.mo OI Wan, Jian-Bo/0000-0002-6750-2617 FU Macao Science and Technology Development Fund [018/2013/A1]; multi-year research grant, University of Macau [MYRG122 (Y1-L3)-ICMS12-SHX, MYRG110 (Y1-L2)-ICMS13-SHX] FX This study was supported by Macao Science and Technology Development Fund (018/2013/A1), multi-year research grant, University of Macau, MYRG122 (Y1-L3)-ICMS12-SHX and MYRG110 (Y1-L2)-ICMS13-SHX, and the National Key Clinical Department, National Key Discipline, and Guangdong Key Laboratory for diagnosis and treatment of major neurological disease. NR 65 TC 10 Z9 10 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2014 VL 55 IS 7 BP 1288 EP 1297 DI 10.1194/jlr.M046466 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9GZ UT WOS:000338017400009 PM 24875538 ER PT J AU Thomas, LE Czuczman, AD Boulanger, AB Peak, DA Miller, ES Brown, DFM Marill, KA AF Thomas, Lisa E. Czuczman, Amanda D. Boulanger, Alyson B. Peak, David A. Miller, Emily S. Brown, David F. M. Marill, Keith A. TI Low risk for subsequent subarachnoid hemorrhage for emergency department patients with headache, bloody cerebrospinal fluid, and negative findings on cerebrovascular imaging SO JOURNAL OF NEUROSURGERY LA English DT Article DE subarachnoid hemorrhage; lumbar puncture; angiography; CT angiography; MR angiography; cerebrospinal fluid; headache; vascular disorders ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; DIGITAL-SUBTRACTION-ANGIOGRAPHY; MAGNETIC-RESONANCE ANGIOGRAPHY; INTRACRANIAL ANEURYSMS; CT ANGIOGRAPHY; CEREBRAL ANEURYSMS; LUMBAR PUNCTURE; MANAGEMENT; DIAGNOSIS; ACCURACY AB Object. When patients present to the emergency department (ED) with acute headache concerning for subarachnoid hemorrhage (SAH) and a lumbar puncture (LP) shows blood in the CSF, it is difficult to distinguish the results of a traumatic LP from those of SAH. CT angiography (CTA) is often performed, but the long-term outcome for patients with a positive LP and normal neurovascular imaging remains uncertain. The primary objective of this study was to determine whether patients who presented to the ED with acute headache and had red blood cells (RBCs) in their CSF on LP but negative cerebrovascular imaging suffered subsequent SAH. Methods. A case series study of consecutive adult ED patients who incurred charges for LP between 2001 and 2009 was performed from 2010 through 2011. Inclusion criteria were: headache, > 5 RBCs/mm(3) in CSF, noncontrast head CT with no evidence of hemorrhage, and cerebrovascular CTA or MRA without aneurysm or vascular lesion within 2 weeks of the ED visit. Patients with less than 6 months of available follow-up were excluded. The primary outcomes were 1) subsequent nontraumatic SAH and 2) new vascular lesion. Secondary outcomes were complications related to SAH, or LP or angiography. Results. Of 4641 ED patients billed for an LP, 181 patients (mean age 42 years) were included in this study. Over a median follow-up of 53 months, 0 (0%) of 181 patients (95% CI 0%-2.0%) had a subsequent SAH or new vascular lesion identified. Although not the primary outcome, there was 1 patient who was ultimately diagnosed with vasculitis. Eighteen (9.9%) of 181 patients (95% CI 6.0%-15.3%) had an LP-related complication and 0 (0%) of 181 patients (95% CI 0%-2.0%) had an angiography-related complication. Conclusions. Patients who present to the ED with acute headache concerning for SAH and have a finding of bloody CSF on LP but negative findings on cerebrovascular imaging are at low risk for subsequent SAH and thus are likely to be safe for discharge. Replacement of the CT/LP with a CT/CTA diagnostic algorithm merits further investigation. C1 [Thomas, Lisa E.] UM UCMC, Dept Emergency Med, Bel Air, MD 21014 USA. [Thomas, Lisa E.; Czuczman, Amanda D.; Boulanger, Alyson B.; Peak, David A.; Miller, Emily S.; Brown, David F. M.; Marill, Keith A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Czuczman, Amanda D.] North Suburban Med Ctr, Dept Emergency Med, Thornton, CO USA. RP Thomas, LE (reprint author), UM UCMC, Dept Emergency Med, 500 Upper Chesapeake Dr, Bel Air, MD 21014 USA. EM lisaethomas@gmail.com FU National Heart, Lung, and Blood Institute [5K12HL109068] FX The project described was supported by Award Number 5K12HL109068 from the National Heart, Lung, and Blood Institute (K.A.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. NR 34 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2014 VL 121 IS 1 BP 24 EP 31 DI 10.3171/2014.3.JNS132239 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AJ8EK UT WOS:000337935300006 PM 24745707 ER PT J AU Gentil, AF Lopes, AC Dougherty, DD Rucx, C Mataix-Cols, D Lukacs, TL Canteras, MM Eskandar, EN Larsson, KJ Hoexter, MQ Batistuzzo, MC Greenberg, BD Miguel, EC AF Gentil, Andre F. Lopes, Antonio C. Dougherty, Darin D. Rucx, Christian Mataix-Cols, David Lukacs, Teagan L. Canteras, Miguel M. Eskandar, Emad N. Larsson, K. Johan Hoexter, Marcelo Q. Batistuzzo, Marcelo C. Greenberg, Benjamin D. Miguel, Euripedes C. TI Hoarding symptoms and prediction of poor response to limbic system surgery for treatment-refractory obsessive-compulsive disorder SO JOURNAL OF NEUROSURGERY LA English DT Article DE obsessive-compulsive disorder; radiosurgery; capsulotomy; anterior cingulotomy; hoarding; functional neurosurgery ID DEEP BRAIN-STIMULATION; TERM-FOLLOW-UP; SEROTONIN REUPTAKE INHIBITORS; NUCLEUS-ACCUMBENS; DIMENSIONS; CAPSULOTOMY; CINGULOTOMY; CHECKING; OUTCOMES; THERAPY AB Object. Recent findings have suggested a correlation between obsessive-compulsive disorder (OCD) symptom dimensions and clinical outcome after limbic system surgery for treatment-refractory patients. Based on previous evidence that the hoarding dimension is associated with worse outcome in conventional treatments, and may have a neural substrate distinct from OCD, the authors examined a large sample of patients undergoing limbic surgery (40 with capsulotomy, 37 with cingulotomy) and investigated if symptom dimensions, in particular hoarding, could influence treatment outcome. Methods. Data from 77 patients from 3 different research centers at Sao Paulo (n = 17), Boston (n = 37), and Stockholm (n = 23) were analyzed. Dimensional Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Sao Paulo) or Y-BOCS Symptom Checklist scores (Boston and Stockholm) were used to code the presence of 4 well-established symptom dimensions: forbidden thoughts, contamination/cleaning, symmetry/order, and hoarding. Reductions in Y-BOCS scores determined clinical outcome. Results. Mean Y-BOCS scores decreased 34.2% after surgery (95% CI 27.2%-41.3%), with a mean follow-up of 68.1 months. Patients with hoarding symptoms had a worse response to treatment (mean Y-BOCS decrease of 22.7% +/- 25.9% vs 41.6% +/- 32.2%, respectively; p = 0.006), with no significant effect of surgical modality (capsulotomy vs cingulotomy). Patients with forbidden thoughts apparently also had a worse response to treatment, but this effect was dependent upon the co-occurrence of the hoarding dimension. Only the negative influence of the hoarding dimension remained when an ANOVA model was performed, which also controlled for preoperative symptom severity. Conclusions. The presence of hoarding symptoms prior to surgery was associated with worse clinical outcome after the interventions. Patients with OCD under consideration for ablative surgery should be carefully screened for hoarding symptoms or comorbid hoarding disorder. For these patients, the potentially reduced benefits of surgery need to be carefully considered against potential risks. C1 [Gentil, Andre F.; Lopes, Antonio C.; Hoexter, Marcelo Q.; Batistuzzo, Marcelo C.; Miguel, Euripedes C.] Univ Sao Paulo, Sch Med, Hosp Clin, Dept & Inst Psychiat, Sao Paulo, Brazil. [Dougherty, Darin D.; Lukacs, Teagan L.; Eskandar, Emad N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Rucx, Christian; Larsson, K. Johan] Karolinska Inst, Dept Clin Neurosci, Div Psychiat, Stockholm, Sweden. [Mataix-Cols, David] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Canteras, Miguel M.] Hosp Santa Paula, Inst Neurol Radiosurg, Sao Paulo, Brazil. [Greenberg, Benjamin D.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Div Neurosurg, Providence, RI 02906 USA. RP Gentil, AF (reprint author), Inst Psiquiatria, R Dr Ovidio Pires Campos 785, BR-01060970 Sao Paulo, Brazil. EM afgentil@usp.br RI Hoexter, Marcelo/D-7620-2013; Batistuzzo, Marcelo/H-7790-2015; OI Hoexter, Marcelo/0000-0002-9302-4380; Ruck, Christian/0000-0002-8742-0168 NR 55 TC 2 Z9 2 U1 1 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD JUL PY 2014 VL 121 IS 1 BP 123 EP 130 DI 10.3171/2014.2.JNS131423 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AJ8EK UT WOS:000337935300017 PM 24702323 ER PT J AU Afeiche, MC Gaskins, AJ Williams, PL Toth, TL Wright, DL Tanrikut, C Hauser, R Chavarro, JE AF Afeiche, Myriam C. Gaskins, Audrey J. Williams, Paige L. Toth, Thomas L. Wright, Diane L. Tanrikut, Cigdem Hauser, Russ Chavarro, Jorge E. TI Processed Meat Intake Is Unfavorably and Fish Intake Favorably Associated with Semen Quality Indicators among Men Attending a Fertility Clinic SO JOURNAL OF NUTRITION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; RABBIT SPERMATOZOA MOTILITY; ALPHA-LINOLENIC SERIES; YOUNG DANISH MEN; N-3 FATTY-ACIDS; LIPID-COMPOSITION; DIETARY PATTERNS; TESTICULAR CELLS; SEMINAL PLASMA; RAT TESTICLES AB Emerging literature suggests that men's diets may affect spermatogenesis as reflected in semen quality indicators, but literature on the relation between meat intake and semen quality is limited. Our objective was to prospectively examine the relation between meat intake and indicators of semen quality. Men in subfertile couples presenting for evaluation at the Massachusetts General Hospital Fertility Center were invited to participate in an ongoing study of environmental factors and fertility. A total of 155 men completed a validated food-frequency questionnaire and subsequently provided 338 semen samples over an 18-mo period from 2007-2012. We used linear mixed regression models to examine the relation between meat intake and semen quality indicators (total sperm count, sperm concentration, progressive motility, morphology, and semen volume) while adjusting for potential confounders and accounting for within-person variability across repeat semen samples. Among the 155 men (median age: 36.1 y; 83% white, non-Hispanic), processed meat intake was inversely related to sperm morphology. Men in the highest quartile of processed meat intake had, on average, 1.7 percentage units (95% CI: -3.3, -0.04) fewer morphologically normal sperm than men in the lowest quartile of intake (P-trend = 0.02). Fish intake was related to higher sperm count and percentage of morphologically normal sperm. The adjusted mean total sperm count increased from 102 million (95% Cl: 80, 131) in the lowest quartile to 168 million (95% CI: 136, 207) sperm in the highest quartile of fish intake (P-trend = 0.005). Similarly, the adjusted mean percentages of morphologically normal sperm for men in increasing quartiles of fish intake were 5.9 (95% CI: 5.0, 6.8), 5.3 (95% CI: 4.4, 6.3), 6.3 (95% CI: 5,2, 7.4), and 7.5 (95% CI: 6.5, 8.5) (P-trend = 0.01). Consuming fish may have a positive impact on sperm counts and morphology, particularly when consumed instead of processed red meats. C1 [Afeiche, Myriam C.; Gaskins, Audrey J.; Chavarro, Jorge E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gaskins, Audrey J.; Hauser, Russ; Chavarro, Jorge E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Toth, Thomas L.; Wright, Diane L.; Hauser, Russ] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tanrikut, Cigdem] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Chavarro, Jorge E.] Harvard Univ, Sch Med, Boston, MA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Chavarro, Jorge E.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Afeiche, MC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM mafeiche@hsph.harvard.edu FU NIH [R01ES009718, P30ES000002, P30DK46200, T32DK007703] FX Supported by NIH grants R01ES009718, P30ES000002, P30DK46200, and T32DK007703. NR 47 TC 9 Z9 10 U1 0 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2014 VL 144 IS 7 BP 1091 EP 1098 DI 10.3946/jn.113.190173 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ8UU UT WOS:000337984200014 PM 24850626 ER PT J AU Kleweno, C Morgan, J Redshaw, J Harris, M Rodriguez, E Zurakowski, D Vrahas, M Appleton, P AF Kleweno, Conor Morgan, Jordan Redshaw, James Harris, Mitchel Rodriguez, Edward Zurakowski, David Vrahas, Mark Appleton, Paul TI Short Versus Long Cephalomedullary Nails for the Treatment of Intertrochanteric Hip Fractures in Patients Older than 65 Years SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE fracture; intertrochanteric; fixation; failure; hip ID GAMMA-NAIL; PERITROCHANTERIC FRACTURES; SURGICAL-MANAGEMENT; ELDERLY-PATIENTS; RISK-FACTORS; FIXATION; SCREW; FEMUR AB Objectives:To compare failure rates between short and long cephalomedullary nails used for the treatment of intertrochanteric hip fractures in patients over 65 years of age.Design:Retrospective cohort study. Data were collected from medical records and radiographs.Setting:Three level 1 trauma centers.Patients/Participants:Patients aged 65 years or older who underwent treatment of an intertrochanteric hip fracture with a cephalomedullary nail between January 2004 and December 2010.Intervention:Open reduction and internal fixation of intertrochanteric hip fracture with either short or long cephalomedullary nail.Main Outcome Measurement:Postoperative treatment failure rate, defined as periprosthetic fracture or reoperation requiring removal or revision of nail, including conversion to arthroplasty.Results:Incidence of treatment failure (periprosthetic fracture and reoperation requiring removal of nail) was 30 of 559 (5.4%) for the entire cohort; 13 of 219 (5.9%) occurred after placement of a short nail compared with 17 of 340 (5.0%) after placement of a long nail (P = 0.70). There were 11 of 559 (2.0%) patients who sustained a periprosthetic fracture after nailing, 6 of 219 (2.7%) after short nails and 5 of 340 (1.5%) after long nails (P = 0.35). The remaining 19 treatment failures were major reoperations requiring removal of nail, 7 of 219 (3.2%) after short nails and 12 of 340 (3.5%) after long nails (P = 0.81). The reasons for these 19 revision procedures were: screw/helical blade cutout (16), progressive arthritis with conversion to arthroplasty (1), avascular necrosis of femoral head with conversion to arthroplasty (1), and symptomatic leg length discrepancy with conversion to arthroplasty (1). Median follow-up period for patients living at least 1 year postoperatively was 30 months (range, 12-85 months). Overall, 175 of 698 (25%) patients died within 1 year after index surgery.Conclusions:When using contemporary cephalomedullary implants, short and long nails exhibit similar treatment failure rates. C1 [Kleweno, Conor; Morgan, Jordan; Vrahas, Mark] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Redshaw, James; Rodriguez, Edward; Appleton, Paul] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Orthopaed Surg, Boston, MA 02114 USA. [Harris, Mitchel] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Zurakowski, David] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Zurakowski, David] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Surg, Boston, MA 02114 USA. RP Kleweno, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg,Yawkey Ctr, 55 Fruit St,Suite 3C, Boston, MA 02114 USA. EM conorkleweno@gmail.com NR 21 TC 13 Z9 16 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD JUL PY 2014 VL 28 IS 7 BP 391 EP 397 DI 10.1097/BOT.0000000000000036 PG 7 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA AJ5QC UT WOS:000337739400010 PM 24231580 ER PT J AU Bromley, B Spitz, J Fuchs, K Thornburg, LL AF Bromley, Bryann Spitz, Jean Fuchs, Karin Thornburg, Loralei L. TI Do Clinical Practitioners Seeking Credentialing for Nuchal Translucency Measurement Demonstrate Compliance With Biosafety Recommendations? Experience of the Nuchal Translucency Quality Review Program SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE ALARA; biosafety; fetal sonography; nuchal translucency; Nuchal Translucency Quality Review Program; thermal index; ultrasound education ID DIAGNOSTIC ULTRASOUND; SAFETY; PREGNANCY; DOPPLER; 1ST-TRIMESTER; OUTPUT; SCAN AB Objectives-The purpose of this study was to evaluate compliance with the ALARA (as low as reasonably achievable) principle by practitioners seeking credentialing for nuchal translucency (NT) measurement between 11 and 14 weeks' gestation. Methods-Nuchal Translucency Quality Review Program credentialing requires quailtitative scoring of S NT measurements from 5 different fetuses. Images submitted by 100 consecutive practitioners were retrospectively evaluated for the output display standard (ODS). The thermal index (TI) type (bone [TIb] or soft tissue [TIs]) and numeric value of the index were recorded. The TIb was considered the correct index for this study. Compliance with the numeric value was evaluated in several ways. Collectively, a TIb lower than 0.5 was considered optimal, lower than 0.7 compliant, and 1.0 or lower satisfactory. Results-An ODS was present in at least 1 image submitted by 77 practitioners. The TIb was used exclusively by 15 ( 19.5%), the TIs by 37 (48.1%), and 25 used a combination of the TIb and TIs. Only 4 of 77 providers (5%) used the correct TI type (TIE) at lower than 0.5 for all submitted images, 5 of 77 (6%) at lower than 0.7, and 9 of 77 (12%) at 1.0 or lower. A TI (TIE or TIs) higher than 1.0 was used by 15 of 77 providers (19.5%). Proficiency in NT measurement and educational background (physician or sonographer) did not influence compliance with ALARA. Conclusions-Clinicians seeking credentialing in NT do not demonstrate compliance with the recommended use of the TIb in monitoring acoustic output. C1 [Bromley, Bryann] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Bromley, Bryann] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryann] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Spitz, Jean] Perinatal Qual Fdn, Nuchal Translucency Qual Review Program, Oklahoma City, OK USA. [Fuchs, Karin] Columbia Univ, Div Maternal Fetal Med, Med Ctr, New York, NY USA. [Thornburg, Loralei L.] Univ Rochester, Div Maternal Fetal Med, Rochester, NY USA. RP Bromley, B (reprint author), Diagnost Ultrasound, 1 Brookline Pl, Brookline, MA 02445 USA. EM bbsono@aol.com NR 30 TC 0 Z9 0 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUL PY 2014 VL 33 IS 7 BP 1209 EP 1214 DI 10.7863/ultra.33.7.1209 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AJ9CB UT WOS:000338003300011 PM 24958407 ER PT J AU Capistrant, BD Mejia, NI Liu, SY Wang, QY Glymour, MM AF Capistrant, Benjamin D. Mejia, Nicte I. Liu, Sze Y. Wang, Qianyi Glymour, M. Maria TI The Disability Burden Associated With Stroke Emerges Before Stroke Onset and Differentially Affects Blacks: Results From the Health and Retirement Study Cohort SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Minority aging; Disablement process; Stroke; Cardiovascular; Epidemiology ID INSTRUMENTAL ACTIVITIES; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; FUNCTIONAL STATUS; RISK-FACTORS; MORTALITY; PREDICTORS; FRAILTY; INFLAMMATION; POPULATION AB Few longitudinal studies compare changes in instrumental activities of daily living (IADLs) among stroke-free adults to prospectively document IADL changes among adults who experience stroke. We contrast annual declines in IADL independence for older individuals who remain stroke free to those for individuals who experienced stroke. We also assess whether these patterns differ by sex, race, or Southern birthplace. Health and Retirement Study participants who were stroke free in 1998 (n = 17,741) were followed through 2010 (average follow-up = 8.9 years) for self- or proxy-reported stroke. We used logistic regressions to compare annual changes in odds of self-reported independence in six IADLs among those who remained stroke free throughout follow-up (n = 15,888), those who survived a stroke (n = 1,412), and those who had a stroke and did not survive to participate in another interview (n = 442). We present models adjusted for demographic and socioeconomic covariates and also stratified on sex, race, and Southern birthplace. Compared with similar cohort members who remained stroke free, participants who developed stroke had faster declines in IADL independence and lower probability of IADL independence prior to stroke. After stroke, independence declined at an annual rate similar to those who did not have stroke. The black-white disparity in IADL independence narrowed poststroke. Racial differences in IADL independence are apparent long before stroke onset. Poststroke differences in IADL independence largely reflect prestroke disparities. C1 [Capistrant, Benjamin D.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Mejia, Nicte I.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mejia, Nicte I.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Liu, Sze Y.; Glymour, M. Maria] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Liu, Sze Y.] Harvard Univ, Harvard Ctr Populat & Dev Studies, Cambridge, MA 02138 USA. [Wang, Qianyi] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Glymour, M. Maria] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Capistrant, BD (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, 1300 S Second St,Suite 300, Minneapolis, MN 55454 USA. EM bcapistr@umn.edu OI Glymour, M. Maria/0000-0001-9644-3081 FU National Institutes of Health [R21 AG034385, T32 HD007168, R24 HD050924]; American Heart Association [10SDG2640243]; National Institute on Aging [NIA U01AG009740] FX This work was supported by the National Institutes of Health (R21 AG034385, T32 HD007168, R24 HD050924) and American Heart Association (10SDG2640243). The U.S. Health and Retirement Study (HRS), conducted by the University of Michigan, is sponsored by the National Institute on Aging (NIA U01AG009740). NR 40 TC 2 Z9 2 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2014 VL 69 IS 7 BP 860 EP 870 DI 10.1093/gerona/glt191 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AJ9DG UT WOS:000338006400010 PM 24444610 ER PT J AU Kaup, AR Simonsick, EM Harris, TB Satterfield, S Metti, AL Ayonayon, HN Rubin, SM Yaffe, K AF Kaup, Allison R. Simonsick, Eleanor M. Harris, Tamara B. Satterfield, Suzanne Metti, Andrea L. Ayonayon, Hilsa N. Rubin, Susan M. Yaffe, Kristine TI Older Adults With Limited Literacy Are at Increased Risk for Likely Dementia SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Cognitive aging; Risk factors; Epidemiology ID ETHNICALLY DIVERSE ELDERS; POPULATION-BASED COHORT; HEALTH LITERACY; COGNITIVE DECLINE; BODY-COMPOSITION; READING-ABILITY; SOCIOECONOMIC-STATUS; ALZHEIMERS-DISEASE; EDUCATION; MORTALITY AB Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults. Participants were 2,458 black and white elders (aged 71-82) from the Health, Aging and Body Composition study, who completed the Rapid Estimate of Adult Literacy in Medicine and were followed for 8 years. Participants were free of dementia at baseline; incidence of likely dementia was defined by hospital records, prescription for dementia medication, or decline in Modified Mini-Mental State Examination score. We conducted Cox proportional hazard models to evaluate the association between literacy and incidence of likely dementia. Demographics, education, income, comorbidities, lifestyle variables, and apolipoprotein E (APOE) epsilon 4 status were included in adjusted analyses. Twenty-three percent of participants had limited literacy (< 9th-grade level). Limited literacy, as opposed to adequate literacy (a parts per thousand yen9th-grade level), was associated with greater incidence of likely dementia (25.5% vs17.0%; unadjusted hazard ratio [HR] = 1.75, 95% confidence interval 1.44-2.13); this association remained significant after adjustment. There was a trend for an interaction between literacy and APOE epsilon 4 status (p = .07); the association between limited literacy and greater incidence of likely dementia was strong among epsilon 4 noncarriers (unadjusted HR = 1.85) but nonsignificant among epsilon 4 carriers (unadjusted HR = 1.25). Limited literacy is an important risk factor for likely dementia, especially among APOE epsilon 4-negative older adults, and may prove fruitful to target in interventions aimed at reducing dementia risk. C1 [Kaup, Allison R.; Yaffe, Kristine] San Francisco VA Med Ctr, Sierra Pacific Mental Illness Res Educ & Clin Ctr, San Francisco, CA 94121 USA. [Kaup, Allison R.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] Harbor Hosp, Translat Gerontol Branch, NIA, Baltimore, MD USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Metti, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Ayonayon, Hilsa N.; Rubin, Susan M.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Kaup, AR (reprint author), San Francisco VA Med Ctr, 4150 Clement St,116H, San Francisco, CA 94121 USA. EM allison.kaup@ucsf.edu FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24AG031155]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported by the National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; R01-AG028050, K24AG031155 to K.Y.) and National Institute of Nursing Research (R01-NR012459). This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Writing of this manuscript was supported by Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the San Francisco Veterans Affairs Medical Center, and the Department of Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center. NR 39 TC 10 Z9 11 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2014 VL 69 IS 7 BP 900 EP 906 DI 10.1093/gerona/glt176 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AJ9DG UT WOS:000338006400015 PM 24158765 ER PT J AU Poon, AH Houseman, EA Ryan, L Sparrow, D Vokonas, PS Litonjua, AA AF Poon, Audrey H. Houseman, E. Andres Ryan, Louise Sparrow, David Vokonas, Pantel S. Litonjua, Augusto A. TI Variants of Asthma and Chronic Obstructive Pulmonary Disease Genes and Lung Function Decline in Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Genetics; Pulmonary; Normative aging; Successful aging ID PROTEIN-COUPLED RECEPTOR-154; NUTRITION-EXAMINATION-SURVEY; AIRWAY HYPERRESPONSIVENESS; CIGARETTE-SMOKING; NATIONAL-HEALTH; UNITED-STATES; KV4 CHANNELS; ASSOCIATION; POPULATION; POLYMORPHISMS AB A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men. We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time. One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time. Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes. C1 [Poon, Audrey H.; Litonjua, Augusto A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02445 USA. [Poon, Audrey H.; Litonjua, Augusto A.] Harvard Univ, Sch Med, Boston, MA USA. [Poon, Audrey H.] MUHC, Meakins Christie Labs, Montreal, PQ, Canada. [Houseman, E. Andres] Oregon State Univ, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Ryan, Louise] CSIRO, Div Math Informat & Stat CMIS, N Ryde, NSW 2113, Australia. [Sparrow, David; Vokonas, Pantel S.] VA Boston Healthcare Syst, Normat Aging Study, Boston, MA USA. [Sparrow, David; Vokonas, Pantel S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Litonjua, Augusto A.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02445 USA. RP Litonjua, AA (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02445 USA. EM augusto.litonjua@channing.harvard.edu RI Ryan, Louise/A-4562-2009; OI Ryan, Louise/0000-0001-5957-2490; Houseman, Eugene Andres/0000-0003-0703-1830 FU National Institutes of Health [AG 027014]; Croucher Foundation; VA Research Career Scientist award; Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs FX This work was funded by the National Institutes of Health (AG 027014); Dr. A.H.P. was supported by a grant from The Croucher Foundation; Dr. D.S. was supported by a VA Research Career Scientist award; The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs, and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts. NR 49 TC 5 Z9 5 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2014 VL 69 IS 7 BP 907 EP 913 DI 10.1093/gerona/glt179 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AJ9DG UT WOS:000338006400016 PM 24253534 ER PT J AU Yabroff, KR Guy, GP Ekwueme, DU McNeel, T Rozjabek, HM Dowling, E Li, CY Virgo, KS AF Yabroff, K. Robin Guy, Gery P., Jr. Ekwueme, Donatus U. McNeel, Timothy Rozjabek, Heather M. Dowling, Emily Li, Chunyu Virgo, Katherine S. TI Annual Patient Time Costs Associated With Medical Care Among Cancer Survivors in the United States SO MEDICAL CARE LA English DT Article DE cost of illness; costs and cost analysis; utilization; neoplasms; Medical Expenditure Panel Survey ID HEALTH INTERVIEW SURVEY; 2ND PRIMARY CANCERS; BREAST-CANCER; ECONOMIC BURDEN; COLONOSCOPY; PREVALENCE; SURGERY; ADULTS; TRAVEL AB Background:Although patient time costs are recommended for inclusion in cost-effectiveness analyses, these data are not routinely collected. We used nationally representative data and a medical service-based approach to estimate the annual patient time costs among cancer survivors.Methods:We identified adult 6699 cancer survivors and 86,412 individuals without a cancer history ages 18 years or more from 2008-2011 Medical Expenditure Panel Survey (MEPS). Service use was categorized as hospitalizations, emergency room use, provider visits, ambulatory surgery, chemotherapy, and radiation therapy. Service time estimates were applied to frequencies for each service category and the US median wage rate in 2011 was used to value time. We evaluated the association between cancer survivorship and service use frequencies and patient time costs with multivariable regression models, stratified by age group (18-64 and 65+ y). Sensitivity analyses evaluated different approaches for valuing time.Results:Cancer survivors were more likely to have hospitalizations, emergency room visits, ambulatory surgeries, and provider visits in the past year than individuals without a cancer history in adjusted analyses (P<0.05). Annual patient time was higher for cancer survivors than individuals without a cancer history among those aged 18-64 years (30.2 vs. 13.6 h; P<0.001) and 65+ years (55.1 vs. 36.6 h; P<0.001), as were annual patient time costs (18-64 y: $500 vs. $226; P<0.001 and 65+ y: $913 vs. $607; P<0.001).Conclusions:Cancer survivors had greater annual medical service use and patient time costs than individuals without a cancer history. This medical service-based approach for estimating annual time costs can also be applied to other conditions. C1 [Yabroff, K. Robin; Rozjabek, Heather M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Guy, Gery P., Jr.; Ekwueme, Donatus U.; Li, Chunyu] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Atlanta, GA USA. [McNeel, Timothy] Informat Management Serv Inc, Rockville, MD USA. [Dowling, Emily] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Virgo, Katherine S.] Emory Univ, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, 9609 Med Ctr Dr 3E436, Rockville, MD 20850 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 7 Z9 7 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2014 VL 52 IS 7 BP 594 EP 601 DI 10.1097/MLR.0000000000000151 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AJ5TI UT WOS:000337750800006 PM 24926706 ER PT J AU Derose, SF Gabayan, GZ Chiu, VY Yiu, SC Sun, BC AF Derose, Stephen F. Gabayan, Gelareh Z. Chiu, Vicki Y. Yiu, Sau C. Sun, Benjamin C. TI Emergency Department Crowding Predicts Admission Length-of-Stay But Not Mortality in a Large Health System SO MEDICAL CARE LA English DT Article DE emergency medicine; ED crowding; length-of-stay; emergency care; inpatient mortality ID AMBULANCE DIVERSION; INPATIENT LENGTH; ASSOCIATION; SURVIVAL; OUTCOMES AB Background:Emergency department (ED) crowding has been identified as a major threat to public health.Objectives:We assessed patient transit times and ED system crowding measures based on their associations with outcomes.Research Design:Retrospective cohort study.Subjects:We accessed electronic health record data on 136,740 adults with a visit to any of 13 health system EDs from January 2008 to December 2010.Measures:Patient transit times (waiting, evaluation and treatment, boarding) and ED system crowding [nonindex patient length-of-stay (LOS) and boarding, bed occupancy] were determined. Outcomes included individual inpatient mortality and admission LOS. Covariates included demographic characteristics, past comorbidities, severity of illness, arrival time, and admission diagnoses.Results:No patient transit time or ED system crowding measure predicted increased mortality after control for patient characteristics. Index patient boarding time and lower bed occupancy were associated with admission LOS (based on nonoverlapping 95% CI vs. the median value). As boarding time increased from none to 14 hours, admission LOS increased an additional 6 hours. As mean occupancy decreased below the median (80% occupancy), admission LOS decreased as much as 9 hours.Conclusions:Measures indicating crowded ED conditions were not predictive of mortality after case-mix adjustment. The first half-day of boarding added to admission LOS rather than substituted for it. Our findings support the use of boarding time as a measure of ED crowding based on robust prediction of admission LOS. Interpretation of measures based on other patient ED transit times may be limited to the timeliness of care. C1 [Derose, Stephen F.; Chiu, Vicki Y.; Yiu, Sau C.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Gabayan, Gelareh Z.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Gabayan, Gelareh Z.] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Med, Los Angeles, CA USA. [Sun, Benjamin C.] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. RP Derose, SF (reprint author), Kaiser Permanente So Calif, Dept Res & Evaluat, 100 S Los Robles,Floor 3, Pasadena, CA 91101 USA. EM stephen.f.derose@kp.org FU federal NIH/AHRRQ grant [R03HS018994]; Kaiser Permanente of Southern California; National Center for Advancing Translational Sciences [KL2TR000122] FX Supported by federal NIH/AHRRQ grant #R03HS018994 and Kaiser Permanente of Southern California.; During the time of the study, G.Z. Gabayan received support from the National Center for Advancing Translational Sciences, Grant KL2TR000122. The other authors declare no conflict of interest. NR 38 TC 4 Z9 4 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2014 VL 52 IS 7 BP 602 EP 611 DI 10.1097/MLR.0000000000000141 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AJ5TI UT WOS:000337750800007 PM 24926707 ER PT J AU Emmons, KM Puleo, E Greaney, ML Gillman, MW Bennett, GG Haines, J Sprunck-Harrild, K Viswanath, K AF Emmons, Karen M. Puleo, Elaine Greaney, Mary L. Gillman, Matthew W. Bennett, Gary G. Haines, Jess Sprunck-Harrild, Kim Viswanath, K. TI A randomized comparative effectiveness study of Healthy Directions 2-A multiple risk behavior intervention for primary care SO PREVENTIVE MEDICINE LA English DT Article DE Multimorbidities; Primary care intervention; Smoking cessation; Cancer prevention; Red meat; Physical activity ID MAJOR CHRONIC DISEASE; PHYSICAL-ACTIVITY; SMOKING-CESSATION; CONTROLLED-TRIAL; VEGETABLE CONSUMPTION; CANCER PREVENTION; EXTERNAL VALIDITY; UNITED-STATES; WORKING-CLASS; DIET AB Objective. To evaluate the effectiveness of the Healthy Directions 2 (HD2) intervention in the primary care setting. Methods. HD2 was a cluster randomized trial (conducted 3/09-11/11). The primary sampling unit was provider (n = 33), with secondary sampling of patients within provider (n = 2440). Study arms included: 1) usual care (UC); 2) HD2 a patient self-guided intervention. targeting 5 risk behaviors; and 3) HD2 plus 2 brief telephone coaching calls (HD2 + CC). The outcome measure was the proportion of participants with a lower multiple risk behavior (MRB) score by follow-up. Results. At baseline, only 4% of the participants met all behavioral recommendations. Both HD2 and HD2 + CC led to improvements in MRB score, relative to UC, with no differences between the two HD2 conditions. Twenty-eight percent of the UC participants had improved MRB scores at 6 months, vs. 39% and 43% in HD2 and HD2 + CC, respectively (ps <= .001); results were similar at 18 months (p <= .05). The incremental cost of one risk factor reduction in MRB score was $310 for HD2 and $450 for HD2 + CC Conclusions. Self-guided and coached intervention conditions had equivalent levels of effect in reducing multiple chronic disease risk factors, were relatively low cost, and thus are potentially useful for routine implementation in similar health settings. (C) 2014 Elsevier Inc. All rights reserved. C1 [Emmons, Karen M.] Kaiser Fdn Res Inst, Oakland, CA 94612 USA. [Puleo, Elaine] Univ Massachusetts, Amherst, MA 01003 USA. [Greaney, Mary L.] Univ Rhode Isl, Kingston, RI USA. [Gillman, Matthew W.] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Haines, Jess] Univ Guelph, Guelph, ON N1G 2W1, Canada. [Sprunck-Harrild, Kim; Viswanath, K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27708 USA. RP Emmons, KM (reprint author), Kaiser Fdn Res Inst, 1800 Harrison Ave, Oakland, CA 94612 USA. EM Karen.m.emmons@kp.org FU NIH [R01 CA123228, K05 CA124415, K24 HL068041] FX We thank Harvard Vanguard Medical Associates for the opportunity to conduct our research in their clinical sites. The authors would also like to acknowledge Martha Zorn for her work on the data management and Nancy Klockson for participation in the manuscript preparation. This work was funded by NIH grants R01 CA123228 and K05 CA124415 (Emmons, PI) and K24 HL068041 (Gillman, PI). NR 54 TC 2 Z9 2 U1 2 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD JUL PY 2014 VL 64 BP 96 EP 102 DI 10.1016/j.ypmed.2014.03.011 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AJ6AX UT WOS:000337773200016 PM 24642140 ER PT J AU Yanai, R Mulki, L Hasegawa, E Takeuchi, K Sweigard, H Suzuki, J Gaissert, P Vavvas, DG Sonoda, KH Rothe, M Schunck, WH Miller, JW Connor, KM AF Yanai, Ryoji Mulki, Lama Hasegawa, Eiichi Takeuchi, Kimio Sweigard, Harry Suzuki, Jun Gaissert, Philipp Vavvas, Demetrios G. Sonoda, Koh-Hei Rothe, Michael Schunck, Wolf-Hagen Miller, Joan W. Connor, Kip M. TI Cytochrome P450-generated metabolites derived from omega-3 fatty acids attenuate neovascularization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE choroidal neovascularization; immune cell recruitment; PPAR gamma; adhesion molecules; epoxy-metabolites ID AGE-RELATED MACULOPATHY; POLYUNSATURATED FATTY-ACIDS; MACULAR DEGENERATION; DIETARY-FAT; CHOROIDAL NEOVASCULARIZATION; EPOXYEICOSATRIENOIC ACIDS; PPAR-GAMMA; ANGIOGENESIS; RISK; ENZYMES AB Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)-epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with omega-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed omega-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary omega-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from omega-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD. C1 [Yanai, Ryoji; Mulki, Lama; Hasegawa, Eiichi; Takeuchi, Kimio; Sweigard, Harry; Suzuki, Jun; Gaissert, Philipp; Vavvas, Demetrios G.; Miller, Joan W.; Connor, Kip M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Sonoda, Koh-Hei] Yamaguchi Univ, Grad Sch Med, Dept Ophthalmol, Ube, Yamaguchi 7558505, Japan. [Rothe, Michael] Lipidomix GmbH, D-13125 Berlin, Germany. [Schunck, Wolf-Hagen] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. RP Connor, KM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. EM kip_connor@meei.harvard.edu FU Research to Prevent Blindness; Massachusetts Lions Eye Research Fund; Japan Eye Bank Association; National Eye Institute of the National Institutes of Health [R01EY022084/S1, T32EY007145, P30EY014104] FX This study was supported by a Special Scholar Award (to K. M. C.) and an unrestricted grant (to J.W.M.) from Research to Prevent Blindness; the Massachusetts Lions Eye Research Fund and an award from the Japan Eye Bank Association (to R.Y.); and by Grants R01EY022084/S1 (to K. M. C.), T32EY007145 (to H. S.), and P30EY014104 from the National Eye Institute of the National Institutes of Health. NR 49 TC 12 Z9 13 U1 1 U2 10 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 JUL 1 PY 2014 VL 111 IS 26 BP 9603 EP 9608 DI 10.1073/pnas.1401191111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900064 PM 24979774 ER PT J AU Tanderup, K Viswanathan, AN Kirisits, C Frank, SJ AF Tanderup, Kari Viswanathan, Attila N. Kirisits, Christian Frank, Steven J. TI Magnetic Resonance Image Guided Brachytherapy SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID CERVIX CANCER BRACHYTHERAPY; DOSE-RATE BRACHYTHERAPY; LOCALIZED PROSTATE-CANCER; SOCIETY CONSENSUS GUIDELINES; LOCALLY ADVANCED-CARCINOMA; TANDEM-OVOID APPLICATORS; II PROSPECTIVE TRIAL; ADAPTIVE BRACHYTHERAPY; INTERSTITIAL BRACHYTHERAPY; INTEROBSERVER VARIABILITY AB The application of magnetic resonance image (MRI)-guided brachytherapy has demonstrated significant growth during the past 2 decades. Clinical improvements in cervix cancer outcomes have been linked to the application of repeated MRI for identification of residual tumor volumes during radiotherapy. This has changed clinical practice in the direction of individualized dose administration, and resulted in mounting evidence of improved clinical outcome regarding local control, overall survival as well as morbidity. MRI-guided prostate high-dose-rate and low-dose-rate brachytherapies have improved the accuracy of target and organs-at-risk delineation, and the potential exists for improved dose prescription and reporting for the prostate gland and organs at risk. Furthermore, MRI-guided prostate brachytherapy has significant potential to identify prostate subvolumes and dominant lesions to allow for dose administration reflecting the differential risk of recurrence. MRI-guided brachytherapy involves advanced imaging, target concepts, and dose planning. The key issue for safe dissemination and implementation of high-quality MRI-guided brachytherapy is establishment of qualified multidisciplinary teams and strategies for training and education. (C) 2014 Elsevier Inc. All rights reserved. C1 [Tanderup, Kari] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 63110 USA. [Tanderup, Kari] Aarhus Univ Hosp, Dept Oncol, DK-8000 Aarhus, Denmark. [Viswanathan, Attila N.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Kirisits, Christian] Med Univ Vienna, Ctr Comprehens Canc, Dept Radiotherapy, Vienna, Austria. [Kirisits, Christian] Med Univ Vienna, Christian Doppler Lab Med Radiat Res Radiat Oncol, Vienna, Austria. [Frank, Steven J.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Tanderup, K (reprint author), Washington Univ, Sch Med, Dept Radiat Oncol, 4921 Parkview Pl,Campus Box 8224, St Louis, MO 63110 USA. EM ktanderup@radonc.wustl.edu OI Kirisits, Christian/0000-0002-2815-8083; Tanderup, Kari/0000-0001-7980-0681 FU Varian Medical Systems, Nucletron-an Elekta Company; Varian Medical Systems; Nucletron FX The GEC-ESTRO GYN network coordinated by Medical University of Vienna and Aarhus University Hospital has received research grants from Varian Medical Systems, Nucletron-an Elekta Company, and Bebig for coordination of research and for conduction of the EMBRACE tnal. Aarhus University Hospital receives financial support for educational purposes from Varian Medical Systems. The Department of Radiotherapy at Medical University of Vienna receives financial and equipment support for research and educational purposes from Nucletron, an Elekta company, and Varian Medical Systems, Inc. Christian Kinsits is a consultant to Nucletron, an Elekta company. Dr Viswanathan has received an honorarium from Nucletron Steven]. Frank is founder and director of C4 Imaging and has received an honorarium from Biocompatibles (BIG).; Aarhus University Hospital was supported by research grants from the Danish Cancer Society, Danish Council for Strategic Research, CIRRO-the Lundbeck Foundation Centre for Interventional Research in Radiation Oncology Funding from the European Programme (FP7/2013-2016) under grant agreement ICT-2011.5.2 (Dr Therapat) was received. The work of Christian Kirisits was supported by the Austrian Science Fund EWE Grant no L562. The work of Alala Viswanathan was supported by the Grant R21 NIH CA167800. The work of Steven J. Frank was supported by the Grant NIH/NCI-R43. Tharakeswara K. Bathala, MD Anderson Cancer Center, is acknowledged for support with prostate MRI figures. NR 78 TC 23 Z9 23 U1 2 U2 6 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 2014 VL 24 IS 3 BP 181 EP 191 DI 10.1016/j.semradonc.2014.02.007 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AJ8VS UT WOS:000337986800006 PM 24931089 ER PT J AU Hartwig, W Vollmer, CM Fingerhut, A Yeo, CJ Neoptolemos, JP Adham, M Andren-Sandberg, A Asbun, HJ Bassi, C Bockhorn, M Charnley, R Conlon, KC Dervenis, C Fernandez-Cruz, L Friess, H Gouma, DJ Imrie, CW Lillemoe, KD Milicevic, MN Montorsi, M Shrikhande, SV Vashist, YK Izbicki, JR Buchler, MW AF Hartwig, Werner Vollmer, Charles M. Fingerhut, Abe Yeo, Charles J. Neoptolemos, John P. Adham, Mustapha Andren-Sandberg, Ake Asbun, Horacio J. Bassi, Claudio Bockhorn, Max Charnley, Richard Conlon, Kevin C. Dervenis, Christos Fernandez-Cruz, Laureano Friess, Helmut Gouma, Dirk J. Imrie, Clem W. Lillemoe, Keith D. Milicevic, Miroslav N. Montorsi, Marco Shrikhande, Shailesh V. Vashist, Yogesh K. Izbicki, Jakob R. Buechler, Markus W. CA Int Study Grp Pancreatic Surg TI Extended pancreatectomy in pancreatic ductal adenocarcinoma: Definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS) SO SURGERY LA English DT Article ID MODULAR PANCREATOSPLENECTOMY PROCEDURE; MESENTERIC VEIN RESECTION; RISK-FACTORS; UNITED-STATES; RETROPERITONEAL LYMPHADENECTOMY; PERIAMPULLARY ADENOCARCINOMA; MULTIVISCERAL RESECTIONS; DISTAL GASTRECTOMY; CURATIVE INTENT; CANCER AB Background. Complete macroscopic tumor resection is one of the most relevant predictors of long-term survival in pancreatic ductal adenocarcinoma. Because locally advanced pancreatic tumors can involve adjacent organs, "extended" pancreatectomy that includes the resection of additional organs may be needed to achieve this goal. Our aim was to develop a common consistent terminology to be used in centers reporting results of pancreatic resections for cancer. Methods. An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature on extended pancreatectomies and worked together to establish a consensus on the definition and the role of extended pancreatectomy in pancreatic cancer. Results. Macroscopic (R1) and microscopic (R0) complete tumor resection can be achieved in patients with locally advanced disease by extended pancreatectomy. Operative time, blood loss, need for blood transfusions, duration of stay in the intensive care unit, and hospital morbidity, and possibly also perioperative mortality are increased with extended resections. Long-term survival is similar compared with standard resections but appears to be better compared with bypass surgery or nonsurgical palliative chemotherapy or chemoradiotherapy. It was not possible to identify any clear prognostic criteria based on the specific additional organ resected. Conclusion. Despite increased pen operative morbidity, extended pancreatectomy is warranted in locally advanced disease to achieve long-term survival in pancreatic ductal adenocarcinoma if macroscopic clearance can be achieved. Definitions of extended pancreatectomies for locally advanced disease (and not distant metastatic disease) are established that are crucial for comparison of results of future trials across different practices and countries, in particular for those using neoadjuvant therapy. C1 [Hartwig, Werner] Univ Munich, Klinikum Grosshadern, Dept Surg, D-80539 Munich, Germany. [Vollmer, Charles M.] Univ Penn, Penn Surg, Dept Gastrointestinal Surg, Philadelphia, PA 19104 USA. [Fingerhut, Abe] Ctr Hosp Intercommunal, Dept Digest Surg, Poissy, France. [Yeo, Charles J.] Thomas Jefferson Univ, Jefferson Pancreas Biliary & Related Canc Ctr, Dept Surg, Philadelphia, PA 19107 USA. [Neoptolemos, John P.] Univ Liverpool, Liverpool Canc Res UK Ctr, Dept Mol & Clin Canc Med, Liverpool L69 3BX, Merseyside, England. [Adham, Mustapha] Hop Edouard Herriot, Dept HPB Surg, Lyon, France. [Andren-Sandberg, Ake] Karolinska Univ Hosp, Karolinska Inst, Dept Surg, Stockholm, Sweden. [Asbun, Horacio J.] Mayo Clin, Dept Gen Surg, Jacksonville, FL 32224 USA. [Bassi, Claudio] Univ Verona, Pancreas Inst, Dept Surg & Oncol, I-37100 Verona, Italy. [Bockhorn, Max; Vashist, Yogesh K.; Izbicki, Jakob R.] Univ Hosp Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany. [Charnley, Richard] Freeman Rd Hosp, Dept HPB & Transplant Surg, Newcastle Upon Tyne, Tyne & Wear, England. [Conlon, Kevin C.] Univ Dublin, Trinity Coll, Professorial Surg Unit, Dublin, Ireland. [Dervenis, Christos] Agia Olga Hosp, Dept Surg 1, Athens, Greece. [Fernandez-Cruz, Laureano] Univ Barcelona, Hosp Clin Barcelona, Dept Surg, Barcelona, Spain. [Friess, Helmut] Tech Univ Munich, Klinikum Rechts Isar, Dept Surg, D-80290 Munich, Germany. [Gouma, Dirk J.] Univ Amsterdam, Acad Med Ctr, Dept Surg, NL-1105 AZ Amsterdam, Netherlands. [Imrie, Clem W.] Univ Glasgow, Acad Surg Unit, Glasgow, Lanark, Scotland. [Lillemoe, Keith D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Milicevic, Miroslav N.] Univ Belgrade, Clin Ctr Serbia, Surg Clin 1, Belgrade, Serbia. [Montorsi, Marco] Univ Milan, Inst Clin Humanitas IRCCS, Dept Gen Surg, Milan, Italy. [Shrikhande, Shailesh V.] Tata Mem Hosp, Dept Gastrointestinal & HPB Surg Oncol, Mumbai 400012, Maharashtra, India. [Buechler, Markus W.] Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, D-69120 Heidelberg, Germany. RP Buchler, MW (reprint author), Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Neuenheimer Feld 110, D-69120 Heidelberg, Germany. EM markus.buechler@med.uni-heidelberg.de RI Adham, Mustapha/A-1270-2017; OI Imrie, Clem/0000-0002-1190-7084 NR 49 TC 40 Z9 54 U1 2 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUL PY 2014 VL 156 IS 1 BP 1 EP 14 DI 10.1016/j.surg.2014.02.009 PG 14 WC Surgery SC Surgery GA AJ8BO UT WOS:000337927800001 PM 24856668 ER PT J AU Jakobiec, FA Stacy, RC Mendoza, PR Chodosh, J AF Jakobiec, Frederick A. Stacy, Rebecca C. Mendoza, Pia R. Chodosh, James TI Hyperplastic corneal pannus: An immunohistochemical analysis and review SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE cornea; pannus; hyperplastic; keloids; hypertrophic; pseudosarcoma; myofibroblast; histiocytes; T lymphocytes; immunohistochemistry; smooth muscle actin; CD68 ID ULTRASTRUCTURAL CHARACTERISTICS; WOUND REPAIR; MECHANISMS; MANAGEMENT; EPITHELIUM; DISEASE; KELOIDS; STROMA; CELLS AB An exuberant corneal pannus usually develops in adults with a history of surgery or trauma in the anterior central stroma and appears as a glistening, vascularized, moderately elevated, well circumscribed white nodule. We describe a 78-year-old woman with such a pannus, which in the past has typically been referred to as keloidal or hypertrophic. The involved eye had only light perception, and she underwent a penetrating keratoplasty that improved her vision to 20/100. Histopathologic and immunohistochemical evaluations of a the specimen disclosed a reactive spindle cell stromal proliferation of myofibroblasts that were smooth muscle actin positive with a low Ki67 proliferation index. Desmin, caldesmon, and calponin were negative, in keeping with the incomplete myofilamentary differentiation of a myofibroblast. There was a generous admixture of CD68/163-positive histiocytes and dispersed C3/5-positive T-lymphocytes. An absence of CD138- and IgG4-positive plasma cells ruled out an IgG4-related disease. For a lesion to be keloidal, the collagen must have a thick hyaline character, sharp edges, and a sparsity of intervening cells and vessels. A hypertrophic pannus would be composed of large swollen cells not necessarily increased in number. We therefore recommend adoption of the term hyperplastic for lesions like that described here because of the obvious increase in cellularity from proliferating myofibroblasts and the lack of true keloidal collagen. (C) 2014 Elsevier Inc. All rights reserved. C1 [Jakobiec, Frederick A.; Stacy, Rebecca C.; Mendoza, Pia R.] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Chodosh, James] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cornea & External Dis Serv, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Stacy, Rebecca C.; Mendoza, Pia R.; Chodosh, James] Harvard Univ, Sch Med, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St Suite 328, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 37 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JUL-AUG PY 2014 VL 59 IS 4 BP 448 EP 453 DI 10.1016/j.survophthal.2013.10.005 PG 6 WC Ophthalmology SC Ophthalmology GA AJ5IH UT WOS:000337715400006 PM 24309126 ER PT J AU Baek, JH Nierenberg, AA AF Baek, J. H. Nierenberg, A. A. TI Lithium tremor, beta-blockers, and depression Reply SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Letter C1 [Baek, J. H.; Nierenberg, A. A.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Nierenberg, A. A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Baek, JH (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. EM anierenberg@partners.org NR 2 TC 0 Z9 0 U1 1 U2 1 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 2014 VL 130 IS 1 BP 73 EP 73 DI 10.1111/acps.12267 PG 1 WC Psychiatry SC Psychiatry GA AJ5AS UT WOS:000337693300013 PM 24730760 ER PT J AU Wang, MP Wang, X Lam, TH Viswanath, K Chan, SS AF Wang, Man Ping Wang, Xin Lam, Tai Hing Viswanath, Kasisomayajula Chan, Sophia S. TI Ex-smokers are happier than current smokers among Chinese adults in Hong Kong SO ADDICTION LA English DT Article DE Chinese; happiness; Hong Kong; life satisfaction; smoking; survey ID CROSS-SECTIONAL SURVEY; SMOKING-CESSATION; NEGATIVE AFFECT; HAPPINESS; TOBACCO; LIFE; NICOTINE; WITHDRAWAL; ADDICTION AB Aim To investigate the cross-sectional association between smoking and happiness in Chinese adults in Hong Kong. Design, Setting and Participants Telephone surveys were conducted between 2009 and 2012, with 4553 randomly sampled Chinese adults (male 54%, mean age 58.3 years) in Hong Kong. Measurements Happiness was measured using the four-item Subjective Happiness Scale (SHS) and single-item Global Happiness Item (GHI). Smoking status was categorized as current smokers (7.7%%), ex-smokers (6.5%, 93% quit for >6 months) and never smokers (85.8%). Linear and ordinal logistic regressions were used to calculate adjusted -coefficients for SHS and proportional adjusted odds ratios (aOR) for GHI in relation to smoking. Findings Compared with current smokers, ex-smokers enjoyed greater happiness according to both SHS (adjusted =0.16, P<0.05) and GHI (aOR=1.52, P<0.05) measurements, but current and never smokers were similar. Among current smokers, the number of cigarettes smoked was not associated with happiness, but the lack of any attempt to quit was associated significantly with greater happiness (adjusted =0.31 for SHS, aOR=1.82 for GHI) compared with smokers who had tried to quit but not succeeded. Smokers not intending to quit in the next 6 months had higher odds of happiness (GHI) than those wanting to quit within 6 months (aOR=1.86, P<0.05). Conclusions Ex-smokers in Hong Kong are happier than current smokers and never smokers, whose happiness measurements are similar. Causal associations have yet to be established. C1 [Wang, Man Ping; Chan, Sophia S.] Univ Hong Kong, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. [Wang, Xin; Lam, Tai Hing] Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Ctr Community Based Res,Dept Social & Behav Sci, Boston, MA 02115 USA. RP Lam, TH (reprint author), Univ Hong Kong, Sch Publ Hlth, 21 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. EM hrmrlth@hku.hk FU Hong Kong Jockey Club Charities Trust FX This study was part of the project 'FAMILY: a Jockey Club Initiative for a Harmonious Society', funded by the Hong Kong Jockey Club Charities Trust. NR 42 TC 6 Z9 6 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD JUL PY 2014 VL 109 IS 7 BP 1165 EP 1171 DI 10.1111/add.12531 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AJ3LY UT WOS:000337569200024 PM 24588872 ER PT J AU Auer, R Vittinghoff, E Kiefe, C Reis, JP Rodondi, N Khodneva, YA Kertesz, SG Cornuz, J Pletcher, MJ AF Auer, Reto Vittinghoff, Eric Kiefe, Catarina Reis, Jared P. Rodondi, Nicolas Khodneva, Yulia A. Kertesz, Stefan G. Cornuz, Jacques Pletcher, Mark J. TI Change in physical activity after smoking cessation: the Coronary Artery Risk Development in Young Adults (CARDIA) study SO ADDICTION LA English DT Article DE behavior change; marginal structural model; middle age; mixed longitudinal model; physical activity; smoking cessation; trajectory analysis; young adults ID HEALTH-RELATED BEHAVIORS; CIGARETTE-SMOKING; WEIGHT-GAIN; FOLLOW-UP; SELF-REPORTS; LIFE-STYLE; EXERCISE; WOMEN; DISEASE; MIDDLE AB Aims To estimate physical activity trajectories for people who quit smoking, and compare them to what would have been expected had smoking continued. Design, Setting and Participants A total of 5115 participants in the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, a population-based study of African American and European American people recruited at age 18-30 years in 1985/6 and followed over 25 years. Measurements Physical activity was self-reported during clinical examinations at baseline (1985/6) and at years 2, 5, 7, 10, 15, 20 and 25 (2010/11); smoking status was reported each year (at examinations or by telephone, and imputed where missing). We used mixed linear models to estimate trajectories of physical activity under varying smoking conditions, with adjustment for participant characteristics and secular trends. Findings We found significant interactions by race/sex (P=0.02 for the interaction with cumulative years of smoking), hence we investigated the subgroups separately. Increasing years of smoking were associated with a decline in physical activity in black and white women and black men [e.g. coefficient for 10 years of smoking: -0.14; 95% confidence interval (CI)=-0.20 to -0.07, P<0.001 for white women]. An increase in physical activity was associated with years since smoking cessation in white men (coefficient 0.06; 95% CI=0 to 0.13, P=0.05). The physical activity trajectory for people who quit diverged progressively towards higher physical activity from the expected trajectory had smoking continued. For example, physical activity was 34% higher (95% CI=18 to 52%; P<0.001) for white women 10 years after stopping compared with continuing smoking for those 10 years (P=0.21 for race/sex differences). Conclusions Smokers who quit have progressively higher levels of physical activity in the years after quitting compared with continuing smokers. C1 [Auer, Reto; Vittinghoff, Eric; Pletcher, Mark J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kiefe, Catarina] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Rodondi, Nicolas] Univ Bern, Inselspital, Dept Gen Internal Med, CH-3010 Bern, Switzerland. [Khodneva, Yulia A.; Kertesz, Stefan G.] Univ Alabama Birmingham, Birmingham Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL USA. [Kertesz, Stefan G.] Birmingham VA Med Ctr, Ctr Surg Med & Acute Care Res, Birmingham, AL USA. [Kertesz, Stefan G.] Univ Alabama Birmingham, Div Prevent Med, Med Sch Birmingham, Birmingham, AL USA. [Cornuz, Jacques] Univ Lausanne Hosp, Dept Ambulatory & Community Med, Lausanne, Switzerland. RP Auer, R (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Suite 5700, San Francisco, CA 94143 USA. EM reto.auer@ucsf.edu FU National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; National Institute on Aging (NIA); NIA; NHLBI [AG0005]; Swiss National Science Foundation [PBLAP3-136774]; Societe Academique Vaudoise; SICPA Foundation FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C) and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. Dr Auer's research on cardiovascular prevention is supported by a grant from the Swiss National Science Foundation PBLAP3-136774, the Societe Academique Vaudoise and the SICPA Foundation. NR 53 TC 3 Z9 3 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD JUL PY 2014 VL 109 IS 7 BP 1172 EP 1183 DI 10.1111/add.12561 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AJ3LY UT WOS:000337569200025 PM 24690003 ER PT J AU Rosow, C AF Rosow, Carl TI Improving Safety During Sedation by Nonanesthesiologists: Do We Lead or Follow? SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Rosow, C (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM crosow@partners.org NR 7 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD JUL PY 2014 VL 119 IS 1 BP 7 EP 8 DI 10.1213/ANE.0000000000000277 PG 2 WC Anesthesiology SC Anesthesiology GA AJ5JB UT WOS:000337717400003 PM 24945117 ER PT J AU Li, XM Su, F Ji, MH Zhang, GF Qiu, LL Jia, M Gao, J Xie, ZC Yang, JJ AF Li, Xiao-Min Su, Fan Ji, Mu-Huo Zhang, Guang-Fen Qiu, Li-Li Jia, Min Gao, Jun Xie, Zhongcong Yang, Jian-Jun TI Disruption of Hippocampal Neuregulin 1-ErbB4 Signaling Contributes to the Hippocampus-dependent Cognitive Impairment Induced by Isoflurane in Aged Mice SO ANESTHESIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; PARVALBUMIN-POSITIVE INTERNEURONS; GENERAL-ANESTHESIA; MEMORY IMPAIRMENT; ERBB4; DYSFUNCTION; RATS; DECLINE; SCHIZOPHRENIA; ACTIVATION AB Background: A prolonged isoflurane exposure may lead to cognitive decline in rodents. Neuregulin 1 (NRG1)-ErbB4 signaling plays a key role in the modulation of hippocampal synaptic plasticity through regulating the neurotransmission. The authors hypothesized that hippocampal NRG1-ErbB4 signaling is involved in isoflurane-induced cognitive impairments in aged mice. Methods: Fourteen-month-old C57BL/6 mice were randomized to receive 100% O-2 exposure, vehicle injection after 100% O-2 exposure, vehicle injection after exposure to isoflurane carried by 100% O-2, NRG1-1 injection after exposure to isoflurane carried by 100% O-2, and NRG1-1 and an ErbB4 inhibitor AG1478 injection after exposure to isoflurane carried by 100% O-2. Fear conditioning test was used to assess the cognitive function of mice 48-h postexposure. The brain tissues were harvested 48-h postexposure to determine the levels of NRG1, ErbB4, p-ErbB4, parvalbumin, and glutamic acid decarboxylase 67 in the hippocampus using Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence. Results: The percentage of freezing time to context was decreased from 50.28 11.53% to 30.82 +/- 10.00%, and the hippocampal levels of NRG1, p-ErbB4/ErbB4, parvalbumin, and glutamic acid decarboxylase 67 were decreased from 172.79 +/- 20.85 ng/g, 69.15 +/- 12.20%, 101.68 +/- 11.21%, and 104.71 +/- 6.85% to 112.92 +/- 16.65 ng/g, 42.26 +/- 9.71%, 75.89 +/- 10.26%, and 73.87 +/- 16.89%, respectively, after isoflurane exposure. NRG1-1 attenuated the isoflurane-induced hippocampus-dependent cognitive impairment and the declines in the hippocampal NRG1, p-ErbB4/ErbB4, parvalbumin, and glutamic acid decarboxylase 67. AG1478 inhibited the rescuing effects of NRG1-1. Conclusion: Disruption of NRG1-ErbB4 signaling in the parvalbumin-positive interneurons might, at least partially, contribute to the isoflurane-induced hippocampus-dependent cognitive impairment after exposure to isoflurane carried by 100% O-2 in aged mice. C1 [Li, Xiao-Min; Ji, Mu-Huo; Zhang, Guang-Fen; Qiu, Li-Li; Jia, Min; Yang, Jian-Jun] Nanjing Univ, Sch Med, Jinling Hosp, Dept Anesthesiol, Nanjing 210008, Jiangsu, Peoples R China. [Su, Fan] Shandong Med Univ Tradit Chinese Med, Affiliate Hosp, Dept Anesthesiol, Jinan, Peoples R China. [Gao, Jun] Nanjing Med Univ, Key Lab Neurodegenerat Dis Jiangsu Prov, Dept Neurobiol, Nanjing, Jiangsu, Peoples R China. [Gao, Jun] Nanjing Med Univ, Key Lab Neurodegenerat Dis Jiangsu Prov, Dept Pharmacol, Nanjing, Jiangsu, Peoples R China. [Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Charlestown, MA USA. RP Yang, JJ (reprint author), Jinling Hosp, Dept Anesthesiol, 305 East Zhongshan Rd, Nanjing 210002, Jiangsu, Peoples R China. EM yjyangjj@126.com FU National Natural Science Foundation of China, Beijing, China [81271216, 81222013]; Natural Science Foundation of Jiangsu Province, Nanjing, China [BK2012778]; National Institutes of Health, Bethesda, Maryland [R01 GM088801, R01 AG041274]; Cure Alzheimer's Fund, Wellesley, Massachusetts FX This work was supported by the grants from the National Natural Science Foundation of China, Beijing, China (Numbers 81271216 and 81222013) and the Natural Science Foundation of Jiangsu Province, Nanjing, China (Number BK2012778) and R01 GM088801 and R01 AG041274 from National Institutes of Health, Bethesda, Maryland, and Cure Alzheimer's Fund, Wellesley, Massachusetts. NR 41 TC 12 Z9 15 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2014 VL 121 IS 1 BP 79 EP 88 DI 10.1097/ALN.0000000000000191 PG 10 WC Anesthesiology SC Anesthesiology GA AJ5VQ UT WOS:000337758500013 PM 24589481 ER PT J AU Wagner, AJ AF Wagner, Andrew J. TI Patient-Derived Sarcoma Xenografts for Individual-Patient Selection of Chemotherapy-Ready for Prime Time? SO CANCER LA English DT Editorial Material ID RESISTANCE ASSAYS; AMERICAN-SOCIETY; SENSITIVITY; CHEMOSENSITIVITY C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol,Dept Med, Boston, MA 02215 USA. RP Wagner, AJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol,Dept Med, Boston, MA 02215 USA. EM awagner@partners.org NR 15 TC 2 Z9 2 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 2014 VL 120 IS 13 BP 1917 EP 1919 DI 10.1002/cncr.28694 PG 3 WC Oncology SC Oncology GA AJ5XJ UT WOS:000337763300005 PM 24706515 ER PT J AU Herrera, AF Crosby-Thompson, A Friedberg, JW Abel, GA Czuczman, MS Gordon, LI Kaminski, MS Millenson, MM Nademanee, AP Niland, JC Rodig, SJ Rodriguez, MA Zelenetz, AD LaCasce, AS AF Herrera, Alex F. Crosby-Thompson, Allison Friedberg, Jonathan W. Abel, Gregory A. Czuczman, Myron S. Gordon, Leo I. Kaminski, Mark S. Millenson, Michael M. Nademanee, Auayporn P. Niland, Joyce C. Rodig, Scott J. Rodriguez, Maria A. Zelenetz, Andrew D. LaCasce, Ann S. TI Comparison of Referring and Final Pathology for Patients With T-Cell Lymphoma in the National Comprehensive Cancer Network SO CANCER LA English DT Article DE lymphoma; T-cell lymphoma; diagnosis; outcomes research; pathology ID NON-HODGKINS-LYMPHOMA; BRENTUXIMAB VEDOTIN SGN-35; HIGH-DOSE CHEMOTHERAPY; CLASSIFICATION PROJECT; PHASE-II; TRANSPLANTATION; SURVIVAL AB BACKGROUND: T-cell lymphomas (TCLs) are uncommon in the United States. The accurate diagnosis of TCL is challenging and requires morphologic interpretation, immunophenotyping, and molecular techniques. The authors compared pathologic diagnoses at referring centers with diagnoses from expert hematopathology review to determine concordance rates and to characterize the usefulness of second-opinion pathology review for TCL. METHODS: Patients in the National Comprehensive Cancer Network non-Hodgkin lymphoma database with peripheral TCL, not otherwise specified (PTCL-NOS), angioimmunoblastic TCL (AITL), and anaplastic lymphoma kinase (ALK)-positive and ALK-negative anaplastic large cell lymphoma (ALCL) were eligible if they had prior tissue specimens examined at a referring institution. Pathologic concordance was evaluated using available pathology and diagnostic testing reports and provider progress notes. The etiology of discordance and the potential impact on treatment were examined. RESULTS: Among 131 eligible patients, 57 (44%) had concordant results, totaling 64% of the 89 patients who were referred with a final diagnosis. Thirty-two patients (24%) had discordant results, representing 36% of those who were referred with a final diagnosis. The rates of discordance among patients with of PTCL-NOS, AITL, ALK-negative ALCL, and ALK-positive ALCL were 19%, 33%, 34%, and 6%, respectively. In 14 patients (44% of discordant results), pathologic reclassification could have resulted in a different therapeutic strategy. Forty-two patients (32%) were referred for classification with a provisional diagnosis. CONCLUSIONS: In a large cohort of patients with TCL who were referred to National Comprehensive Cancer Network centers, the likelihood of a concordant final diagnosis at a referring institution was low. As current and future therapies target TCL subsets, these data suggest that patients with suspected TCLs would benefit from evaluation by an expert hematopathologist. (C) 2014 American Cancer Society. C1 [Herrera, Alex F.; Abel, Gregory A.; LaCasce, Ann S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Crosby-Thompson, Allison] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02215 USA. [Friedberg, Jonathan W.] Univ Rochester, James P Wilmot Canc Ctr, Dept Hematol & Oncol, Rochester, NY USA. [Czuczman, Myron S.] Roswell Pk Canc Inst, Dept Hematol & Oncol, Buffalo, NY 14263 USA. [Gordon, Leo I.] Northwestern Univ, Dept Hematol Oncol, Chicago, IL 60611 USA. [Kaminski, Mark S.] Univ Michigan, Ctr Comprehens Canc, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Millenson, Michael M.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Nademanee, Auayporn P.; Niland, Joyce C.] City Hope Canc Ctr, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA USA. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Rodriguez, Maria A.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, New York, NY 10021 USA. RP LaCasce, AS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM ann_lacasce@dfci.harvard.edu OI Gordon, Leo/0000-0003-1666-7064 FU Pfizer; Glaxo-Smith Kline; Amgen FX Dr. Rodriguez reports research funding from Pfizer, Glaxo-Smith Kline, and Amgen unrelated to the submitted work. NR 21 TC 7 Z9 7 U1 0 U2 5 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 2014 VL 120 IS 13 BP 1993 EP 1999 DI 10.1002/cncr.28676 PG 7 WC Oncology SC Oncology GA AJ5XJ UT WOS:000337763300014 PM 24706502 ER PT J AU Percac-Lima, S Lopez, L Ashburner, JM Green, AR Atlas, SJ AF Percac-Lima, Sanja Lopez, Lenny Ashburner, Jeffrey M. Green, Alexander R. Atlas, Steven J. TI The Longitudinal Impact of Patient Navigation on Equity in Colorectal Cancer Screening in a Large Primary Care Network SO CANCER LA English DT Article DE colorectal cancer screening; patient navigation; vulnerable populations; disparities ID RANDOMIZED-CONTROLLED-TRIAL; COMMUNITY-HEALTH CENTERS; AFRICAN-AMERICANS; CLINICAL-TRIAL; IMPROVE CARE; COLON-CANCER; COLONOSCOPY; DISPARITIES; INTERVENTIONS; MINORITIES AB BACKGROUND: The long-term effects of interventions to improve colorectal (CRC) screening in vulnerable populations are uncertain. The authors evaluated the impact of patient navigation (PN) on the equity of CRC prevention over a 5-year period. METHODS: A culturally tailored CRC screening PN program was implemented in 1 community health center (CHC) in 2007. In a primary care network, CRC screening rates from 2006 to 2010 among eligible patients from the CHC with PN were compared with the rates from other practices without PN. Multivariable logistic regression models for repeated measures were used to assess differences over time. RESULTS: Differences in CRC screening rates diminished among patients at the CHC with PN and at other practices between 2006 (49.2% vs 62.5%, respectively; P < .001) and 2010 (69.2% vs 73.6%, respectively; P < .001). The adjusted rate of increase over time was higher at the CHC versus other practices (5% vs 3.4% per year; P < .001). Among Latino patients at the CHC compared with other practices, lower CRC screening rates in 2006 (47.5% vs 52.1%, respectively; P = .02) were higher by 2010 (73.5% vs 67.3%, respectively; P < .001). Similar CRC screening rates among non-English speakers at the CHC and at other practices in 2006 (44.3% vs 44.7%, respectively; P = .79) were higher at the CHC by 2010 (70.6% vs 58.6%, respectively; P < .001). Adjusted screening rates increased more over time for Latino and non-English speakers at the CHC compared with other practices (both P < .001). CONCLUSIONS: A PN program increased CRC screening rates in a CHC and improved equity in vulnerable patients. Long-term funding of PN programs has the potential to reduce cancer screening disparities. (C) 2014 American Cancer Society. C1 [Percac-Lima, Sanja] Massachusetts Gen Hosp, Chelsea HealthCare Ctr, Chelsea, MA 02150 USA. [Percac-Lima, Sanja; Lopez, Lenny; Ashburner, Jeffrey M.; Green, Alexander R.; Atlas, Steven J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Lopez, Lenny; Green, Alexander R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Lopez, Lenny; Green, Alexander R.] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. RP Percac-Lima, S (reprint author), Massachusetts Gen Hosp, Chelsea HealthCare Ctr, 151 Everett Ave, Chelsea, MA 02150 USA. EM spercaclima@partners.org FU Clinical Innovation Award through Massachusetts General Hospital [CDC SIP 16]; Massachusetts Cancer Prevention Community Research Network; Trefler Foundation; Agency for Healthcare Research and Quality [AHRQ R18-HS018161] FX The patient navigator program was supported by a Clinical Innovation Award through Massachusetts General Hospital (CDC SIP 16), the Massachusetts Cancer Prevention Community Research Network, and the Trefler Foundation. Drs. Percac-Lima and Atlas were supported in part by a grant from the Agency for Healthcare Research and Quality (AHRQ R18-HS018161). NR 46 TC 13 Z9 13 U1 3 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 2014 VL 120 IS 13 BP 2025 EP 2031 DI 10.1002/cncr.28682 PG 7 WC Oncology SC Oncology GA AJ5XJ UT WOS:000337763300018 PM 24691564 ER PT J AU Sato, S Zhang, XK AF Sato, S. Zhang, X. K. TI The Friend leukaemia virus integration 1 (Fli-1) transcription factor affects lupus nephritis development by regulating inflammatory cell infiltration into the kidney SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE chemokines; chemotaxis; Fli-1; infiltration; lupus nephritis ID HUMAN CRESCENTIC GLOMERULONEPHRITIS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; REDUCES RENAL-DISEASE; ETS GENE FAMILY; PROLONGS SURVIVAL; MRL-FAS(LPR) MICE; EXPRESSION; ERYTHEMATOSUS; MEMBER; DEFICIENCY AB The transcription factor Friend leukaemia virus integration 1 (Fli-1) is implicated in the pathogenesis of systemic lupus erythematosus in both human patients and murine models of lupus. Murphy Roths large (MRL)/lpr mice and New Zealand mixed (NZM)2410 mice, murine models of lupus, with decreased expression of Fli-1 had significantly prolonged survival and reduced nephritis. Lupus nephritis is a major cause of mortality and morbidity in patients, and inflammatory cell infiltration plays a key role in the development of the disease. To study how the expression of Fli-1 affects the infiltration of inflammatory cells into the kidneys, we generated congenic enhanced green fluorescent protein (GFP) transgenic MRL/lpr mice. A significantly increased number of GFP-expressing inflammatory cells infiltrated the kidneys of wild-type MRL/lpr mice compared to Fli-1 heterozygous (Fli-1+/-) MRL/lpr mice after injection of GFP+ cells. Expression of inflammatory chemokine mRNA, including chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4 and CCL5, was significantly lower in the kidneys from Fli-1+/- MRL/lpr mice compared to wild-type littermates. Numbers of infiltrated cells into the kidneys correlate with expression levels of CCL2, CCL4 and CCL5, but not the titres of anti-dsDNA autoantibodies in these mice. Significantly increased inflammatory cells from wild-type MRL/lpr mice infiltrated into kidneys compared to the cells from Fli-1+/- MRL/lpr mice. The chemotaxis of inflammatory cells from Fli-1+/- MRL/lpr mice towards each chemokine was decreased significantly compared to inflammatory cells from wild-type MRL/lpr mice in the transwell migration assay in vitro. Our results indicate that Fli-1 affects lupus nephritis development by regulating the expression of chemokines in the kidney and the migration of inflammatory cells. C1 [Sato, S.; Zhang, X. K.] Ralph H Johnson Vet Affairs Med Ctr, Dept Med, Div Rheumatol & Immunol, Charleston, SC USA. [Zhang, X. K.] Ralph H Johnson Vet Affairs Med Ctr, Med Res Serv, Charleston, SC USA. RP Zhang, XK (reprint author), Med Univ S Carolina, Div Rheumatol & Immunol, 96 Jonathan Lucas St MSC637, Charleston, SC 29425 USA. EM zhangjo@musc.edu FU National Institutes of Health [AR056670]; Medical Research Service, Department of Veterans Affairs FX This work was supported by grants from the National Institutes of Health (AR056670 to X. Z.) and the Medical Research Service, Department of Veterans Affairs (to X. Z.). We would like to thank Ms Eva Karam and Ms Sarah Williams for their excellent technical support and Dr Mara Lennard Richard for critical review of the manuscript. We thank Dr M. Okabe (Osaka University, Japan) for providing enhanced GFP C57BL/6 mice. NR 38 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2014 VL 177 IS 1 BP 102 EP 109 DI 10.1111/cei.12310 PG 8 WC Immunology SC Immunology GA AJ3SW UT WOS:000337588700011 PM 24580413 ER PT J AU Hedgire, SS Tabatabaei, S McDermott, S Feldman, A Dahl, DM Harisinghani, MG AF Hedgire, Sandeep S. Tabatabaei, Shahin McDermott, Shaunagh Feldman, Adam Dahl, Douglas M. Harisinghani, Mukesh G. TI Diversion ahead: imaging appearance of urinary diversions and reservoirs SO CLINICAL IMAGING LA English DT Review DE Urinary diversion; Heal conduit; Continent urinary diversions; Neobladder ID ORTHOTOPIC ILEAL NEOBLADDER; RADICAL CYSTECTOMY; FOLLOW-UP; COMPLICATIONS; ANASTOMOSIS; UROGRAPHY; BLADDER; TRACT; CT AB The imaging appearance of urinary diversion is determined by the indication and type of surgical procedure performed. These patients often undergo an imaging follow-up to detect complications or recurrence. Understanding the postoperative anatomy and early detection of complications are keys to adept interpretation of radiological evaluation of urinary reservoirs. The purpose of following review is to offer a brief account of commonly used surgical techniques, relevant anatomy, and concise overview of the imaging techniques for evaluation of the urinary diversions and features of their complications. (C) 2014 Elsevier Inc. All rights reserved. C1 [Hedgire, Sandeep S.; McDermott, Shaunagh; Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Tabatabaei, Shahin; Feldman, Adam; Dahl, Douglas M.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Hedgire, SS (reprint author), Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. EM Hedgire.Sandeep@mgh.harvard.edu NR 26 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 0899-7071 EI 1873-4499 J9 CLIN IMAG JI Clin. Imaging PD JUL-AUG PY 2014 VL 38 IS 4 BP 418 EP 427 DI 10.1016/j.clinimag.2014.01.017 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4KH UT WOS:000337644600006 PM 24602415 ER PT J AU Butros, SR Shenoy-Bhangle, A Mueller, PR Arellano, RS AF Butros, Selim R. Shenoy-Bhangle, Anuradha Mueller, Peter R. Arellano, Ronald S. TI Radiofrequency ablation of intrahepatic cholangiocarcinoma: feasability, local tumor control, and long-term outcome SO CLINICAL IMAGING LA English DT Article DE Radiofrequency ablation; Thermal ablation; Cholangiocarcinoma; Liver tumor ID SMALL HEPATOCELLULAR-CARCINOMA; MANAGEMENT; MORTALITY; RESECTION; RATES AB A retrospective analysis of patients who underwent radiofrequency ablation (RFA) of intrahepatic cholangiocarcinoma (IHCC) was performed. Seven patients with 9 tumors underwent RFA. The mean tumor size was 2.4 cm (range=1.3-3.3 cm). RFA achieved technique effectiveness and local tumor control in 89% (8/9 tumors) of the patients respectively, with a mean overall survival of 38.5 months (range=12-69 months). To conclude, RFA was effective in achieving local tumor control and may offer a therapeutic option for patients with recurrent or primary IHCC. (C) 2014 Elsevier Inc. All rights reserved. C1 [Butros, Selim R.; Shenoy-Bhangle, Anuradha; Mueller, Peter R.; Arellano, Ronald S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Butros, SR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 32 Fruit St, Boston, MA 02114 USA. EM sbutros@partners.org NR 24 TC 10 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-7071 EI 1873-4499 J9 CLIN IMAG JI Clin. Imaging PD JUL-AUG PY 2014 VL 38 IS 4 BP 490 EP 494 DI 10.1016/j.clinimag.2014.01.013 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4KH UT WOS:000337644600018 PM 24637151 ER PT J AU Callegari, LS Zhao, XH Nelson, KM Lehavot, K Bradley, KA Borrero, S AF Callegari, Lisa S. Zhao, Xinhua Nelson, Karin M. Lehavot, Keren Bradley, Katharine A. Borrero, Sonya TI Associations of mental illness and substance use disorders with prescription contraception use among women veterans SO CONTRACEPTION LA English DT Article DE Contraceptive behavior; Veterans health; Mental disorder; Alcohol-related disorders; Substance-related disorders; Highly effective reversible contraception ID POSTTRAUMATIC-STRESS-DISORDER; UNITED-STATES; MINORITY WOMEN; BIRTH-WEIGHT; CONDOM USE; DRUG-USE; DEPRESSION; PREGNANCY; ALCOHOL; HEALTH AB Objective: To investigate whether mental illness and substance use disorder (SUD) are associated with having a prescription contraceptive method among women veterans. Study design: We conducted a retrospective analysis of National Veterans Administration (VA) administrative and clinical data for women veterans aged 18-45 years who made at least one primary care visit in 2008. We assessed associations between mental illness (depression, posttraumatic stress disorder, anxiety, bipolar disorder, schizophrenia and adjustment disorder) and SUD (drug/alcohol use disorder) with having a prescription contraceptive method from VA (pill, patch, ring, injection, implant and intrauterine device) using multivariable logistic regression with random effects for VA facility, adjusting for confounders. Results: Among 94,115 reproductive aged women, 36.5% had mental illness only, 0.6% had SUD only, 5.3% had both mental illness and SUD and 57.7% had neither diagnosis. In these groups, 22.1%, 14.6%, 18.2% and 17.7% (p<0.001), respectively, had documentation in 2008 of prescription contraception. After adjusting for potential confounders, women with mental illness only were as likely as women with neither diagnosis to have a prescription method and were more likely to use a highly effective prescription method (implant or intrauterine device) if using contraception [adjusted odds ratio (aOR) 1.17, 95% confidence interval (CI) = 1.08-1.27]. Women with SUD (with or without mental illness) were significantly less likely to have a prescription method than women with neither diagnosis (aOR 0.73, 95% CI = 0.57-0.95 and aOR 0.79, 95% CI = 0.73-0.86, respectively). Conclusion: Women veterans with SUD are less likely to have prescription contraception compared to other women, which may increase their risk of unintended pregnancy. Published by Elsevier Inc. C1 [Callegari, Lisa S.; Nelson, Karin M.; Bradley, Katharine A.] Dept Vet Affairs VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Callegari, Lisa S.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Zhao, Xinhua; Borrero, Sonya] VA Pittsburgh Hlth Care Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Zhao, Xinhua; Borrero, Sonya] VA Pittsburgh Hlth Care Syst, Ctr Hlth Equ Res & Promot, Seattle, WA USA. [Nelson, Karin M.; Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Lehavot, Keren] VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Lehavot, Keren] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Bradley, Katharine A.] Grp Hlth Res Inst, Seattle, WA USA. [Borrero, Sonya] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Callegari, LS (reprint author), Puget Sound Vet Adm Univ Washington, Seattle HSR&D Ctr, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM lcallega@uw.edu FU Department of Veterans Affairs, Veteran Health Administration, Office of Research and Development, VISN 4 CHERP Pilot Project Award; VA Health Services Research and Development Postdoctoral Fellowship [TPM 61-041]; VA Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment FX This study was supported by the Department of Veterans Affairs, Veteran Health Administration, Office of Research and Development, VISN 4 CHERP Pilot Project Award (PI: Sonya Borrero). L.S.C. was supported by a VA Health Services Research and Development Postdoctoral Fellowship (TPM 61-041). K.L. was supported by the VA Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment. NR 37 TC 4 Z9 4 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD JUL PY 2014 VL 90 IS 1 BP 97 EP 103 DI 10.1016/j.contraception.2014.02.028 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AJ0HO UT WOS:000337331600017 PM 24731860 ER PT J AU Safdar, N O'Horo, JC Ghufran, A Bearden, A Didier, ME Chateau, D Maki, DG AF Safdar, Nasia O'Horo, John C. Ghufran, Aiman Bearden, Allison Didier, Maria Eugenia Chateau, Dan Maki, Dennis G. TI Chlorhexidine-Impregnated Dressing for Prevention of Catheter-Related Bloodstream Infection: A Meta-Analysis SO CRITICAL CARE MEDICINE LA English DT Article DE catheter-related infection; chlorhexidine; nosocomial infection ID RANDOMIZED CONTROLLED-TRIAL; CRITICALLY-ILL ADULTS; INTENSIVE-CARE-UNIT; RESISTANT STAPHYLOCOCCUS-AUREUS; CENTRAL VENOUS CATHETERS; DISEASES SOCIETY; POVIDONE-IODINE; IN-VITRO; GUIDELINES; COLONIZATION AB Objective: To assess the efficacy of a chlorhexidine-impregnated dressing for prevention of central venous catheter-related colonization and catheter-related bloodstream infection using meta-analysis. Data Sources: Multiple computerized database searches supplemented by manual searches including relevant conference proceedings. Study Selection: Randomized controlled trials evaluating the efficacy of a chlorhexidine-impregnated dressing compared with conventional dressings for prevention of catheter colonization and catheter-related bloodstream infection. Data Extraction: Data were extracted on patient and catheter characteristics and outcomes. Data Synthesis: Nine randomized controlled trials met the inclusion criteria. Use of a chlorhexidine-impregnated dressing resulted in a reduced prevalence of catheter-related bloodstream infection (random effects relative risk, 0.60; 95% CI, 0.41-0.88, p = 0.009). The prevalence of catheter colonization was also markedly reduced in the chlorhexidine-impregnated dressing group (random effects relative risk, 0.52; 95% CI, 0.43-0.64; p < 0.001). There was significant benefit for prevention of catheter colonization and catheter-related bloodstream infection, including arterial catheters used for hemodynamic monitoring. Other than in low birth weight infants, adverse effects were rare and minor. Conclusions: Our analysis shows that a chlorhexidine-impregnated dressing is beneficial in preventing catheter colonization and, more importantly, catheter-related bloodstream infection and warrants routine use in patients at high risk of catheter-related bloodstream infection and central venous catheter or arterial catheter colonization. C1 [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Safdar, Nasia; Ghufran, Aiman; Bearden, Allison; Didier, Maria Eugenia; Maki, Dennis G.] Univ Wisconsin Sch Med & Publ Hlth, Infect Dis Sect, Dept Med, Madison, WI USA. [O'Horo, John C.] Mayo Clin, Div Pulm & Crit Care Med, Dept Med, Rochester, MN USA. [Chateau, Dan] Univ Manitoba, Dept Community Hlth Sci, Biostat Consulting Unit, Winnipeg, MB R3T 2N2, Canada. RP Safdar, N (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu RI O'Horo, John/N-8681-2013 OI O'Horo, John/0000-0002-0880-4498 FU National Institute on Aging, National Institutes of Health [AG40669]; VA MERIT grant FX Dr. Safdar is supported by grant number AG40669 from the National Institute on Aging, National Institutes of Health, and a VA MERIT grant. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 62 TC 21 Z9 22 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2014 VL 42 IS 7 BP 1703 EP 1713 DI 10.1097/CCM.0000000000000319 PG 11 WC Critical Care Medicine SC General & Internal Medicine GA AJ5DU UT WOS:000337703000035 PM 24674924 ER PT J AU Wiener-Kronish, J Nozari, A AF Wiener-Kronish, Jeanine Nozari, Ala TI Blood Transfusions and Infected Lungs-Worse Outcomes? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE lung infections; sepsis; transfusion; transfusion-related acute lung injury ID INJURY C1 [Wiener-Kronish, Jeanine; Nozari, Ala] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Wiener-Kronish, J (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. FU NIGMS NIH HHS [T32 GM008440] NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2014 VL 42 IS 7 BP 1739 EP 1740 DI 10.1097/CCM.0000000000000362 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA AJ5DU UT WOS:000337703000047 PM 24933055 ER PT J AU Okazaki, T Liang, F Li, T Lemaire, C Danialou, G Shoelson, SE Petrof, BJ AF Okazaki, Tatsuma Liang, Feng Li, Tong Lemaire, Christian Danialou, Gawiyou Shoelson, Steven E. Petrof, Basil J. TI Muscle-Specific Inhibition of the Classical Nuclear Factor-kappa B Pathway Is Protective Against Diaphragmatic Weakness in Murine Endotoxemia SO CRITICAL CARE MEDICINE LA English DT Article DE cytokines; diaphragm; muscle weakness; nuclear factor-B; respiratory failure; sepsis ID GROWTH-FACTOR PRODUCTION; NITRIC-OXIDE SYNTHASE; INTENSIVE-CARE-UNIT; SKELETAL-MUSCLE; MECHANICAL VENTILATION; PULMONARY INFLAMMATION; CONTRACTILE FUNCTION; MESSENGER-RNA; TNF-ALPHA; ACTIVATION AB Objective: Diaphragmatic weakness and acute respiratory failure are common in sepsis. Nuclear factor-B acts as a general coordinator of the systemic inflammatory response, but its role within the diaphragm itself during sepsis is unknown. We investigated the potential protective effect upon the diaphragm of inhibiting nuclear factor-B only within muscle fibers during acute endotoxemia. Design: Prospective study in experimental animals. Setting: University research laboratory. Interventions: Wild-type and transgenic (muscle-specific IB super-repressor) mice with skeletal muscle-specific inhibition of the classical nuclear factor-B pathway were subjected to acute endotoxemia. Muscle-specific ubiquitin ligases (muscle RING-finger protein 1 and atrogin-1), caspase-3 activity, inhibitor of apoptosis proteins, proinflammatory cytokines (interleukin-1, monocyte chemoattractant protein-1, and tumor necrosis factor-), and diaphragmatic contractility were evaluated after 24 hours. Measurements and Main Results: In wild-type mice, endotoxemia significantly increased proinflammatory cytokines (fold-change messenger RNA: interleukin-1 = 7.6, monocyte chemoattractant protein-1 = 15.3, and tumor necrosis factor- = 2.2) and proteolysis effectors (fold-change messenger RNA: muscle RING-finger protein 1 = 5.7, atrogin-1 = 2.8; caspase-3 activity elevated by 28%) in the diaphragm, while reducing its force-generating capacity by 38%. In nonendotoxemic muscle-specific IB super-repressor diaphragms, caspase-3 activity was unexpectedly increased by 40% above basal wild-type levels and inhibitors of apoptosis proteins were down-regulated, but force production remained normal. In muscle-specific IB super-repressor mice subjected to endotoxemia, proinflammatory cytokines, muscle RING-finger protein 1, and atrogin-1 were not significantly increased above their basal levels, and diaphragmatic weakness and further increases in caspase-3 activity were completely prevented. Conclusions: These results suggest that nuclear factor-B signaling within skeletal muscle fibers is a key pathway leading to diaphragmatic weakness during acute endotoxemia, most likely via effects on multiple inflammatory mediators. In addition, inhibition of nuclear factor-B signaling within diaphragm muscle fibers has complex effects on caspase-3 activation, which could have implications for the treatment of sepsis-induced diaphragmatic dysfunction. C1 [Okazaki, Tatsuma; Liang, Feng; Li, Tong; Lemaire, Christian; Petrof, Basil J.] McGill Univ, Meakins Christie Labs, Montreal, PQ H2X 2P2, Canada. [Okazaki, Tatsuma; Liang, Feng; Li, Tong; Lemaire, Christian; Petrof, Basil J.] McGill Univ, Div Resp, Montreal, PQ H2X 2P2, Canada. [Danialou, Gawiyou] Royal Mil Coll St Jean, St Jean, PQ, Canada. [Shoelson, Steven E.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Shoelson, Steven E.] Harvard Univ, Sch Med, Boston, MA USA. RP Petrof, BJ (reprint author), McGill Univ, Meakins Christie Labs, 3626 St Urbain St, Montreal, PQ H2X 2P2, Canada. EM basil.petrof@mcgill.ca FU McGill University Health Centre Research Institute; Japanese Ministry of Education and Science and Culture; Fonds de la recherche en sante du Quebec (Quebec Respiratory Health Network); Canadian Institutes of Health Research (CIHR); National Institutes of Health (NIH) [R01 DK51729]; NIH NIDDK; Takeda; CIHR; Genzyme FX Supported, in part, by McGill University Health Centre Research Institute.; Dr. Okazaki received grant support from the Japanese Ministry of Education and Science and Culture and Fonds de la recherche en sante du Quebec (Quebec Respiratory Health Network) and received support for article research from the Canadian Institutes of Health Research (CIHR). Dr. Shoelson served as board member for Catabasis Pharmaceutical, consulted for Catabasis Pharmaceutical, lectured for Merck, has Catabasis stock options, received support for travel from Merck, and received support for article research from the National Institutes of Health (NIH) (R01 DK51729). His institution received grant support from the NIH NIDDK and from Takeda. Dr. Petrof lectured for Genzyme and received support for article research from the CIHR. His institution received grant support from the CIHR and Genzyme and received support for travel from the CIHR. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 50 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2014 VL 42 IS 7 BP E501 EP E509 DI 10.1097/CCM.0000000000000407 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA AJ5DU UT WOS:000337703000002 PM 24933061 ER PT J AU Wellman, TJ Winkler, T Costa, ELV Musch, G Harris, RS Zheng, H Venegas, JG Melo, MFV AF Wellman, Tyler J. Winkler, Tilo Costa, Eduardo L. V. Musch, Guido Harris, R. Scott Zheng, Hui Venegas, Jose G. Melo, Marcos F. Vidal TI Effect of Local Tidal Lung Strain on Inflammation in Normal and Lipopolysaccharide-Exposed Sheep SO CRITICAL CARE MEDICINE LA English DT Article DE endotoxemia; lung inflammation; lung strain; mechanical ventilation; positron emission tomography; ventilator-induced lung injury ID RESPIRATORY-DISTRESS-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; MECHANICAL VENTILATION; PULMONARY INFLAMMATION; METABOLIC-ACTIVITY; PROTECTIVE-VENTILATION; REGIONAL VENTILATION; EPITHELIAL-CELLS; INJURY; VOLUMES AB Objectives: Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflammation in vivo during the early stages of lung injury in lungs with regional aeration heterogeneity comparable to that of humans and 2) determine how this strain-inflammation relationship is affected by endotoxemia. Design: Interventional animal study. Setting: Experimental laboratory and PET facility. Subjects: Eighteen 2- to 4-month-old sheep. Interventions: Three groups of sheep (n = 6) were mechanically ventilated to the same plateau pressure (30-32 cm H2O) with high-strain (V-T = 18.2 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (V-T = 18.4 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (V-T = 8.1 +/- 0.2 mL/kg, positive end-expiratory pressure = 17 +/- 3 cm H2O). At baseline, we acquired respiratory-gated PET scans of inhaled (NN)-N-13 to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [F-18]fluoro-2-deoxy-d-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest. Measurements and Main Results: Baseline regional tidal strain had a significant effect on [F-18]fluoro-2-deoxy-d-glucose net uptake rate K-i in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k(3) in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k(3)-tidal strain slope three-fold (p = 0.009), without significant lung edema. The low-strain lipopolysaccharide group showed lower baseline regional tidal strain (0.33 +/- 0.17) than high-strain (1.21 +/- 0.62; p < 0.001) or high-strain lipopolysaccharide (1.26 +/- 0.44; p < 0.001) and lower k(3) (p < 0.001) and K-i (p < 0.05) than high-strain lipopolysaccharide. Conclusions: Local inflammation develops proportionally to regional tidal strain during early lung injury. The regional inflammatory effect of strain is greatly amplified by IV lipopolysaccharide. Tidal strain enhances local [F-18]fluoro-2-deoxy-d-glucose uptake primarily by increasing the rate of intracellular [F-18]fluoro-2-deoxy-d-glucose phosphorylation. C1 [Wellman, Tyler J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Wellman, Tyler J.; Winkler, Tilo; Costa, Eduardo L. V.; Musch, Guido; Venegas, Jose G.; Melo, Marcos F. Vidal] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Wellman, Tyler J.; Winkler, Tilo; Costa, Eduardo L. V.; Musch, Guido; Harris, R. Scott; Zheng, Hui; Venegas, Jose G.; Melo, Marcos F. Vidal] Harvard Univ, Sch Med, Boston, MA USA. [Harris, R. Scott] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Melo, MFV (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM mvidalmelo@partners.org RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 FU National Heart, Lung, and Blood Institute [R01-HL086827, R01-HL121228]; National Institutes of Health (NIH); NIH [R01HL094639]; NIH (RO1 grant) FX Supported by grants R01-HL086827 and R01-HL121228 from the National Heart, Lung, and Blood Institute.; Dr. Wellman received support for article research from the National Institutes of Health (NIH). Dr. Winkler has a patent and received support for article research from the NIH. Dr. Musch received support for article research from the NIH. His institution received grant support from the NIH (R01HL094639). Dr. Venegas received support for article research from the NIH. His institution received grant support. Dr. Vidal Melo has a patent and received support for article research from the NIH. His institution received grant support from the NIH (RO1 grant as listed in the article). The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 49 TC 23 Z9 23 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2014 VL 42 IS 7 BP E491 EP E500 DI 10.1097/CCM.0000000000000346 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA AJ5DU UT WOS:000337703000001 PM 24758890 ER PT J AU Cefalu, WT Boulton, AJM Tamborlane, WV Moses, RG LeRoith, D Greene, EL Hu, FB Bakris, G Wylie-Rosett, J Rosenstock, J Weinger, K Blonde, L de Groot, M Riddle, MC Henry, RR Golden, SH Rich, S Reynolds, L AF Cefalu, William T. Boulton, Andrew J. M. Tamborlane, William V. Moses, Robert G. LeRoith, Derek Greene, Eddie L. Hu, Frank B. Bakris, George Wylie-Rosett, Judith Rosenstock, Julio Weinger, Katie Blonde, Lawrence de Groot, Mary Riddle, Matthew C. Henry, Robert R. Golden, Sherita Hill Rich, Stephen Reynolds, Lyn TI Status of Diabetes Care: "It Just Doesn't Get Any Better ... or Does It?" SO DIABETES CARE LA English DT Article ID LOOP INSULIN DELIVERY; ANTI-VEGF THERAPY; ARTIFICIAL PANCREAS; DIETARY SUGAR; BODY-WEIGHT; LIFE-STYLE; PREVENTION; METAANALYSIS; RISK; INTERVENTIONS C1 [Cefalu, William T.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70803 USA. [Boulton, Andrew J. M.] Univ Manchester, Manchester Diabet Ctr, Manchester, Lancs, England. [Tamborlane, William V.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Moses, Robert G.] ISLHD, Wollongong, NSW, Australia. [LeRoith, Derek] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY USA. [Greene, Eddie L.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bakris, George] Univ Chicago Med, ASH Comprehens Hypertens Ctr, Dept Med, Div Endocrinol Diabet & Metab, Chicago, IL USA. [Wylie-Rosett, Judith] Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. [Rosenstock, Julio] Med City, Dallas Diabet & Endocrine Ctr, Dallas, TX USA. [Weinger, Katie] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Blonde, Lawrence] Ochsner Med Ctr, Dept Endocrinol Diabet & Metab, Ochsner Diabet Clin Res Unit, New Orleans, LA USA. [de Groot, Mary] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Riddle, Matthew C.] Oregon Hlth & Sci Univ, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97201 USA. [Henry, Robert R.] VA San Diego Healthcare Syst, San Diego, CA USA. [Golden, Sherita Hill] Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD USA. [Rich, Stephen] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Reynolds, Lyn] Amer Diabet Assoc, Indianapolis, IN USA. RP Cefalu, WT (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70803 USA. EM cefaluwt@pbrc.edu NR 41 TC 4 Z9 4 U1 3 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2014 VL 37 IS 7 BP 1782 EP 1785 DI 10.2337/dc14-1073 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ9HX UT WOS:000338020400008 PM 25093231 ER PT J AU Larkin, ME Barnie, A Braffett, BH Cleary, PA Diminick, L Harth, J Gatcomb, P Golden, E Lipps, J Lorenzi, G Mahony, C Nathan, DM AF Larkin, Mary E. Barnie, Annette Braffett, Barbara H. Cleary, Patricia A. Diminick, Lisa Harth, Judy Gatcomb, Patricia Golden, Ellen Lipps, Janie Lorenzi, Gayle Mahony, Carol Nathan, David M. CA Diabet Control Complications Trial TI Musculoskeletal Complications in Type 1 Diabetes SO DIABETES CARE LA English DT Article ID MELLITUS; TRIAL/EPIDEMIOLOGY; INTERVENTIONS; FLUORESCENCE; DISORDERS; GLYCATION; PRODUCTS; SHOULDER; TRIAL AB OBJECTIVE The development of periarticular thickening of skin on the hands and limited joint mobility (cheiroarthropathy) is associated with diabetes and can lead to significant disability. The objective of this study was to describe the prevalence of cheiroarthropathy in the well-characterized Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort and examine associated risk factors, microvascular complications, and the effect of former DCCT therapy (intensive [INT] vs. conventional [CONV]) on its development. RESEARCH DESIGN AND METHODS This cross-sectional analysis was performed in 1,217 participants (95% of the active cohort) in EDIC years 18/19 after an average of 24 years of follow-up. Cheiroarthropathy-defined as the presence of any one of the following: adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, Dupuytren's contracture, or a positive prayer sign-was assessed using a targeted medical history and standardized physical examination. A self-administered questionnaire (Disabilities of the Arm, Shoulder and Hand [DASH]) assessed functional disability. RESULTS Cheiroarthropathy was present in 66% of subjects (64% of the INT group and 68% of the CONV group; P = 0.1640) and was associated with age, sex, diabetes duration, skin intrinsic fluorescence, HbA(1c), neuropathy, and retinopathy (P < 0.005 for each). DASH functional disability scores were worse among subjects with cheiroarthropathy (P < 0.0001). CONCLUSIONS Cheiroarthropathy is common in people with type 1 diabetes of long duration (similar to 30 years) and is related to longer duration and higher levels of glycemia. Clinicians should include cheiroarthropathy in their routine history and physical examination of patients with type 1 diabetes because it causes clinically significant functional disability. C1 [Larkin, Mary E.; Mahony, Carol; Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02163 USA. [Barnie, Annette] Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Braffett, Barbara H.; Cleary, Patricia A.; Diminick, Lisa] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Harth, Judy] Univ Western Ontario, London, ON, Canada. [Gatcomb, Patricia] Yale Univ, Sch Med, New Haven, CT USA. [Golden, Ellen] Joslin Diabet Ctr, Boston, MA 02215 USA. [Lipps, Janie] Vanderbilt Univ, Div Diabet Endocrinol & Metab, Nashville, TN 37235 USA. [Lorenzi, Gayle] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Larkin, ME (reprint author), Harvard Univ, Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02163 USA. EM mlarkin1@partners.org FU Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK-094176, U01-DK-094157]; National Eye Institute, the National Institute of Neurological Disorders and Stroke; Genetic Clinical Research Centers Program; Clinical and Translational Science Center Awards Program, Bethesda, MD FX The DCCT/EDIC was supported by U01 Cooperative Agreement grants (1982-93, 2011-2016) and contracts (1982-2011) with the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant nos. U01-DK-094176 and U01-DK-094157), and through support from the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the Genetic Clinical Research Centers Program (1993-2007), and the Clinical and Translational Science Center Awards Program (2006 to the present), Bethesda, MD. NR 21 TC 9 Z9 10 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2014 VL 37 IS 7 BP 1863 EP 1869 DI 10.2337/dc13-2361 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ9HX UT WOS:000338020400019 PM 24722493 ER PT J AU DePaoli, AM Higgins, LS Henry, RR Mantzoros, C Dunn, FL AF DePaoli, Alex M. Higgins, Linda S. Henry, Robert R. Mantzoros, Christos Dunn, Fredrick L. CA INT131-007 Study Grp TI Can a Selective PPAR gamma Modulator Improve Glycemic Control in Patients With Type 2 Diabetes With Fewer Side Effects Compared With Pioglitazone? SO DIABETES CARE LA English DT Article ID CONGESTIVE-HEART-FAILURE; ROSIGLITAZONE; INT131; THIAZOLIDINEDIONES; MONOTHERAPY; AGONISTS; DEATH AB OBJECTIVE INT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferator-activated receptor gamma (PPAR gamma) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPAR gamma agonists. This placebo-controlled study compared the efficacy and side effects of INT131 besylate versus 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a 24-week randomized, double-blind, placebo-and active-controlled study of 0.5-3.0 mg INT131 versus 45 mg pioglitazone or placebo daily in 367 subjects with T2D on sulfonylurea or sulfonylurea plus metformin. The primary efficacy analysis was the comparison of change from baseline to week 24 in hemoglobin A(1c) (HbA(1c)) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema. RESULTS INT131 had a steep dose response for efficacy as measured by changes in HbA(1c). After 24 weeks' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA(1c) -0.3 +/- 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA(1c) -1.1 +/- 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA(1c) -0.9 +/- 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA(1c) 0.8 +/- 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemo-dilution than observed with 45 mg pioglitazone. CONCLUSIONS INT131 demonstrated dose-dependent reductions in HbA(1c), equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design. C1 [DePaoli, Alex M.; Higgins, Linda S.] InteKrin Therapeut Inc, Los Altos, CA USA. [Henry, Robert R.] VA San Diego Healthcare Syst, Ctr Metab Res, San Diego, CA USA. [Henry, Robert R.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Mantzoros, Christos] Boston VA Healthcare Syst, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Mantzoros, Christos] Harvard Univ, Sch Med, Boston, MA USA. [Dunn, Fredrick L.] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA. [Dunn, Fredrick L.] VA North Texas Healthcare Syst, Dallas, TX USA. RP Dunn, FL (reprint author), Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA. EM fredrick.dunn@utsouthwestern.edu FU Department of Veteran Affairs; VA San Diego Healthcare System FX R.R.H. was supported by the Department of Veteran Affairs and VA San Diego Healthcare System. NR 24 TC 14 Z9 14 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2014 VL 37 IS 7 BP 1918 EP 1923 DI 10.2337/dc13-2480 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ9HX UT WOS:000338020400026 PM 24722496 ER PT J AU Chiang, JL Kirkman, MS Laffel, LMB Peters, AL AF Chiang, Jane L. Kirkman, M. Sue Laffel, Lori M. B. Peters, Anne L. TI Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association SO DIABETES CARE LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; EXCHANGE CLINIC REGISTRY; CELIAC-DISEASE; MICROVASCULAR COMPLICATIONS; PRECONCEPTION CARE; GLYCEMIC CONTROL; INSULIN THERAPY; YOUNG-CHILDREN; SUBCLINICAL HYPOTHYROIDISM; CONGENITAL-ANOMALIES C1 [Chiang, Jane L.] Amer Diabet Assoc, Alexandria, VA 22311 USA. [Kirkman, M. Sue] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Laffel, Lori M. B.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Laffel, Lori M. B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Peters, Anne L.] Univ So Calif, Keck Sch Med, Dept Endocrinol, Los Angeles, CA 90033 USA. RP Chiang, JL (reprint author), Amer Diabet Assoc, Alexandria, VA 22311 USA. EM jchiang@diabetes.org FU Novo Nordisk; Bayer Diabetes Care; Medtronic MiniMed Foundation FX M.S.K. received research support from Novo Nordisk (to the University of North Carolina) for a study of an investigational drug for type 1 diabetes. In 2013-2014, L. M. B. L. received grant support from Bayer Diabetes Care; served as a consultant/advisory board member for Bristol-Myers Squibb/AstraZeneca, Sanofi, Novo Nordisk, and Boehringer Ingelheim; and served as a consultant for Johnson & Johnson, LifeScan/Animas, Lilly, Menarini, and Dexcom. In the past year, A. L. P. consulted with Abbott Diabetes Care, BD, Janssen, Lilly, Medscape, Medtronic MiniMed, Novo Nordisk, Sanofi, and Takeda; has been on the speaker's bureau for Bristol-Myers Squibb/AstraZeneca and Novo Nordisk; and received grant funding from the Medtronic MiniMed Foundation. No other potential conflicts of interest relevant to this article were reported. NR 108 TC 134 Z9 143 U1 7 U2 28 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2014 VL 37 IS 7 BP 2034 EP 2054 DI 10.2337/dc14-1140 PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ9HX UT WOS:000338020400043 PM 24935775 ER PT J AU Bonner-Weir, S In't Veld, PA Weir, GC AF Bonner-Weir, S. In't Veld, P. A. Weir, G. C. TI Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies SO DIABETES OBESITY & METABOLISM LA English DT Article DE incretin therapy; islets; type 2 diabetes ID TYPE-2 DIABETES-MELLITUS; ISLET PATHOLOGY; HUMANS; EXPANSION; TUMORS AB A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including 'a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by alpha-cell hyperplasia with the potential for evolution into neuroendocrine tumours'. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major concerns with regard to patient safety. We reassessed both the clinical case information and virtual microscopy images of the same 34 cases that were used in the Butler study as well as Network for Pancreatic Organ Donation (nPOD) cases that were not included. Whereas we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in the Butler paper have serious methodological deficiencies that preclude any meaningful conclusions. C1 [Bonner-Weir, S.; Weir, G. C.] Harvard Univ, Sch Med, Dept Med, Joslin Diabet Ctr, Boston, MA USA. [In't Veld, P. A.] Vrije Univ Brussel, Diabet Res Ctr, Dept Pathol, Brussels, Belgium. [In't Veld, P. A.] Vrije Univ Brussel, JDRF Ctr Beta Cell Therapy Diabet, Brussels, Belgium. RP Bonner-Weir, S (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM susan.bonner-weir@joslin.harvard.edu FU JDRF FX This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF, Organ Procurement Organisations (OPO) partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php. This biobank is an incredible resource to the scientific world. NR 20 TC 30 Z9 30 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 EI 1463-1326 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD JUL PY 2014 VL 16 IS 7 BP 661 EP 666 DI 10.1111/dom.12257 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ9ES UT WOS:000338010800010 PM 24400596 ER PT J AU Mezza, T Kulkarni, RN AF Mezza, Teresa Kulkarni, Rohit N. TI The regulation of pre- and post-maturational plasticity of mammalian islet cell mass SO DIABETOLOGIA LA English DT Review DE Ageing; Alpha cell plasticity; Beta cell mass; Beta cell maturation; Microbiome; Review ID PANCREATIC BETA-CELL; GENOME-WIDE ASSOCIATION; 60-PERCENT PARTIAL-PANCREATECTOMY; TYPE-2 DIABETES-MELLITUS; ENDOCRINE PANCREAS; INSULIN-SECRETION; GROWTH-FACTOR; IN-VIVO; MOUSE PANCREAS; ALPHA-CELLS AB Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and age-dependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes. C1 [Mezza, Teresa; Kulkarni, Rohit N.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Mezza, Teresa; Kulkarni, Rohit N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Mezza, Teresa] Univ Cattolica Sacro Cuore, Rome, Italy. RP Kulkarni, RN (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM Rohit.Kulkarni@joslin.harvard.edu OI Mezza, Teresa/0000-0001-5407-9576 FU National Institutes of Health [RO1 DK67536, RO1 DK055523]; Juvenile Diabetes Research Foundation; European Association; Societa Italiana di Diabetologia; European Society FX RNK acknowledges support from National Institutes of Health Grants RO1 DK67536, RO1 DK055523 and a grant from the Juvenile Diabetes Research Foundation.; TM acknowledges support from Reynolds Travel Fellowship by European Association for the Study of Diabetes and Fellowship Prize by the Societa Italiana di Diabetologia and the European Society for Clinical Nutrition and Metabolism. NR 148 TC 13 Z9 13 U1 0 U2 7 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 2014 VL 57 IS 7 BP 1291 EP 1303 DI 10.1007/s00125-014-3251-7 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ2OZ UT WOS:000337498700005 PM 24824733 ER PT J AU Yan, M Dong, ZM Zhao, F Chauncey, T Deauna-Limayo, D Wang-Rodriguez, J Liu, DY Wang, HY Pilz, R AF Yan, Min Dong, Zhaoming Zhao, Frank Chauncey, Thomas Deauna-Limayo, Delva Wang-Rodriguez, Jessica Liu, Dayu Wang, Huan-You Pilz, Renate TI CD20-positive plasmablastic lymphoma with excellent response to bortezomib combined with rituximab SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE plasmablastic lymphoma; CD20; CD138; bortezomib; rituximab; lymphoma ID CHEMOTHERAPY AB As a distinct type of aggressive mature large B-cell lymphoma, plasmablastic lymphoma (PBL) poses diagnostic and treatment challenges. PBL is distinguished from other B-cell lymphomas by the presence of plasmacytic differentiation markers such as CD38, CD138, and MUM1. Clinically, PBLs from oral and extra-oral sites are rapidly progressive tumors with frequent relapse after treatment with standard diffuse large B-cell lymphoma regimens. Here, we report a near-complete response of one patient with relapsed PBL following treatment with a non-cytotoxic regimen containing bortezomib, rituximab, and dexamethasone. C1 [Yan, Min; Zhao, Frank; Wang-Rodriguez, Jessica; Wang, Huan-You; Pilz, Renate] Univ Calif San Diego Hlth Syst, Moores Canc Ctr, La Jolla, CA 92093 USA. [Dong, Zhaoming; Chauncey, Thomas] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Deauna-Limayo, Delva] VA Hosp Southern Nevada, North Las Vegas, NV USA. [Liu, Dayu] Shandong Univ, Qilu Hosp, Jinan 250100, Peoples R China. RP Yan, M (reprint author), Univ Calif San Diego Hlth Syst, Moores Canc Ctr, 3855 Hlth Sci Dr,Mc 0829, La Jolla, CA 92093 USA. EM M5yan@ucsd.edu; Rpilz@ucsd.edu NR 11 TC 11 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-4441 EI 1600-0609 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD JUL PY 2014 VL 93 IS 1 BP 77 EP 80 DI 10.1111/ejh.12286 PG 4 WC Hematology SC Hematology GA AJ4SP UT WOS:000337666400011 PM 24528507 ER PT J AU Czerwonka, L Freeman, J McIver, B Randolph, GW Shah, JP Shaha, AR Sherman, SI Tuttle, RM Witterick, IJ AF Czerwonka, Lukasz Freeman, Jeremy McIver, Bryan Randolph, Gregory W. Shah, Jatin P. Shaha, Ashok R. Sherman, Steven I. Tuttle, R. Michael Witterick, Ian J. TI Summary of proceedings of the second World Congress on Thyroid Cancer SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE thyroid cancer; ultrasound; molecular testing; observation; personalized medicine ID RECURRENT LARYNGEAL NERVE; NEEDLE-ASPIRATION BIOPSY; CERVICAL LYMPH-NODES; DIAGNOSTIC TERMINOLOGY; PRACTICE GUIDELINE; 60-YEAR PERIOD; NODULES; MICROCARCINOMA; MANAGEMENT; ABLATION AB The second World Congress on Thyroid Cancer was held from July 10 to July 14, 2013, in Toronto, Canada. Its purpose was to provide a platform for the multidisciplinary discussion on research, education, and patient management of thyroid malignancy. Herein, we summarize the latest major trends and controversies within the field of thyroid oncology as discussed in the Congress including the use of ultrasound, standardization of cytology, role of molecular testing, treatment options for small recurrence including ablation and observation, management of recurrent laryngeal nerve injury, importance of identification of the external branch of the superior laryngeal nerve, role of minimally invasive thyroid surgery, trends in radioactive iodine treatment, advancements in targeted agents, and the importance of personalizing treatment to individual patients. (C) 2014 Wiley Periodicals, Inc. C1 [Czerwonka, Lukasz; Freeman, Jeremy; Witterick, Ian J.] Mt Sinai Hosp, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5G 1X5, Canada. [McIver, Bryan] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Endocrinol, Tampa, FL 33682 USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Shah, Jatin P.; Shaha, Ashok R.] Mem Sloan Kettering Canc Ctr, Dept Head & Neck Oncol, New York, NY 10021 USA. [Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. [Tuttle, R. Michael] Mem Sloan Kettering Canc Ctr, Dept Med, Serv Endocrinol, New York, NY 10021 USA. RP Freeman, J (reprint author), Mt Sinai Hosp, Dept Otolaryngol Head & Neck Surg, 600 Univ Ave,Suite 401, Toronto, ON M5G 1X5, Canada. EM JFreeman@mtsinai.on.ca OI Sherman, Steven/0000-0002-3079-5153; Shah, Jatin/0000-0002-6444-6592 NR 33 TC 1 Z9 1 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD JUL PY 2014 VL 36 IS 7 BP 917 EP 920 DI 10.1002/hed.23631 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AJ4CU UT WOS:000337618800003 PM 24677329 ER PT J AU Brown, TI Hasselmo, ME Stern, CE AF Brown, Thackery I. Hasselmo, Michael E. Stern, Chantal E. TI A High-resolution study of hippocampal and medial temporal lobe correlates of spatial context and prospective overlapping route memory SO HIPPOCAMPUS LA English DT Review DE dentate gyrus; CA3; CA1; fMRI; navigation ID PATTERN SEPARATION; PARAHIPPOCAMPAL CORTEX; ENTORHINAL CORTEX; RHESUS-MONKEY; DENTATE GYRUS; CA3 SUBREGION; COMPUTATIONAL CONSTRAINTS; ANTERIOR HIPPOCAMPUS; ORBITOFRONTAL CORTEX; DOUBLE DISSOCIATION AB When navigating our world we often first plan or retrieve an ideal route to our goal, avoiding alternative paths that lead to other destinations. The medial temporal lobe (MTL) has been implicated in processing contextual information, sequence memory, and uniquely retrieving routes that overlap or cross paths. However, the identity of subregions of the hippocampus and neighboring cortex that support these functions in humans remains unclear. The present study used high-resolution functional magnetic resonance imaging (hr-fMRI) in humans to test whether the CA3/DG hippocampal subfield and parahippocampal cortex are important for processing spatial context and route retrieval, and whether the CA1 subfield facilitates prospective planning of mazes that must be distinguished from alternative overlapping routes. During hr-fMRI scanning, participants navigated virtual mazes that were well-learned from prior training while also learning new mazes. Some routes learned during scanning shared hallways with those learned during pre-scan training, requiring participants to select between alternative paths. Critically, each maze began with a distinct spatial contextual Cue period. Our analysis targeted activity from the Cue period, during which participants identified the current navigational episode, facilitating retrieval of upcoming route components and distinguishing mazes that overlap. Results demonstrated that multiple MTL regions were predominantly active for the contextual Cue period of the task, with specific regions of CA3/DG, parahippocampal cortex, and perirhinal cortex being consistently recruited across trials for Cue periods of both novel and familiar mazes. During early trials of the task, both CA3/DG and CA1 were more active for overlapping than non-overlapping Cue periods. Trial-by-trial Cue period responses in CA1 tracked subsequent overlapping maze performance across runs. Together, our findings provide novel insight into the contributions of MTL subfields to processing spatial context and route retrieval, and support a prominent role for CA1 in distinguishing overlapping episodes during navigational look-ahead periods. (c) 2014 Wiley Periodicals, Inc. C1 [Brown, Thackery I.; Hasselmo, Michael E.; Stern, Chantal E.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Brown, Thackery I.; Hasselmo, Michael E.; Stern, Chantal E.] Boston Univ, Ctr Memory & Brain, Boston, MA 02215 USA. [Brown, Thackery I.; Stern, Chantal E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Stern, CE (reprint author), Boston Univ, Ctr Memory & Brain, 617-353-1396,2 Cummington Mall, Boston, MA 02215 USA. EM chantal@bu.edu OI Hasselmo, Michael/0000-0002-9925-6377 FU National Institutes of Health; Office of Naval Research Multidisciplinary University Research Initiative [P50 MH094263, ONR MURI N00014-10-1-0936]; NIH NCRR Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; NCRR Biomedical Technology Program of the National Center for Research Resources [NIH S10RR021110, P41RR14075] FX Grant sponsors: National Institutes of Health grant and Office of Naval Research Multidisciplinary University Research Initiative grant to the Cognitive Neuroimaging Lab, Center for Memory and Brain, Boston University (Boston, MA); Grant numbers: P50 MH094263 and ONR MURI N00014-10-1-0936; Grant sponsors: NIH NCRR Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program and NCRR Biomedical Technology Program of the National Center for Research Resources; Grant numbers: NIH S10RR021110 and P41RR14075. NR 101 TC 10 Z9 10 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD JUL PY 2014 VL 24 IS 7 BP 819 EP 839 DI 10.1002/hipo.22273 PG 21 WC Neurosciences SC Neurosciences & Neurology GA AJ4TD UT WOS:000337668200010 PM 24659134 ER PT J AU Kim, JY Park, DY Kim, GH Jeon, TY Lauwers, GY AF Kim, Joo-Yeon Park, Do Youn Kim, Gwang Ha Jeon, Tae-Yong Lauwers, Gregory Y. TI Does clear cell carcinoma of stomach exist? Clinicopathological and prognostic significance of clear cell changes in gastric adenocarcinomas SO HISTOPATHOLOGY LA English DT Article DE adenocarcinoma; clear cell change; stomach; survival ID HEPATOCYTE NUCLEAR FACTOR-1-BETA; DISTINCT-HISTOLOGIC-TYPE; POOR-PROGNOSIS; EXPRESSION; HISTOGENESIS; RESISTANCE; URETHRA; OVARIAN; BLADDER AB Aims: In contrast to clear cell carcinomas developing in other organs (e. g. ovary and uterus), gastric adenocarcinomas with clear cell features are not well characterized. Methods and results: We evaluated a series of 762 gastric adenocarcinomas for the presence of clear cell changes; and investigated the nature of the changes using several histochemical and immunohistochemical markers, their association with various clinicopathological features, and their prognostic significance. Clear cell changes were observed in 8.5% (n = 65) of gastric cancers. Cases with clear cell changes (GCC) were associated significantly with older age, intestinal type histology, body/fundic location, greater depth of invasion, lymph node metastases and lymphovascular invasion. An increasing proportion of clear cell changes indicated a worsening prognosis, and was identified as an independent marker of poor prognosis using the Cox proportional hazard model (hazard ratio, 0.462; P = 0.003). Of 62 GCCs subjected to special staining, 35 cases (55.6%) displayed cytoplasmic accumulation of glycogen, while 21 (33.3%) contained mucin. GCCs showing glycogen accumulation expressed AFP, glypican-3 and CD10 more commonly than those with mucin, which commonly expressed Muc5AC and Muc6. Conclusion: Clear cell gastric adenocarcinoma is a unique subgroup of gastric cancer which, although heterogeneous, has a poor prognosis. C1 [Kim, Joo-Yeon; Park, Do Youn] Pusan Natl Univ Hosp, Dept Pathol, Pusan 602739, South Korea. [Kim, Joo-Yeon; Park, Do Youn; Kim, Gwang Ha; Jeon, Tae-Yong] Pusan Natl Univ, Sch Med, Pusan 602739, South Korea. [Kim, Joo-Yeon; Park, Do Youn; Kim, Gwang Ha; Jeon, Tae-Yong] Pusan Natl Univ Hosp, Biomed Res Inst, Pusan 602739, South Korea. [Kim, Gwang Ha] Pusan Natl Univ Hosp, Dept Internal Med, Pusan 602739, South Korea. [Jeon, Tae-Yong] Pusan Natl Univ Hosp, Dept Surg, Pusan 602739, South Korea. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Park, DY (reprint author), Pusan Natl Univ Hosp, Dept Pathol, 1-10 Ami Dong, Pusan 602739, South Korea. EM pdy220@pusan.ac.kr FU National R&D Program for Cancer Control, Ministry for Health, Welfare, and Family Affairs, Republic of Korea [0920050]; Ministry of Health, Welfare and Family Affairs FX This study was supported by a grant (0920050) from the National R&D Program for Cancer Control, Ministry for Health, Welfare, and Family Affairs, Republic of Korea. The biospecimens for this study were provided by the Pusan National University Hospital, a member of the National Biobank of Korea, which is supported by the Ministry of Health, Welfare and Family Affairs. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols. We kindly appreciate Jin-Hwa Choi for technical assistance with immunohistochemistry. NR 18 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD JUL PY 2014 VL 65 IS 1 BP 90 EP 99 DI 10.1111/his.12372 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AJ5BE UT WOS:000337694700010 PM 25032253 ER PT J AU Deo, R Yang, W Khan, AM Bansal, N Zhang, XM Leonard, MB Keane, MG Soliman, EZ Steigerwalt, S Townsend, RR Shlipak, MG Feldman, HI AF Deo, Rajat Yang, Wei Khan, Abigail M. Bansal, Nisha Zhang, Xiaoming Leonard, Mary B. Keane, Martin G. Soliman, Elsayed Z. Steigerwalt, Susan Townsend, Raymond R. Shlipak, Michael G. Feldman, Harold I. CA CRIC Study Investigators TI Serum Aldosterone and Death, End-Stage Renal Disease, and Cardiovascular Events in Blacks and Whites Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study SO HYPERTENSION LA English DT Article DE aldosterone; death; heart failure; renal insufficiency; chronic ID CHRONIC KIDNEY-DISEASE; HEART-FAILURE; MINERALOCORTICOID RECEPTOR; BLOOD-PRESSURE; MYOCARDIAL-INFARCTION; HEMODIALYSIS-PATIENTS; HYPERTENSION; MORTALITY; RISK; SPIRONOLACTONE AB Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin-angiotensin-aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93-1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85-1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with chronic kidney disease because elevated cortisol levels may activate the mineralocorticoid receptor. C1 [Deo, Rajat; Khan, Abigail M.] Univ Penn, Dept Med, Div Cardiovasc Med, Perelman Sch Med, Philadelphia, PA 19146 USA. [Townsend, Raymond R.] Univ Penn, Dept Med, Renal Electrolyte & Hypertens Div, Perelman Sch Med, Philadelphia, PA 19146 USA. [Yang, Wei; Zhang, Xiaoming; Leonard, Mary B.; Feldman, Harold I.] Univ Penn, Sch Med, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19146 USA. [Yang, Wei; Zhang, Xiaoming; Leonard, Mary B.; Feldman, Harold I.] Univ Penn, Sch Med, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19146 USA. [Bansal, Nisha] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Leonard, Mary B.] Childrens Hosp Philadelphia, Div Nephrol, Philadelphia, PA USA. [Keane, Martin G.] Temple Univ, Div Cardiovasc Med, Philadelphia, PA 19122 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC USA. [Steigerwalt, Susan] St John Hosp & Med Ctr, Div Nephrol & Hypertens, Detroit, MI USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA. RP Deo, R (reprint author), Univ Penn, 3400 Spruce St,9 Founders Cardiol, Philadelphia, PA 19146 USA. EM Rajat.Deo@uphs.upenn.edu FU National Institutes of Health (NIH) [K23DK089118]; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (NCATS) [UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland General Clinical Research Center [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland, NCATS component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research [UL1TR000433]; University of Illinois at Chicago Clinical and Translational Science Award [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/National Center for Research Resources UCSF-CTSI [UL1 RR-024131] FX This work was supported by National Institutes of Health (NIH) grant K23DK089118 to R. Deo. Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported, in part, by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland General Clinical Research Center M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the NCATS component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1TR000433, University of Illinois at Chicago Clinical and Translational Science Award UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser Permanente NIH/National Center for Research Resources UCSF-CTSI UL1 RR-024131. NR 39 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JUL PY 2014 VL 64 IS 1 BP 103 EP 110 DI 10.1161/HYPERTENSIONAHA.114.03311 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AJ5CY UT WOS:000337700400018 PM 24752431 ER PT J AU Subhash, SS Cavaiuolo, M Radonovich, LJ Eagan, A Lee, ML Campbell, S Martinello, RA AF Subhash, Shobha S. Cavaiuolo, Maria Radonovich, Lewis J., Jr. Eagan, Aaron Lee, Martin L. Campbell, Sheldon Martinello, Richard A. TI Effectiveness of Common Healthcare Disinfectants against H1N1 Influenza Virus on Reusable Elastomeric Respirators SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID EFFICACY; HANDS AB This study evaluated the efficacy of 3 common hospital disinfectants to inactivate influenza virus on elastomeric respirators. Quaternary ammonium/isopropyl alcohol and bleach detergent wipes eliminated live virus, whereas 70% isopropyl alcohol alone was ineffective. C1 [Subhash, Shobha S.; Radonovich, Lewis J., Jr.; Eagan, Aaron] Vet Hlth Adm, Off Publ Hlth, Natl Ctr Occupat Hlth & Infect Control, Gainesville, FL USA. [Cavaiuolo, Maria; Campbell, Sheldon] Vet Affairs Connecticut Hlth Care Syst, West Haven, CT USA. [Radonovich, Lewis J., Jr.] Univ Florida, Dept Med, Gainesville, FL USA. [Lee, Martin L.] Univ Calif Los Angeles, Sch Publ Hlth, Vet Affairs Greater Los Angeles Healthcare Syst S, Los Angeles, CA 90024 USA. [Lee, Martin L.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Campbell, Sheldon] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [Martinello, Richard A.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Martinello, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Martinello, Richard A.] Off Publ Hlth, Dept Vet Affairs, Washington, DC USA. RP Subhash, SS (reprint author), 1601 Southwest Archer Rd 151E, Gainesville, FL 32608 USA. EM shobha.subhash@va.gov FU Veterans Health Administration FX This study was funded by the Veterans Health Administration. NR 10 TC 1 Z9 1 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2014 VL 35 IS 7 BP 894 EP 897 DI 10.1086/676863 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AJ5OV UT WOS:000337735400021 PM 24915224 ER PT J AU Meelu, P Marin, R Clish, C Zella, G Cox, S Yajnik, V Nguyen, DD Korzenik, JR AF Meelu, Parool Marin, Romela Clish, Clary Zella, Garret Cox, Stephen Yajnik, Vijay Nguyen, Deanna D. Korzenik, Joshua R. TI Impaired Innate Immune Function Associated with Fecal Supernatant from Crohn's Disease Patients: Insights into Potential Pathogenic Role of the Microbiome SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; metabolomics; fecal supernatant; innate immune function; microbiota ID INFLAMMATORY-BOWEL-DISEASE; SUSCEPTIBILITY LOCI; ILEAL MUCOSA; PERMEABILITY; COLI; METABOLITE; PROFILES; CELLS; TWINS; RISK AB Background:Although a dysbiosis of the intestinal microbiome plays a role in the pathogenesis of Crohn's disease (CD), the functional implication is unclear. We sought to determine the influence of fecal supernatant from patients with CD on innate immune function in neutrophil, macrophage, and epithelial cells. Metabolomic analysis was subsequently performed in an attempt to identify potential compounds responsible for the effects identified.Methods:In the fecal samples from 11 pediatric patients with CD and 10 healthy controls, 16S ribosomal and metabolomic analyses were performed. We evaluated the effect of preincubation with fecal supernatant on neutrophil, macrophage, epithelial cell survival, superoxide production, bacterial invasion, and/or bactericidal function using gentamicin protection assay. Ten substances identified as most elevated in CD compared with control samples by metabolomic analysis were similarly tested for effect on bactericidal function.Results:There were no statistically significant differences in microbial membership in fecal samples from patients with CD compared with healthy controls. However, bactericidal function was impaired in neutrophils and monocytes preincubated with supernatant from fecal samples from patients with CD. Although levels of many metabolites were noted to be altered in samples from patients with CD, the combination of the 10 most elevated compounds failed to demonstrate any effect on neutrophil bactericidal capacity.Conclusions:Fecal supernatant from patients with CD impairs intracellular bactericidal activity in neutrophils and macrophages. The functional consequences of the intestinal microbiome and its associated secreted products on innate immune function may be more critical than microbial membership in understanding the pathophysiology of CD. C1 [Meelu, Parool; Marin, Romela; Yajnik, Vijay; Nguyen, Deanna D.] Massachusetts Gen Hosp, Dept Internal Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Clish, Clary] Broad Inst, Cambridge, MA USA. [Zella, Garret] Massachusetts Gen Hosp, Dept Pediat, Div Gastroenterol & Nutr, Boston, MA 02114 USA. [Cox, Stephen] Res & Testing Lab, Lubbock, TX USA. [Korzenik, Joshua R.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Korzenik, JR (reprint author), Brigham & Womens Hosp, Crohns & Colitis Ctr, 75 Francis St, Boston, MA 02115 USA. EM jkorzenik@partners.org FU Benedict Foundation FX Funding was generously supported by the Benedict Foundation. NR 43 TC 2 Z9 2 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD JUL PY 2014 VL 20 IS 7 BP 1139 EP 1146 DI 10.1097/MIB.0000000000000081 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ5TC UT WOS:000337750000006 PM 24892965 ER PT J AU Lopez, J Konijeti, GG Nguyen, DD Sauk, J Yajnik, V Ananthakrishnan, AN AF Lopez, Joanna Konijeti, Gauree G. Nguyen, Deanna D. Sauk, Jenny Yajnik, Vijay Ananthakrishnan, Ashwin N. TI Natural History of Crohn's Disease Following Total Colectomy and End Ileostomy SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; ileostomy; recurrence; postoperative ID INFLAMMATORY-BOWEL-DISEASE; POSTOPERATIVE RECURRENCE; RISK-FACTORS; MANAGEMENT; SURGERY; RESECTION; THERAPY; RATES; PHENOTYPE; DIAGNOSIS AB Background:Crohn's disease (CD) requires surgical management in up to two-thirds of patients. Few studies have addressed the issue of ileal recurrence after colectomy and permanent ileostomy. The aims of our study were to assess the rate and predictors of postoperative recurrence of CD in patients with permanent ileostomy.Methods:In a retrospective study from a tertiary referral center, we analyzed the natural history of patients with CD who underwent total colectomy and permanent ileostomy. Our primary outcomes were (1) overall disease recurrence including luminal recurrence, perianal disease or peristomal lesions requiring therapy, and (2) luminal recurrence alone defined as endoscopic and clinical recurrence within the terminal ileum. We examined if patient characteristics predicted recurrence using multivariate Cox proportional hazard models.Results:Our study included 73 patients with CD followed for a mean of 28 months (range, 0-168 mo) after total colectomy and permanent ileostomy. Twenty patients had overall disease recurrence within 10 years after surgery, at rates of 15% and 50% at 1 and 5 years, respectively. Rate of luminal recurrence was 8% and 35% at 1 and 5 years, respectively. Diagnosis at age less than 18 years (hazard ratio, 2.94; 95% confidence interval, 1.14-7.62) and anti-tumor necrosis factor therapy before surgery (hazard ratio, 4.75; 95% confidence interval, 1.25-18.13) were the only independent predictive factors for overall disease recurrence.Conclusions:Up to one-third of patients with CD have overall recurrence of disease after treatment with total colectomy and permanent ileostomy. There is need to develop algorithms for surveillance and management of this select subgroup of patients. C1 [Lopez, Joanna; Konijeti, Gauree G.; Nguyen, Deanna D.; Sauk, Jenny; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Konijeti, Gauree G.; Nguyen, Deanna D.; Sauk, Jenny; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Nguyen, Deanna D.; Sauk, Jenny; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Harvard Univ, Sch Med, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org FU National Institutes of Health [P30 DK043351, K23 DK097142] FX Supported by the National Institutes of Health (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A. N. Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). NR 36 TC 10 Z9 10 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD JUL PY 2014 VL 20 IS 7 BP 1236 EP 1241 DI 10.1097/MIB.0000000000000072 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ5TC UT WOS:000337750000017 PM 24859297 ER PT J AU Young, RH Oliva, E AF Young, Robert H. Oliva, Esther TI Selected Topics in Gynecologic Pathology Honoring Robert E. Scully, M. D. His Life and Legacy Introduction to Symposium SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Editorial Material C1 [Young, Robert H.; Oliva, Esther] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Young, Robert H.; Oliva, Esther] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Young, RH (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 2,55 Fruit St, Boston, MA 02114 USA. EM rhyoung@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2014 VL 33 IS 4 BP 323 EP 324 DI 10.1097/PGP.0000000000000140 PG 2 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA AJ5PP UT WOS:000337737900001 PM 24901390 ER PT J AU Young, RH AF Young, Robert H. TI A Tribute to Robert E. Scully, MD SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Biographical-Item C1 [Young, Robert H.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Young, Robert H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Young, RH (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 2,55 Fruit St, Boston, MA 02114 USA. EM rhyoung@partners.org NR 1 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2014 VL 33 IS 4 BP 325 EP 329 DI 10.1097/PGP.0000000000000136 PG 5 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA AJ5PP UT WOS:000337737900002 PM 24901391 ER PT J AU Oliva, E AF Oliva, Esther TI Cellular Mesenchymal Tumors of the Uterus: A Review Emphasizing Recent Observations SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Review DE Uterus; Mesenchymal neoplasms; Highly cellular leiomyoma; Endometrial stromal tumor; High-grade endometrial stromal sarcoma with t(10;17); Uterine tumor resembling ovarian sex cord tumor ID ENDOMETRIAL STROMAL SARCOMA; SMOOTH-MUSCLE TUMORS; SEX-CORD TUMORS; UNUSUAL HISTOLOGIC FEATURES; JAZF1-JJAZ1 GENE FUSION; HIGH-GRADE SARCOMAS; OF-THE-LITERATURE; UTERINE-TUMORS; GLANDULAR DIFFERENTIATION; CLINICOPATHOLOGICAL FEATURES AB Cellular mesenchymal tumors of the uterus may be divided in 2 main groups, smooth muscle and endometrial stromal. Among the former, highly cellular leiomyoma is the classic example. This tumor is not infrequently confused with an endometrial stromal tumor due to its often yellow color and soft consistency, dense cellularity, striking vascularity, not uncommon irregular margin and even rarely association with seedling cellular leiomyomas, both mimicking the infiltration of a low-grade endometrial stromal sarcoma. Cellular intravenous leiomyomatosis can also mimic endometrial stromal sarcoma due to their shared intravascular growth. A variety of histologic features typical of cellular smooth muscle including clefts and differing vasculature help in this distinction. Although endometrial stromal tumors are typically highly cellular, recent studies have expanded their spectrum to include those that are less so due to smooth muscle metaplasia, fibrous and myxoid change, and even oxyphilic cytoplasm. A subset now designated high-grade endometrial stromal sarcoma showing a t(10;17) has been characterized to show small epithelioid cells associated with brisk miotic activity, typically being CD10, ER and PR negative, and cyclin D1 positive. These tumors are juxtaposed to areas of fibromyxoid endometrial stromal neoplasia in 50% of cases. An enigmatic category of uterine mesenchymal neoplasms, often densely cellular, are those descriptively referred to as uterine tumors resembling ovarian sex cord tumors. Their spectrum is briefly noted as is their crucial distinction from stromal sarcoma with sex cord-like differentiation. Other tumors that rarely occur in the uterus that are densely cellular include but are not limited to undifferentiated uterine sarcoma, embryonal rhabdomyosarcoma, primitive neuroectodermal tumor, lymphoma or small cell, or undifferentiated carcinoma. In this essay, I review the most helpful morphologic, immunohistochemical, and/or cytogenetic features in the diagnosis of each one of these entities. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Oliva, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Pathol Labs, Boston, MA 02114 USA. EM eoliva@partners.org NR 71 TC 10 Z9 11 U1 2 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2014 VL 33 IS 4 BP 374 EP 384 DI 10.1097/PGP.0000000000000141 PG 11 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA AJ5PP UT WOS:000337737900008 PM 24901397 ER PT J AU Baker, PM Clement, PB Young, RH AF Baker, Patricia M. Clement, Philip B. Young, Robert H. TI Selected Topics in Peritoneal Pathology SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Review DE Peritoneum; Peritoneal inclusion cysts; Reactive mesothelial lesions; Mesothelioma; Peritoneal serous tumors; Benign mullerian lesions ID SEROUS BORDERLINE TUMORS; DIFFERENTIATED PAPILLARY MESOTHELIOMA; STROMAL ENDOMETRIOSIS; GENITAL-TRACT; CLINICOPATHOLOGICAL ANALYSIS; PSEUDOMYXOMA PERITONEI; INCLUSION CYSTS; UTERINE CERVIX; CELL-CARCINOMA; OVARY AB This essay considers selected peritoneal lesions many of which were the subject of studies coauthored by Dr Robert E. Scully. His article on multilocular peritoneal inclusion cysts has largely led to these lesions being considered non-neoplastic, eschewing the term cystic mesothelioma. These cysts are often associated with reactive mural mesothelial proliferations that can potentially lead to a misdiagnosis of mesothelioma. Clinical findings, such as a common association with endometriosis or prior operations, can prompt consideration of a reactive lesion. Mesothelial hyperplasia may be difficult to distinguish, when florid, from mesothelioma but a variety of gross and microscopic features will aid their recognition. Nodular peritoneal aggregates of histiocytes (sometimes admixed with mesothelial cells) may occasionally be a striking finding that can be misdiagnosed as a metastasis if the patient has a known neoplasm. Appreciation of their bland nuclear features and histiocytic nature, confirmed by immunohistochemical markers, facilitate the diagnosis. Various forms of peritonitis are briefly considered including sclerosing peritonitis, a process sometimes associated with luteinized thecomas (thecomatosis) of the ovaries, an entity first appreciated by Dr Scully. Mesotheliomas are briefly reviewed emphasizing the caution that should be used in applying the designation well-differentiated papillary mesothelioma. Many interpret the latter as benign, but multifocal lesions must be thoroughly examined histologically because of potential overlapping features with malignant mesothelioma. The morphologic spectrum of malignant mesothelioma and its usually straightforward distinction from mullerian neoplasms is considered, as is its occasional presentation as a dominant ovarian mass. The spectrum of low-grade serous peritoneal neoplasms including the psammocarcinoma is reviewed. Finally, various benign mullerian lesions, particularly endometriosis and endosalpingiosis, may be conspicuous in peritoneal specimens and sometimes are grossly striking. The usual presence of benign endometrioid epithelium and stroma should facilitate the correct diagnosis of endometriosis, but in cases in which the stroma is atrophic or the sole component (stromal endometriosis), diagnostic problems may arise. C1 [Baker, Patricia M.] Univ Manitoba, Dept Pathol, Hlth Sci Ctr, Fac Med, Winnipeg, MB R3A 1R9, Canada. [Clement, Philip B.] Univ British Columbia, Vancouver Gen Hosp, Vancouver, BC V5Z 1M9, Canada. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Baker, PM (reprint author), Univ Manitoba, Dept Pathol, Hlth Sci Ctr, Fac Med, MS477F,820 Sherbrook St, Winnipeg, MB R3A 1R9, Canada. EM pmbaker@hsc.mb.ca NR 50 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2014 VL 33 IS 4 BP 393 EP 401 DI 10.1097/PGP.0000000000000146 PG 9 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA AJ5PP UT WOS:000337737900010 PM 24901399 ER PT J AU Sachs, GS Peters, AT Sylvia, L Grunze, H AF Sachs, G. S. Peters, A. T. Sylvia, L. Grunze, H. TI Polypharmacy and bipolar disorder: what's personality got to do with it? SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bipolar disorder; medication; personality; polypharmacy ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; DOUBLE-BLIND; ACUTE MANIA; I DISORDER; COMBINATION TREATMENT; MOOD STABILIZER; UPDATE 2009; EFFICACY; LITHIUM AB The majority of patients treated for bipolar disorder receive multiple psychotropic medications concurrently (polypharmacy), despite a lack of empirical evidence for any combination of three or more medications. Some patients benefit from the skillful management of a complex medication regimen, but iterative additions to a treatment regimen often do not lead to clinical improvement, are expensive, and can confound assessment of the underlying mood disorder. Given these potential problems of polypharmacy, this paper reviews the evidence supporting the use of multiple medications and seeks to identify patient personality traits that may put patients at a greater risk for ineffective complex chronic care. Patients with bipolar disorder (n=89), ages 18 and older, were assessed on the Montgomery Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and the NEO Five Factor Inventory (NEO-FFI), and completed a treatment history questionnaire to report psychotropic medication use. We found that patients with lower scores on openness had significantly more current psychotropic medications than patients with higher scores on openness (3.7 +/- 1.9 vs. 2.8 +/- 1.8, p<0.05). Patients with the highest lifetime medication use had significantly lower extraversion (21.8 +/- 8.9 vs. 25.4 +/- 7.6, p<0.05) and lower conscientiousness (21.9 +/- 8.2 vs. 27.9 +/- 8.2, p<0.01) than those reporting lower lifetime medication use. Low levels of openness, extraversion, and conscientiousness may be associated with increased psychotropic medication use. Investigating the role of individual differences, such as patient personality traits, in moderating effective polypharmacy warrants future research. C1 [Sachs, G. S.; Peters, A. T.; Sylvia, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sachs, G. S.; Sylvia, L.] Harvard Univ, Sch Med, Cambridge, MA USA. [Grunze, H.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Sachs, GS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM sachsg@aol.com OI Grunze, Heinz/0000-0003-4712-8979 FU Astra Zeneca; Abbott Labs; BMS; Cephalon; Eli Lilly; Forest; Merck; Organon; Otsuka; Pfizer; Sanofi-Aventis; Sepracor; Sunovion; Takeda; Wyeth; NIMH; Bracket; Clintara FX Dr Sachs: grants/research support, consulting fees and honoraria within the last three years from Astra Zeneca, Abbott Labs, BMS, Cephalon, Eli Lilly, Forest, Merck, Organon, Otsuka, Pfizer, Sanofi-Aventis, Sepracor, Sunovion, Takeda, Wyeth. Employee: Massachusetts General Hospital, Bracket. Patent holder: Interactive computer interviews for rating scales in psychiatric research. Shares in Concordant Rater Systems, Medco Health Systems.; Richter, Janssen-Cilag, Merck, Organon, Pfizer Inc, Sanofi-Aventis, Sepracor, Servier and UBC. Neither he nor any member of his family have shares in any pharmaceutical company or could benefit financially from increases or decreases in the sales of any psychotropic medication.; Dr Sylvia: grants/research support from NIMH. Consulting fees from Bracket and Clintara. NR 40 TC 5 Z9 5 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2014 VL 17 IS 7 BP 1053 EP 1061 DI 10.1017/S1461145713000953 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AJ4WG UT WOS:000337678900006 PM 24067291 ER PT J AU Lanthier, S Calabrese, LH Ferro, JM Putaala, J Strbian, D Chagnon, M Frosch, MP Singhal, AB Salvarani, C Letourneau-Guillon, L Poppe, AY Guilbert, F Raymond, J Muccilli, A AF Lanthier, Sylvain Calabrese, Leonard H. Ferro, Jose M. Putaala, Jukka Strbian, Daniel Chagnon, Miguel Frosch, Matthew P. Singhal, Aneesh B. Salvarani, Carlo Letourneau-Guillon, Laurent Poppe, Alexandre Y. Guilbert, Francois Raymond, Jean Muccilli, Alexandra CA INTERSPACE Investigators TI The INTERnational Study on Primary Angiitis of the CEntral nervous system - a call to the world SO INTERNATIONAL JOURNAL OF STROKE LA English DT Letter C1 [Lanthier, Sylvain; Poppe, Alexandre Y.; Muccilli, Alexandra] CHUM, Div Neurol, Montreal, PQ, Canada. [Lanthier, Sylvain; Letourneau-Guillon, Laurent; Poppe, Alexandre Y.; Guilbert, Francois; Raymond, Jean; Muccilli, Alexandra] CHUM, Res Ctr, Montreal, PQ, Canada. [Lanthier, Sylvain; Poppe, Alexandre Y.; Muccilli, Alexandra] Univ Montreal, Fac Med, Dept Neurosci, Montreal, PQ H3C 3J7, Canada. [Calabrese, Leonard H.] Cleveland Clin, Dept Rheumat & Immunol Dis, Cleveland, OH 44106 USA. [Ferro, Jose M.] Univ Lisbon, Hosp Santa Maria, Dept Neurol, P-1699 Lisbon, Portugal. [Putaala, Jukka; Strbian, Daniel] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Chagnon, Miguel] Univ Montreal, Dept Math & Stat, Montreal, PQ H3C 3J7, Canada. [Frosch, Matthew P.] Massachusetts Gen Hosp, Kubik Lab Neuropathol, Boston, MA 02114 USA. [Singhal, Aneesh B.] Massachusetts Gen Hosp, Div Neurol, Boston, MA 02114 USA. [Salvarani, Carlo] Azienda Osped ASMN, Ist Ricovero & Cura Carattere Sci, Div Rheumatol, Reggio Emilia, Italy. [Letourneau-Guillon, Laurent; Guilbert, Francois; Raymond, Jean] CHUM, Dept Radiol, Montreal, PQ, Canada. [Letourneau-Guillon, Laurent; Guilbert, Francois; Raymond, Jean] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada. RP Lanthier, S (reprint author), CHUM Hop Notre Dame, 1560 East Sherbrooke St,GR-1166, Montreal, PQ H2L 4M1, Canada. EM sylanthier@gmail.com OI Salvarani, Carlo/0000-0001-5426-5133 NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD JUL PY 2014 VL 9 IS 5 BP E23 EP E23 DI 10.1111/ijs.12284 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AJ3SR UT WOS:000337588200003 PM 24909198 ER PT J AU Paul, LA Walsh, K McCauley, JL Ruggiero, KJ Resnick, HS Kilpatrick, DG AF Paul, Lisa A. Walsh, Kate McCauley, Jenna L. Ruggiero, Kenneth J. Resnick, Heidi S. Kilpatrick, Dean G. TI CHARACTERISTICS AND LIFE EXPERIENCES ASSOCIATED WITH RECEIVING A RAPE DISCLOSURE WITHIN A NATIONAL TELEPHONE HOUSEHOLD PROBABILITY SAMPLE OF WOMEN SO JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article ID SEXUAL ASSAULT VICTIMS; SOCIAL REACTIONS; CHILDHOOD RAPE; COLLEGE-WOMEN; SURVIVORS; SUPPORT; VICTIMIZATION; PREDICTORS; FRIENDS; OTHERS AB Disclosure of rape to informal support sources is relatively common, but not well understood. This study expands our limited knowledge of disclosure recipients' experience by examining associations between their sociodemographic and life experiences with receipt of a rape disclosure and encouragement of the victim to formally report her assault. Over 35% of the 3,001 community-residing women in this national sample reported receiving a rape disclosure. Women who had a personal history of sexual assault, met lifetime diagnostic criteria for posttraumatic stress disorder or depression, met past-year diagnostic criteria for substance abuse, engaged in monthly binge drinking and nonexperimental substance use, and sought help for emotional concerns were significantly more likely to be recipients. Approximately two thirds (69%) of disclosure recipients encouraged the victim to formally report the rape, and encouragement was also significantly associated with these characteristics. Implications of these findings for improving the disclosure process are provided. (C) 2014 Wiley Periodicals, Inc. C1 [Paul, Lisa A.] No Illinois Univ, De Kalb, IL 60115 USA. [Walsh, Kate] Columbia Univ, New York, NY 10027 USA. [McCauley, Jenna L.; Ruggiero, Kenneth J.; Resnick, Heidi S.; Kilpatrick, Dean G.] Med Univ S Carolina, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Ralph H Johnson VAMC, Charleston, SC USA. RP Kilpatrick, DG (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, 67 President St,MSC 861,2nd Fl,IOP South Bldg, Charleston, SC 29425 USA. EM kilpatdg@musc.edu FU NIDA NIH HHS [L30 DA036213, K12 DA031794, T32 DA031099]; NIMH NIH HHS [T32 MH018869] NR 30 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0090-4392 EI 1520-6629 J9 J COMMUNITY PSYCHOL JI J. Community Psychol. PD JUL PY 2014 VL 42 IS 5 BP 583 EP 592 DI 10.1002/jcop.21639 PG 10 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA AJ4IP UT WOS:000337639000007 PM 25382881 ER PT J AU Emblem, KE Due-Tonnessen, P Hald, JK Bjornerud, A Pinho, MC Scheie, D Schad, LR Meling, TR Zoellner, FG AF Emblem, Kyrre E. Due-Tonnessen, Paulina Hald, John K. Bjornerud, Atle Pinho, Marco C. Scheie, David Schad, Lothar R. Meling, Torstein R. Zoellner, Frank G. TI Machine Learning in Preoperative Glioma MRI: Survival Associations by Perfusion-Based Support Vector Machine Outperforms Traditional MRI SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE perfusion MRI; glioma; computer aided diagnosis (CAD); histogram analysis; survival associations ID LOW-GRADE GLIOMAS; BLOOD-VOLUME MAPS; GLIOBLASTOMA-MULTIFORME; HISTOGRAM ANALYSIS; BRAIN-TUMORS; SPECTROSCOPY; SURGERY AB Purpose: To retrospectively evaluate the performance of an automatic support vector machine (SVM) routine in combination with perfusion-based dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for preoperative survival associations in patients with gliomas and compare our results to traditional MRI. Materials and Methods: The study was approved by the Ethics Committee and informed consent was signed. Structural, diffusion-and perfusion-weighted MRI was performed at 1.5-T preoperatively in 94 adult patients (49 males, 45 females, 23-82 years; mean 51 years) later diagnosed with a primary glioma. Patients were randomly assigned in training and test datasets and the resulting DSC-based survival associations by SVM were compared to traditional MRI features including contrast-agent enhancement, perfusion-and diffusion-weighted imaging, tumor size, and location. The results were adjusted for age, neurological status, and postoperative factors associated with survival, including surgery and adjuvant therapy. Results: For 1- (26/33 alive, 11/14 deceased), 2- (15/21, 21/26), 3- (12/16, 27/31) and 4- (12/15, 28/32) year survival associations in the test dataset (47 patients), the SVM routine was the only biomarker to consistently associate with survival (Cox; P < 0.001). Conclusion: The automatic machine learning routine presented in our study may provide the operator with a reliable instrument for assessing survival in patients with glioma. C1 [Emblem, Kyrre E.; Pinho, Marco C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Emblem, Kyrre E.; Pinho, Marco C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Emblem, Kyrre E.; Pinho, Marco C.] Harvard Univ, Sch Med, Boston, MA USA. [Emblem, Kyrre E.; Bjornerud, Atle] Oslo Univ Hosp, Rikshosp, Intervent Ctr, Oslo, Norway. [Due-Tonnessen, Paulina; Hald, John K.] Oslo Univ Hosp, Rikshosp, Dept Radiol, Oslo, Norway. [Bjornerud, Atle] Univ Oslo, Dept Phys, Oslo, Norway. [Pinho, Marco C.] Univ Texas SW Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA. [Scheie, David] Oslo Univ Hosp, Dept Pathol, Rikshosp, Oslo, Norway. [Schad, Lothar R.; Zoellner, Frank G.] Heidelberg Univ, Med Fac Mannheim, Heidelberg, Germany. [Meling, Torstein R.] Oslo Univ Hosp, Dept Neurosurg, Rikshosp, Oslo, Norway. RP Emblem, KE (reprint author), Massachusetts Gen Hosp, Bldg 149,13th St, Charlestown, MA 02129 USA. EM kyrre@nmr.mgh.harvard.edu RI Emblem, Kyrre/H-6691-2012; OI Emblem, Kyrre/0000-0002-6580-9519; Pinho, Marco/0000-0002-4645-1638 FU Norwegian Research Council [191088/F20]; South-Eastern Norway Regional Health Authority [2013069]; United States Public Health Service (USPHS) [5R01NS060918] FX Contract grant sponsor: Norwegian Research Council; Contract grant number: 191088/F20 (to K. E. E., A. B.); Contract grant sponsor: South-Eastern Norway Regional Health Authority; Contract grant number: 2013069 (to K. E. E.); Contract grant sponsor: United States Public Health Service (USPHS); Contract grant number: 5R01NS060918 (to M.C.P.). NR 30 TC 4 Z9 4 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUL PY 2014 VL 40 IS 1 BP 47 EP 54 DI 10.1002/jmri.24390 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4JD UT WOS:000337640700006 PM 24753371 ER PT J AU Bilgic, B Chatnuntawech, I Fan, AP Setsompop, K Cauley, SF Wald, LL Adalsteinsson, E AF Bilgic, Berkin Chatnuntawech, Itthi Fan, Audrey P. Setsompop, Kawin Cauley, Stephen F. Wald, Lawrence L. Adalsteinsson, Elfar TI Fast Image Reconstruction With L2-Regularization SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE regularization; susceptibility mapping; diffusion imaging; spectroscopic imaging; lipid suppression ID TRUNCATION ARTIFACT; SUSCEPTIBILITY MAP; HUMAN BRAIN; HIGH-FIELD; K-SPACE; MRI; REGULARIZATION; PHASE; VALIDATION; INVERSION AB Purpose: We introduce L2-regularized reconstruction algorithms with closed-form solutions that achieve dramatic computational speed-up relative to state of the art L1- and L2-based iterative algorithms while maintaining similar image quality for various applications in MRI reconstruction. Materials and Methods: We compare fast L2-based methods to state of the art algorithms employing iterative L1- and L2-regularization in numerical phantom and in vivo data in three applications; (i) Fast Quantitative Susceptibility Mapping (QSM), (ii) Lipid artifact suppression in Magnetic Resonance Spectroscopic Imaging (MRSI), and (iii) Diffusion Spectrum Imaging (DSI). In all cases, proposed L2-based methods are compared with the state of the art algorithms, and two to three orders of magnitude speed up is demonstrated with similar reconstruction quality. Results: The closed-form solution developed for regularized QSM allows processing of a three-dimensional volume under 5 s, the proposed lipid suppression algorithm takes under 1 s to reconstruct single-slice MRSI data, while the PCA based DSI algorithm estimates diffusion propagators from undersampled q-space for a single slice under 30 s, all running in Matlab using a standard workstation. Conclusion: For the applications considered herein, closed-form L2-regularization can be a faster alternative to its iterative counterpart or L1-based iterative algorithms, without compromising image quality. C1 [Bilgic, Berkin; Chatnuntawech, Itthi; Fan, Audrey P.; Adalsteinsson, Elfar] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Bilgic, Berkin; Setsompop, Kawin; Cauley, Stephen F.; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Setsompop, Kawin; Wald, Lawrence L.] Harvard Univ, Sch Med, Boston, MA USA. [Wald, Lawrence L.; Adalsteinsson, Elfar] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Bilgic, B (reprint author), MIT, Room 36-776A,77 Massachusetts Ave, Cambridge, MA 02139 USA. EM berkin@mit.edu RI Cauley, Stephen/P-1386-2014; Setsompop, Kawin/P-1464-2014; bilgic, berkin/P-1811-2014; Wald, Lawrence/D-4151-2009 OI Setsompop, Kawin/0000-0003-0455-7634; FU NIH [R01 EB007942]; NIBIB [K99EB012107, R01EB006847, K99/R00 EB008129]; NCRR [P41RR14075]; NIH Blueprint for Neuroscience Research [U01MH093765]; Siemens Healthcare; Siemens-MIT Alliance; MIT-CIMIT Medical Engineering Fellowship FX Grant Support: NIH R01 EB007942; NIBIB K99EB012107; NIBIB R01EB006847; K99/R00 EB008129; NCRR P41RR14075 and the NIH Blueprint for Neuroscience Research U01MH093765 The Human Connectome project; Siemens Healthcare; Siemens-MIT Alliance; MIT-CIMIT Medical Engineering Fellowship. NR 36 TC 14 Z9 14 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUL PY 2014 VL 40 IS 1 BP 181 EP 191 DI 10.1002/jmri.24365 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4JD UT WOS:000337640700025 PM 24395184 ER PT J AU Ting, BL Bae, DS Waters, PM AF Ting, Beverlie L. Bae, Donald S. Waters, Peter M. TI Chronic Posterior Sternoclavicular Joint Fracture Dislocations in Children and Young Adults: Results of Surgical Management SO JOURNAL OF PEDIATRIC ORTHOPAEDICS LA English DT Article DE sternum; clavicle; sternoclavicular; fracture; dislocation; open reduction; reconstruction; resection; pediatric; chronic injury ID RETROSTERNAL DISLOCATION; TERM OUTCOMES; CLAVICLE; COMPRESSION; INSTABILITY; ARTERY AB Background:Posterior sternoclavicular joint (SCJ) fracture dislocations in children and young adults can be missed on initial examination or could fail closed treatment. We hypothesize that surgical interventions (open reduction and ligamentous reconstruction or medial clavicle resection depending on the clinical scenario) are safe treatment options in patients with symptomatic chronic posteriorly displaced SCJ injuries.Methods:A retrospective review was conducted of all patients younger than 25 years of age who underwent surgical treatment for chronic posteriorly displaced SCJ injuries at our institution from January 1, 1999 to December 31, 2011. Chronic injuries were defined as those presenting and/or treated at a minimum of 6 weeks from the causative injury. Indications for surgery included symptomatic posterior SCJ dislocations or posteriorly angulated physeal fractures that did not remodel and were refractory to nonoperative treatment. Subjective patient outcomes were obtained by mailed survey and telephone contact. Outcomes included a Disabilities of the Arm, Shoulder and Hand score, patient-rated levels of pain and/or disability, SCJ stability, and symptom improvement.Results:Seven patients met the inclusion criteria and all patients reported postoperative improvement or complete resolution of pain at last clinical follow-up (mean, 13 mo). At average 5.5 years follow-up, all respondents (n=4) reported that their injury did not interfere with normal social activities or daily activities. No patients reported difficulty with employment; however, all patients reported mild difficulty with return to their level of athletic activity before SCJ fracture dislocation. Patients rated their level of pain or disability as 1.5 on a 10-point scale.Conclusions:Surgical intervention can reliably provide pain relief and facilitate successful return to activities including work in patients with symptomatic chronic posterior SCJ fracture dislocations. However, patients must be counseled that they may experience persistent symptoms with return to their previous level of sport performance.Level of Evidence:Therapeutic StudyInvestigating the Results of Treatment: Level IV. C1 [Ting, Beverlie L.] Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, Boston, MA 02114 USA. [Bae, Donald S.; Waters, Peter M.] Boston Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Waters, PM (reprint author), Boston Childrens Hosp, Dept Orthopaed Surg, 300 Longwood Ave,Hunnewell 2, Boston, MA 02115 USA. EM peter.waters@childrens.harvard.edu NR 30 TC 1 Z9 1 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-6798 EI 1539-2570 J9 J PEDIATR ORTHOPED JI J. Pediatr. Orthop. PD JUL-AUG PY 2014 VL 34 IS 5 BP 542 EP 547 DI 10.1097/BPO.0000000000000148 PG 6 WC Orthopedics; Pediatrics SC Orthopedics; Pediatrics GA AJ5RV UT WOS:000337745800014 PM 24590336 ER PT J AU Dekel, S Solomon, Z Horesh, D Ein-Dor, T AF Dekel, Sharon Solomon, Zahava Horesh, Danny Ein-Dor, Tsachi TI Posttraumatic stress disorder and depressive symptoms: Joined or independent sequelae of trauma? SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE PTSD; Depression; POWs; Captivity; Combat trauma; Longitudinal study ID COMORBIDITY; PTSD; VETERANS; SURVIVORS AB Objective: The nature of co-morbidity between posttraumatic stress disorder (PTSD) and depression has been the subject of much controversy. This study addresses this issue by investigating associations between probable PTSD and depressive symptoms in a prospective, longitudinal sample of combat veterans. Method: Symptoms of PTSD and depression were assessed at 3 points of time (i.e., 1991, 2003, 2008) over a period of 17 years utilizing the PTSD Inventory and the SCL-90 (Derogatis, 1977). Two groups of combat veterans, 275 former prisoners of war (ex-POWs) and 219 matched combatants (controls), were assessed. Data were analyzed using descriptive statistics, latent variable modeling, and confirmatory factor analysis. Results: A series of chi(2) tests revealed that the prevalence proportions of depressive symptoms and probable PTSD were higher among ex-POWs compared to controls at all time points. The prevalence of depressive symptoms was higher than the prevalence of PTSD symptoms in both groups at the each of the times. Latent Trajectories Modeling (LTM) indicated that while ex-POWs' PTSD symptom severity increased over time, the severity of symptoms remained stable among controls. Parallel Process Latent Growth Modeling (PLGM) revealed a positive bi-directional relationship whereby PTSD symptoms mediated the affect of captivity on depressive symptoms and depressive symptoms mediated the affect of captivity on PTSD symptoms over time. Utilizing Confirmatory Factor Analysis (CFA), a single factor model emerged for depressive and PTSD symptoms. Conclusion: The findings suggest that while depression and PTSD seem to be different long-term manifestations of traumatic stress, accounted for in part by the severity of the trauma, they both may be parts of a common general traumatic stress construct. Clinical and theoretical implications of these findings are discussed. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Dekel, Sharon] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Dekel, Sharon] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Solomon, Zahava] Tel Aviv Univ, Bob Shapell Sch Social Work, IL-69978 Tel Aviv, Israel. [Horesh, Danny] Bar Ilan Univ, Dept Psychol, Ramat Gan, Israel. [Horesh, Danny] NYU, Dept Psychiat, New York, NY 10003 USA. [Ein-Dor, Tsachi] Interdisciplinary Ctr Herzliya, Sch Psychol, Herzliyya, Israel. RP Dekel, S (reprint author), Massachusetts Gen Hosp E, PTSD Res Lab, 120 Second Ave, Charlestown, MA 02129 USA. EM sdekel@mgh.harvard.edu OI Horesh, Danny/0000-0003-3574-4301 FU NARSAD Young Investigator Grant FX Part of this work has been funded by the NARSAD Young Investigator Grant sponsored by Dr. Dylan Tauber which was awarded to Sharon Dekel. NR 41 TC 9 Z9 9 U1 5 U2 19 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 2014 VL 54 BP 64 EP 69 DI 10.1016/j.jpsychires.2014.03.003 PG 6 WC Psychiatry SC Psychiatry GA AJ4MA UT WOS:000337649300008 PM 24703578 ER PT J AU Mandl, KD Kohane, IS McFadden, D Weber, GM Natter, M Mandel, J Schneeweiss, S Weiler, S Klann, JG Bickel, J Adams, WG Ge, YR Zhou, XB Perkins, J Marsolo, K Bernstam, E Showalter, J Quarshie, A Ofili, E Hripcsak, G Murphy, SN AF Mandl, Kenneth D. Kohane, Isaac S. McFadden, Douglas Weber, Griffin M. Natter, Marc Mandel, Joshua Schneeweiss, Sebastian Weiler, Sarah Klann, Jeffrey G. Bickel, Jonathan Adams, William G. Ge, Yaorong Zhou, Xiaobo Perkins, James Marsolo, Keith Bernstam, Elmer Showalter, John Quarshie, Alexander Ofili, Elizabeth Hripcsak, George Murphy, Shawn N. TI Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS): Architecture SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; INTEGRATING BIOLOGY; INFORMATION ECONOMY; BEDSIDE; ARTHRITIS; OUTCOMES; REGISTRY; RECORDS; I2B2 AB We describe the architecture of the Patient Centered Outcomes Research Institute (PCORI) funded Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS, http://www.SCILHS.org) clinical data research network, which leverages the $48 billion dollar federal investment in health information technology (IT) to enable a queryable semantic data model across 10 health systems covering more than 8 million patients, plugging universally into the point of care, generating evidence and discovery, and thereby enabling clinician and patient participation in research during the patient encounter. Central to the success of SCILHS is development of innovative 'apps' to improve PCOR research methods and capacitate point of care functions such as consent, enrollment, randomization, and outreach for patient-reported outcomes. SCILHS adapts and extends an existing national research network formed on an advanced IT infrastructure built with open source, free, modular components. C1 [Mandl, Kenneth D.; Kohane, Isaac S.; Natter, Marc; Mandel, Joshua; Bickel, Jonathan] Harvard MIT Hlth Sci & Technol, Childrens Hosp Informat Program, Boston, MA USA. [Mandl, Kenneth D.; Kohane, Isaac S.; McFadden, Douglas; Weber, Griffin M.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Mandl, Kenneth D.; Kohane, Isaac S.; McFadden, Douglas; Weiler, Sarah] Harvard Univ, Sch Med, Harvard Catalyst, Boston, MA USA. [Mandl, Kenneth D.; Kohane, Isaac S.; Natter, Marc; Mandel, Joshua; Bickel, Jonathan] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Weber, Griffin M.] Beth Israel Deaconess Med Ctr, Biomed Res Informat Core, Boston, MA 02215 USA. [Schneeweiss, Sebastian] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol, Boston, MA 02115 USA. [Klann, Jeffrey G.; Murphy, Shawn N.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Bickel, Jonathan] Boston Childrens Hosp, Informat Serv Dept, Boston, MA 02115 USA. [Adams, William G.] Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. [Adams, William G.] Boston Univ, Clin & Translat Sci Inst, Boston, MA 02215 USA. [Ge, Yaorong] Univ N Carolina, Coll Comp & Informat, Charlotte, NC 28223 USA. [Zhou, Xiaobo] Wake Forest Univ Hlth Sci, Ctr Bioinformat & Syst Biol, Dept Radiol, Winston Salem, NC USA. [Perkins, James] Clark Atlanta Univ, Atlanta, GA 30314 USA. [Perkins, James] Jackson State Univ, Data Coordinating Ctr, Res Ctr Minor Inst Translat Res Network, Jackson, MS USA. [Marsolo, Keith] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Bernstam, Elmer] Univ Texas Hlth Sci Ctr Houston, Div Biomed Informat, Houston, TX 77030 USA. [Bernstam, Elmer] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX 77030 USA. [Showalter, John] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Quarshie, Alexander] Morehouse Sch Med, Dept Internal Med Community Hlth & Prevent Med, Atlanta, GA 30310 USA. [Quarshie, Alexander] Morehouse Sch Med, Clin Res Ctr, Atlanta, GA 30310 USA. [Ofili, Elizabeth] Morehouse Sch Med, Clin Res Ctr, Dept Internal Med, Atlanta, GA 30310 USA. [Hripcsak, George] Columbia Univ, Dept Biomed Informat, New York, NY USA. [Murphy, Shawn N.] Partners HealthCare Syst, Informat Syst, Charlestown, MA USA. RP Mandl, KD (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM kenneth_mandl@harvard.edu RI Schneeweiss, Sebastian/C-2125-2013 FU National Institutes of Health: National Library of Medicine [R01LM011185, U54 LM008748]; National Institute of General Medical Sciences [R01GM104303]; National Center for Advancing Translational Sciences [1KL2TR001100, UL1TR000454]; National Institute on Minority Health and Health Disparities [U54 MD007588]; Office of the National Coordinator of Health Information Technology SHARP Program [90TR0001]; Patient Centered Outcomes Research Institute (PCORI) [CDRN-1306-04608] FX This work was supported by the National Institutes of Health: National Library of Medicine R01LM011185 and U54 LM008748; National Institute of General Medical Sciences R01GM104303; National Center for Advancing Translational Sciences 1KL2TR001100, UL1TR000454; National Institute on Minority Health and Health Disparities U54 MD007588; the Office of the National Coordinator of Health Information Technology SHARP Program Contract 90TR0001; and by Contract CDRN-1306-04608 from the Patient Centered Outcomes Research Institute (PCORI). NR 39 TC 18 Z9 18 U1 2 U2 19 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 615 EP 620 DI 10.1136/amiajnl-2014-002727 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600011 PM 24821734 ER PT J AU Min, H Ohira, R Collins, MA Bondy, J Avis, NE Tchuvatkina, O Courtney, PK Moser, RP Shaikh, AR Hesse, BW Cooper, M Reeves, D Lanese, B Helba, C Miller, SM Ross, EA AF Min, Hua Ohira, Riki Collins, Michael A. Bondy, Jessica Avis, Nancy E. Tchuvatkina, Olga Courtney, Paul K. Moser, Richard P. Shaikh, Abdul R. Hesse, Bradford W. Cooper, Mary Reeves, Dianne Lanese, Bob Helba, Cindy Miller, Suzanne M. Ross, Eric A. TI Sharing behavioral data through a grid infrastructure using data standards SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ELECTRONIC HEALTH RECORDS; SUBJECTIVE NUMERACY SCALE; MEANINGFUL USE; NCI THESAURUS; SCIENCE; PROGRESS; TOOLKIT; SYSTEMS; PHENX AB Objective In an effort to standardize behavioral measures and their data representation, the present study develops a methodology for incorporating measures found in the National Cancer Institute's (NCI) grid-enabled measures (GEM) portal, a repository for behavioral and social measures, into the cancer data standards registry and repository (caDSR). Methods The methodology consists of four parts for curating GEM measures into the caDSR: (1) develop unified modeling language (UML) models for behavioral measures; (2) create common data elements (CDE) for UML components; (3) bind CDE with concepts from the NCI thesaurus; and (4) register CDE in the caDSR. Results UML models have been developed for four GEM measures, which have been registered in the caDSR as CDE. New behavioral concepts related to these measures have been created and incorporated into the NCI thesaurus. Best practices for representing measures using UML models have been utilized in the practice (eg, caDSR). One dataset based on a GEM-curated measure is available for use by other systems and users connected to the grid. Conclusions Behavioral and population science data can be standardized by using and extending current standards. A new branch of CDE for behavioral science was developed for the caDSR. It expands the caDSR domain coverage beyond the clinical and biological areas. In addition, missing terms and concepts specific to the behavioral measures addressed in this paper were added to the NCI thesaurus. A methodology was developed and refined for curation of behavioral and population science data. C1 [Min, Hua] George Mason Univ, Coll Hlth & Human Serv, Dept Hlth Adm & Policy, Fairfax, VA 22030 USA. [Min, Hua; Collins, Michael A.; Tchuvatkina, Olga; Miller, Suzanne M.; Ross, Eric A.] Temple Univ Hlth, Fox Chase Canc Ctr, Philadelphia, PA USA. [Ohira, Riki] Booz Allen Hamilton, Rockville, MD USA. [Bondy, Jessica] Univ Colorado Denver, Denver, CO USA. [Avis, Nancy E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Courtney, Paul K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Moser, Richard P.; Hesse, Bradford W.] NCI, Behav Res Program, Rockville, MD USA. [Shaikh, Abdul R.] PricewaterhouseCoopers LLP, Mclean, VA USA. [Cooper, Mary] Sci Applicat Int Corp, Mclean, VA 22102 USA. [Reeves, Dianne] NCI, Rockville, MD USA. [Lanese, Bob] Case Western Reserve Univ, Ireland Canc Ctr, Cleveland, OH 44106 USA. [Helba, Cindy] Westat Corp, Rockville, MD USA. RP Min, H (reprint author), George Mason Univ, Coll Hlth & Human Serv, Dept Hlth Adm & Policy, 4400 Univ Dr,MS1J3, Fairfax, VA 22030 USA. EM gmu3@gmu.edu OI Lanese, Robert/0000-0002-6246-9475; Hesse, Bradford/0000-0003-1142-1161 NR 34 TC 4 Z9 4 U1 2 U2 16 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 642 EP 649 DI 10.1136/amiajnl-2013-001763 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600016 PM 24076749 ER PT J AU Klann, JG Buck, MD Brown, J Hadley, M Elmore, R Weber, GM Murphy, SN AF Klann, Jeffrey G. Buck, Michael D. Brown, Jeffrey Hadley, Marc Elmore, Richard Weber, Griffin M. Murphy, Shawn N. TI Query Health: standards-based, cross-platform population health surveillance SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID INTEGRATING BIOLOGY; DATA-NETWORKS; INFORMATICS; BEDSIDE AB Objective Understanding population-level health trends is essential to effectively monitor and improve public health. The Office of the National Coordinator for Health Information Technology (ONC) Query Health initiative is a collaboration to develop a national architecture for distributed, population-level health queries across diverse clinical systems with disparate data models. Here we review Query Health activities, including a standards-based methodology, an open-source reference implementation, and three pilot projects. Materials and methods Query Health defined a standards-based approach for distributed population health queries, using an ontology based on the Quality Data Model and Consolidated Clinical Document Architecture, Health Quality Measures Format (HQMF) as the query language, the Query Envelope as the secure transport layer, and the Quality Reporting Document Architecture as the result language. Results We implemented this approach using Informatics for Integrating Biology and the Bedside (i2b2) and hQuery for data analytics and PopMedNet for access control, secure query distribution, and response. We deployed the reference implementation at three pilot sites: two public health departments (New York City and Massachusetts) and one pilot designed to support Food and Drug Administration post-market safety surveillance activities. The pilots were successful, although improved cross-platform data normalization is needed. Discussions This initiative resulted in a standards-based methodology for population health queries, a reference implementation, and revision of the HQMF standard. It also informed future directions regarding interoperability and data access for ONC's Data Access Framework initiative. Conclusions Query Health was a test of the learning health system that supplied a functional methodology and reference implementation for distributed population health queries that has been validated at three sites. C1 [Klann, Jeffrey G.; Murphy, Shawn N.] Partners Healthcare, Boston, MA USA. [Klann, Jeffrey G.; Brown, Jeffrey; Weber, Griffin M.; Murphy, Shawn N.] Harvard Univ, Sch Med, Boston, MA USA. [Klann, Jeffrey G.; Murphy, Shawn N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Buck, Michael D.] New York City Dept Hlth & Mental Hyg, Queens, NY USA. [Brown, Jeffrey] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Hadley, Marc] Mitre Corp, Burlington, MA USA. [Elmore, Richard] Allscripts, Burlington, VT USA. [Weber, Griffin M.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Klann, JG (reprint author), Partners Healthcare Syst, Res Comp, 1 Constitut Ctr, Charlestown, MA 02129 USA. EM jeff.klann@mgh.harvard.edu FU NIH [U54LM00874]; ONC [90TR0001/01]; AHRQ [HS19912-01]; New York State HEAL 17 Grant [1006090831]; [HHSF223200910006I] FX This work was sponsored by NIH U54LM00874, ONC 90TR0001/01, HHSF223200910006I, AHRQ HS19912-01, and the New York State HEAL 17 Grant 1006090831. NR 34 TC 10 Z9 11 U1 2 U2 19 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 650 EP 656 DI 10.1136/amiajnl-2014-002707 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600017 PM 24699371 ER PT J AU Turvey, C Klein, D Fix, G Hogan, TP Woods, S Simon, SR Charlton, M Vaughan-Sarrazin, M Zulman, DM Dindo, L Wakefield, B Graham, G Nazi, K AF Turvey, Carolyn Klein, Dawn Fix, Gemmae Hogan, Timothy P. Woods, Susan Simon, Steven R. Charlton, Mary Vaughan-Sarrazin, Mary Zulman, Donna M. Dindo, Lilian Wakefield, Bonnie Graham, Gail Nazi, Kim TI Blue Button use by patients to access and share health record information using the Department of Veterans Affairs' online patient portal SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID PRIMARY-CARE PHYSICIANS; DIGITAL DIVIDE; COMMUNICATION; EXCHANGE; ADOPTION; DOCTORS; PERCEPTIONS; EXPERIENCE; INTERNET; SYSTEMS AB Objective The Blue Button feature of online patient portals promotes patient engagement by allowing patients to easily download their personal health information. This study examines the adoption and use of the Blue Button feature in the Department of Veterans Affairs' (VA) personal health record portal, My HealtheVet. Materials and methods An online survey presented to a 4% random sample of My HealtheVet users between March and May 2012. Questions were designed to determine characteristics associated with Blue Button use, perceived value of use, and how Veterans with non-VA providers use the Blue Button to share information with their non-VA providers. Results Of the survey participants (N=18 398), 33% were current Blue Button users. The most highly endorsed benefit was that it helped patients understand their health history better because all the information was in one place (73%). Twenty-one percent of Blue Button users with a non-VA provider shared their VA health information, and 87% reported that the non-VA provider found the information somewhat or very helpful. Veterans' self-rated computer ability was the strongest factor contributing to both Blue Button use and to sharing information with non-VA providers. When comparing Blue Button users and non-users, barriers to adoption were low awareness of the feature and difficulty using the Blue Button. Conclusions This study contributes to the understanding of early Blue Button adoption and use of this feature for patient-initiated sharing of health information. Educational efforts are needed to raise awareness of the Blue Button and to address usability issues that hinder adoption. C1 [Turvey, Carolyn; Klein, Dawn; Charlton, Mary; Vaughan-Sarrazin, Mary; Wakefield, Bonnie] Iowa City VA Hlth Care Syst, Comprehens Access & Delivery Res & Evaluat CADRE, Iowa City, IA USA. [Turvey, Carolyn; Klein, Dawn; Dindo, Lilian] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Fix, Gemmae; Hogan, Timothy P.] Edith Nourse Rogers Mem Vet Adm Hosp, CHOIR, A VA HSR&D Ctr Innovat, Bedford, MA 01730 USA. [Fix, Gemmae] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Hogan, Timothy P.] Edith Nourse Rogers Mem Vet Adm Hosp, eHlth Qual Enhancement Res Initiat, Natl eHlth QUERI Coordinating Ctr, Bedford, MA 01730 USA. [Hogan, Timothy P.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Hlth Informat & Implementat Sci, Worcester, MA USA. [Woods, Susan] Portland VA Med Ctr, Hlth Serv Res & Dev, Portland, OR USA. [Woods, Susan] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Simon, Steven R.] Vet Affairs Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. [Simon, Steven R.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA. [Charlton, Mary] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Vaughan-Sarrazin, Mary] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Zulman, Donna M.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Zulman, Donna M.] Stanford Univ, Div Gen Med Disciplines, Stanford, CA 94305 USA. [Wakefield, Bonnie] Univ Missouri, Sinclair Sch Nursing, Columbia, MO USA. [Graham, Gail; Nazi, Kim] Vet Hlth Adm, Off Informat & Analyt, Vet & Consumers Hlth Informat Off, Washington, DC USA. RP Turvey, C (reprint author), Iowa City VA Hlth Care Syst 152, 601 Highway West, Iowa City, IA 52246 USA. EM carolyn.turvey@va.gov OI Fix, Gemmae/0000-0001-6055-4177 FU Department of Veterans Affairs, Health Services Research & Development, eHealth Quality Enhancement Research Initiative [RRP 11-407] FX This work was supported by the Department of Veterans Affairs, Health Services Research & Development, eHealth Quality Enhancement Research Initiative (RRP 11-407). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 45 TC 26 Z9 26 U1 1 U2 23 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 657 EP 663 DI 10.1136/amiajnl-2014-002723 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600018 PM 24740865 ER PT J AU Giardina, TD Menon, S Parrish, DE Sittig, DF Singh, H AF Giardina, Traber Davis Menon, Shailaja Parrish, Danielle E. Sittig, Dean F. Singh, Hardeep TI Patient access to medical records and healthcare outcomes: a systematic review SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; CANCER-PATIENTS; OWN RECORDS; PATIENTS SATISFACTION; COLLABORATIVE CARE; GENERAL-PRACTICE; SAFETY; INFORMATION; COMMUNICATION; INVOLVEMENT AB Objectives We conducted a systematic review to determine the effect of providing patients access to their medical records (electronic or paper-based) on healthcare quality, as defined by measures of safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity. Methods Articles indexed in PubMed from January 1970 to January 2012 were reviewed. Twenty-seven English-language controlled studies were included. Outcomes were categorized as measures of effectiveness (n=19), patient-centeredness (n=16), and efficiency (n=2); no study addressed safety, timeliness, or equity. Results Outcomes were equivocal with respect to several aspects of effectiveness and patient-centeredness. Efficiency outcomes in terms of frequency of in-person and telephone encounters were mixed. Access to health records appeared to enhance patients' perceptions of control and reduced or had no effect on patient anxiety. Conclusion Although few positive findings generally favored patient access, the literature is unclear on whether providing patients access to their medical records improves quality. C1 [Giardina, Traber Davis; Menon, Shailaja; Singh, Hardeep] Michael E DeBakey VA Med Ctr, Houston VA HSR&D Ctr Innovat Qual Effectiveness &, Houston, TX USA. [Giardina, Traber Davis; Menon, Shailaja; Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Giardina, Traber Davis; Parrish, Danielle E.] Univ Houston, Grad Coll Social Work, Houston, TX USA. [Sittig, Dean F.] Univ Texas Sch Biomed Informat, Houston, TX USA. [Sittig, Dean F.] UT Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. RP Giardina, TD (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM Traber.Davis@va.gov FU VA National Center of Patient Safety; Houston VA Center for Innovations in Quality, Effectiveness and Safety [CIN 13-413] FX This work was supported by the VA National Center of Patient Safety and in part by the Houston VA Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413). These sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 64 TC 12 Z9 12 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 737 EP 741 DI 10.1136/amiajnl-2013-002239 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600030 ER PT J AU Marmon, S Shek, SYN Yeung, CK Chan, NPY Chan, JCY Chan, HHL AF Marmon, Shoshana Shek, Samantha Y. N. Yeung, C. K. Chan, Nicola P. Y. Chan, Johnny C. Y. Chan, Henry H. L. TI Evaluating the Safety and Efficacy of the 1,440-nm Laser in the Treatment of Photodamage in Asian Skin SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE Asians; fractional photothermolysis; photoaging; nonablative ID FRACTIONAL PHOTOTHERMOLYSIS; REJUVENATION AB Background and Objective: As the demand for diminished procedure-associated downtime continues to increase, nonablative fractional laser resurfacing is becoming a more popular intervention in the progression of photoaging. Patients with pigmented skin and a mild degree of photodamage may be particularly suited for a less intensive laser treatment. In this study, we have evaluated the safety and efficacy of a low energy, low density 1,440-nm fractional laser in the treatment of multiple signs of photoaging including dyspigmentation, wrinkling, tissue laxity, enlarged pores, and skin roughness in Asians. Study Design/Materials and Methods: Ten Chinese subjects with Fitzpatrick skin types III-V and visible signs of photodamage participated in this study. Patients received four treatments at 2-week intervals with a 1,440-nm diode-based fractional laser. Photographs were taken at baseline, 2 weeks after each of the first three treatments and 4 weeks after the final treatment. Images were evaluated independently by two physicians. Clinical improvement and adverse events were analyzed. Discomfort, heat sensation and overall patient satisfaction associated with the procedure were also quantified. Results: In this prospective single-arm study, signs of photoaging were examined after treatment with the 1,440-nm laser. Here we show that a series of four treatments with this device produced a mild improvement in skin texture, pigmentation, and wrinkling. Changes in pore size and skin laxity failed to reach statistical significance. Immediate after-effects of the procedure included erythema and edema which were transient and left no permanent sequela. A significant proportion of patients reported some degree of discomfort during the procedure despite use of a topical anesthetic. One patient developed a discrete, localized area of post-inflammatory hyperpigmentation which completely resolved by the final follow up visit. Conclusion: The low energy, low density nonablative 1,440-nm fractional laser produces a mild improvement in select signs of photodamage after four treatments without any long-term adverse effects. (C) 2014 Wiley Periodicals, Inc. C1 [Marmon, Shoshana; Shek, Samantha Y. N.; Yeung, C. K.; Chan, Henry H. L.] Hong Kong Dermatol & Laser Ctr, Hong Kong, Hong Kong, Peoples R China. [Shek, Samantha Y. N.; Yeung, C. K.; Chan, Nicola P. Y.; Chan, Johnny C. Y.; Chan, Henry H. L.] Univ Hong Kong, Dept Med, Div Dermatol, Hong Kong, Hong Kong, Peoples R China. [Chan, Henry H. L.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Marmon, S (reprint author), Hong Kong Dermatol & Laser Ctr, 11-F Silver Fortune Plaza,1 Wellington St, Hong Kong, Hong Kong, Peoples R China. EM shmarmon@hhlchan.com RI Chan, Henry Hin Lee/L-2267-2013 NR 16 TC 3 Z9 3 U1 0 U2 10 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 2014 VL 46 IS 5 BP 375 EP 379 DI 10.1002/lsm.22242 PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA AJ5AW UT WOS:000337693800001 PM 24634348 ER PT J AU Noiret, L Baigent, S Jalan, R AF Noiret, Lorette Baigent, Stephen Jalan, Rajiv TI Arterial ammonia levels in cirrhosis are determined by systemic and hepatic hemodynamics, and by organ function: a quantitative modelling study SO LIVER INTERNATIONAL LA English DT Article DE ammonia; cirrhosis; fluxes; interorgan; portosystemic shunting ID ALCOHOLIC LIVER-DISEASE; BLOOD-FLOW; SPLANCHNIC HEMODYNAMICS; ALBUMIN DIALYSIS; PORTAL PRESSURE; RENAL SODIUM; ENCEPHALOPATHY; FAILURE; METABOLISM; SEVERITY AB Background & Aims: Hyperammonaemia is a common complication of chronic liver failure. Two main factors are thought to underlie this complication: a loss of hepatic detoxification function and the development of portosystemic shunting. However, few studies have tried to quantify the importance of portosystemic shunting. Here, we used a theoretical approach to test the hypothesis that the development of portosystemic shunting is sufficient to cause hyperammonaemia in cirrhosis. Methods: Two mathematical models are developed. The first one describes the main vascular resistances of the circulation and is used to provide scenarios for the distributions of organ blood flow in cirrhosis, which are necessary to run the second model. The second model predicts arterial ammonia levels resulting from ammonia metabolism in gut, liver, kidney, muscle and brain, and the distribution of organ blood flow. Results: The fraction of gastrointestinal blood flow shunted through collaterals was estimated to be 41% in mild cirrhosis, 69% in moderate and 85% in severe cases. In the second model, the redistribution of organ blood flow associated with severe cirrhosis was sufficient to cause hyperammonaemia, even when the hepatic detoxification function and the ammonia production were set to normal. Conclusions: The model indicates that the development of portosystemic shunting in cirrhosis is sufficient to cause hyperammonaemia. Interventions that reduce the fraction of shunting may be future targets of therapy to control severity of hyperammonaemia. C1 [Noiret, Lorette; Baigent, Stephen] UCL, CoMPLEX, London, England. [Baigent, Stephen] UCL, Dept Math, London, England. [Jalan, Rajiv] UCL Med Sch, Royal Fee Hosp, UCL Inst Liver & Digest Hlth, Liver Failure Grp, London, England. RP Noiret, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM noiret.lorette@mgh.harvard.edu FU EPSRC through UCL CoMPLEX doctoral training centre FX This work was supported by the EPSRC through the UCL CoMPLEX doctoral training centre. NR 54 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD JUL PY 2014 VL 34 IS 6 BP E45 EP E55 DI 10.1111/liv.12361 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ5OG UT WOS:000337733400006 PM 24134128 ER PT J AU Cauley, SF Polimeni, JR Bhat, H Wald, LL Setsompop, K AF Cauley, Stephen F. Polimeni, Jonathan R. Bhat, Himanshu Wald, Lawrence L. Setsompop, Kawin TI Interslice Leakage Artifact Reduction Technique for Simultaneous Multislice Acquisitions SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE leakage; parallel imaging; simultaneous multislice; CAIPIRINHA ID EPI; ARRAYS; IMAGES; SENSE; MRI AB Purpose: Controlled aliasing techniques for simultaneously acquired echo-planar imaging slices have been shown to significantly increase the temporal efficiency for both diffusion-weighted imaging and functional magnetic resonance imaging studies. The "slice-GRAPPA" (SG) method has been widely used to reconstruct such data. We investigate robust optimization techniques for SG to ensure image reconstruction accuracy through a reduction of leakage artifacts. Methods: Split SG is proposed as an alternative kernel optimization method. The performance of Split SG is compared to standard SG using data collected on a spherical phantom and in vivo on two subjects at 3 T. Slice-accelerated and nonaccelerated data were collected for a spin-echo diffusion-weighted acquisition. Signal leakage metrics and time-series SNR were used to quantify the performance of the kernel fitting approaches. Results: The Split SG optimization strategy significantly reduces leakage artifacts for both phantom and in vivo acquisitions. In addition, a significant boost in time-series SNR for in vivo diffusion-weighted acquisitions with in-plane 2x and slice 3x accelerations was observed with the Split SG approach. Conclusion: By minimizing the influence of leakage artifacts during the training of SG kernels, we have significantly improved reconstruction accuracy. Our robust kernel fitting strategy should enable better reconstruction accuracy and higher slice-acceleration across many applications. (C) 2013 Wiley Periodicals, Inc. C1 [Cauley, Stephen F.; Polimeni, Jonathan R.; Wald, Lawrence L.; Setsompop, Kawin] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Polimeni, Jonathan R.; Wald, Lawrence L.; Setsompop, Kawin] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Bhat, Himanshu] Siemens Med Solut Inc, Malvern, PA USA. [Wald, Lawrence L.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Cauley, SF (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM stcauley@nmr.mgh.harvard.edu RI Polimeni, Jonathan/P-1395-2014; Cauley, Stephen/P-1386-2014; Setsompop, Kawin/P-1464-2014; Wald, Lawrence/D-4151-2009 OI Polimeni, Jonathan/0000-0002-1348-1179; Setsompop, Kawin/0000-0003-0455-7634; FU NIH Human Connectome Project NIH U01MH093765 [NIBIB R00EB012107, R01EB006847, NCRR P41RR014075] FX Grant sponsor: NIH Human Connectome Project NIH U01MH093765; Grant numbers: NIBIB R00EB012107; R01EB006847; NCRR P41RR014075. NR 20 TC 24 Z9 24 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 93 EP 102 DI 10.1002/mrm.24898 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400012 PM 23963964 ER PT J AU Fan, AP Bilgic, B Gagnon, L Witzel, T Bhat, H Rosen, BR Adalsteinsson, E AF Fan, Audrey P. Bilgic, Berkin Gagnon, Louis Witzel, Thomas Bhat, Himanshu Rosen, Bruce R. Adalsteinsson, Elfar TI Quantitative Oxygenation Venography from MRI Phase SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE venous oxygen saturation; quantitative susceptibility; brain oxygenation; venography ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; MAGNETIC-FIELD INHOMOGENEITY; ENABLED DIPOLE INVERSION; HUMAN BRAIN; CYLINDER APPROXIMATION; CLINICAL-APPLICATIONS; OXIDATIVE-METABOLISM; SUSCEPTIBILITY MAP; SPATIAL VARIATION AB Purpose: To demonstrate acquisition and processing methods for quantitative oxygenation venograms that map in vivo oxygen saturation (SvO(2)) along cerebral venous vasculature. Methods: Regularized quantitative susceptibility mapping (QSM) is used to reconstruct susceptibility values and estimate SvO(2) in veins. QSM with l(1) and l(2) regularization are compared in numerical simulations of vessel structures with known magnetic susceptibility. Dual-echo, flow-compensated phase images are collected in three healthy volunteers to create QSM images. Bright veins in the susceptibility maps are vectorized and used to form a three-dimensional vascular mesh, or venogram, along which to display SvO(2) values from QSM. Results: Quantitative oxygenation venograms that map SvO(2) along brain vessels of arbitrary orientation and geometry are shown in vivo. SvO(2) values in major cerebral veins lie within the normal physiological range reported by O-15 positron emission tomography. SvO(2) from QSM is consistent with previous MR susceptometry methods for vessel segments oriented parallel to the main magnetic field. In vessel simulations, l(1) regularization results in less than 10% SvO(2) absolute error across all vessel tilt orientations and provides more accurate SvO(2) estimation than l(2) regularization. Conclusion: The proposed analysis of susceptibility images enables reliable mapping of quantitative SvO(2) along venograms and may facilitate clinical use of venous oxygenation imaging. (C) 2013 Wiley Periodicals, Inc. C1 [Fan, Audrey P.; Bilgic, Berkin; Adalsteinsson, Elfar] MIT, Magnet Resonance Imaging Grp, Elect Res Lab, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Fan, Audrey P.; Bilgic, Berkin; Gagnon, Louis; Witzel, Thomas; Rosen, Bruce R.; Adalsteinsson, Elfar] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Gagnon, Louis; Rosen, Bruce R.; Adalsteinsson, Elfar] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. [Bhat, Himanshu] Siemens Med Solut USA Inc, Charlestown, MA USA. RP Fan, AP (reprint author), MIT, 32 Vassar St,Room 36-792, Cambridge, MA 02139 USA. EM apfan@mit.edu RI Witzel, Thomas/P-1402-2014; bilgic, berkin/P-1811-2014 FU National Science Foundation Graduate Research Fellowship, the Advanced Multimodal Neuroimaging Training Program [R90-DA023427]; National Institutes of Health [R01-EB007942] FX Grant sponsor: National Science Foundation Graduate Research Fellowship, the Advanced Multimodal Neuroimaging Training Program; Grant number: R90-DA023427; Grant sponsor: National Institutes of Health; Grant number: R01-EB007942. NR 69 TC 22 Z9 22 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 149 EP 159 DI 10.1002/mrm.24918 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400017 PM 24006229 ER PT J AU Zhao, W Cohen-Adad, J Polimeni, JR Keil, B Guerin, B Setsompop, K Serano, P Mareyam, A Hoecht, P Wald, LL AF Zhao, Wei Cohen-Adad, Julien Polimeni, Jonathan R. Keil, Boris Guerin, Bastien Setsompop, Kawin Serano, Peter Mareyam, Azma Hoecht, Philipp Wald, Lawrence L. TI Nineteen-Channel Receive Array and Four-Channel Transmit Array Coil for Cervical Spinal Cord Imaging at 7T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE high-field MRI; RF coil; transmit array; receive array; cervical spinal cord MRI ID PHASED-ARRAY; MULTIPLE-SCLEROSIS; FAST MRI; RF COIL; TESLA; LESIONS; DESIGN; BRAIN; NMR AB Purpose: To design and validate a radiofrequency (RF) array coil for cervical spinal cord imaging at 7T. Methods: A 19-channel receive array with a four-channel transmit array was developed on a close-fitting coil former at 7T. Transmit efficiency and specific absorption rate were evaluated in a B-1(+) mapping study and an electromagnetic model. Receive signal-to-noise ratio (SNR) and noise amplification for parallel imaging were evaluated and compared with a commercial 3T 19-channel head-neck array and a 7T four-channel spine array. The performance of the array was qualitatively demonstrated in human volunteers using high-resolution imaging (down to 300 mm in-plane). Results: The transmit and receive arrays showed good bench performance. The SNR was approximately 4.2-fold higher in the 7T receive array at the location of the cord with respect to the 3T coil. The g-factor results showed an additional acceleration was possible with the 7T array. In vivo imaging was feasible and showed high SNR and tissue contrast. Conclusion: The highly parallel transmit and receive arrays were demonstrated to be fit for spinal cord imaging at 7T. The high sensitivity of the receive coil combined with ultra-high field will likely improve investigations of microstructure and tissue segmentation in the healthy and pathological spinal cord. (C) 2013 Wiley Periodicals, Inc. C1 [Zhao, Wei; Polimeni, Jonathan R.; Keil, Boris; Guerin, Bastien; Setsompop, Kawin; Serano, Peter; Mareyam, Azma; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Zhao, Wei; Polimeni, Jonathan R.; Keil, Boris; Guerin, Bastien; Setsompop, Kawin; Serano, Peter; Mareyam, Azma; Wald, Lawrence L.] Harvard Univ, Sch Med, Boston, MA USA. [Cohen-Adad, Julien] Ecole Polytech, Dept Elect Engn, Montreal, PQ H3C 3A7, Canada. [Hoecht, Philipp] Siemens AG, Healthcare Sect, Magnet Resonance, Erlangen, Germany. [Wald, Lawrence L.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Zhao, W (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM wei@nmr.mgh.harvard.edu RI Keil, Boris/P-1411-2014; Polimeni, Jonathan/P-1395-2014; Setsompop, Kawin/P-1464-2014; Wald, Lawrence/D-4151-2009 OI Polimeni, Jonathan/0000-0002-1348-1179; Setsompop, Kawin/0000-0003-0455-7634; FU National Institutes of Health [P41EB015896, K24NS59892]; National Multiple Sclerosis Society [FG1892A1/1] FX Grant sponsor: National Institutes of Health; Grant numbers: P41EB015896, K24NS59892; Grant sponsor: National Multiple Sclerosis Society; Grant number: FG1892A1/1. NR 31 TC 15 Z9 15 U1 5 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 291 EP 300 DI 10.1002/mrm.24911 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400032 PM 23963998 ER PT J AU Sepucha, KR Matlock, DD Wills, CE Ropka, M Joseph-Williams, N Stacey, D Ng, C Levin, C Lally, J Borkhoff, CM Thomson, R AF Sepucha, Karen R. Matlock, Daniel D. Wills, Celia E. Ropka, Mary Joseph-Williams, Natalie Stacey, Dawn Ng, ChirkJenn Levin, Carrie Lally, Joanne Borkhoff, Cornelia M. Thomson, Richard TI "It's Valid and Reliable'' Is Not Enough: Critical Appraisal of Reporting of Measures in Trials Evaluating Patient Decision Aids SO MEDICAL DECISION MAKING LA English DT Article DE psychometrics; decision making; decision aids AB Background. This review systematically appraises the quality of reporting of measures used in trials to evaluate the effectiveness of patient decision aids (PtDAs) and presents recommendations for minimum reporting standards. Methods. We reviewed measures of decision quality and decision process in 86 randomized controlled trials (RCTs) from the 2011 Cochrane Collaboration systematic review of PtDAs. Data on development of the measures, reliability, validity, responsiveness, precision, interpretability, feasibility, and acceptability were independently abstracted by 2 reviewers. Results. Information from 178 instances of use of measures was abstracted. Very few studies reported data on the performance of measures, with reliability (21%) and validity (16%) being the most common. Studies using new measures were less likely to include information about their psychometric performance. The review was limited to reporting of measures in studies included in the Cochrane review and did not consult prior publications. Conclusions. Very little is reported about the development or performance of measures used to evaluate the effectiveness of PtDAs in published trials. Minimum reporting standards are proposed to enable authors to prepare study reports, editors and reviewers to evaluate submitted papers, and readers to appraise published studies. C1 [Sepucha, Karen R.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Sepucha, Karen R.] Harvard Univ, Sch Med, Boston, MA USA. [Matlock, Daniel D.] Univ Colorado, Sch Med, Aurora, CO USA. [Wills, Celia E.] Ohio State Univ, Columbus, OH 43210 USA. [Ropka, Mary] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Joseph-Williams, Natalie] Cardiff Univ, Cochrane Inst Primary Care & Publ Hlth, Cardiff CF10 3AX, S Glam, Wales. [Stacey, Dawn] Univ Ottawa, Ottawa, ON, Canada. [Stacey, Dawn] Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Ng, ChirkJenn] Univ Malaya, Dept Primary Care Med, Kuala Lumpur, Malaysia. [Levin, Carrie] Informed Med Decis Fdn, Boston, MA USA. [Lally, Joanne; Thomson, Richard] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Borkhoff, Cornelia M.] Univ Toronto, Toronto, ON, Canada. [Borkhoff, Cornelia M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Sepucha, KR (reprint author), Massachusetts Gen Hosp, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ksepucha@partners.org RI NG, CHIRK JENN/C-1344-2010 FU Informed Medical Decisions Foundation; Informed Medical Decisions Foundation [0100]; National Institutes on Aging [K23AG040696] FX Dr. Levin receives salary support as Research Director from the Informed Medical Decisions Foundation, a not-for-profit (501(c) 3) private foundation (http://www.informedmedicaldecisions.org). The Foundation develops content for patient education programs. The programs are used as part of decision support and disease management services made available to consumers through health care organizations and employers. Dr. Sepucha receives research and salary support from the Informed Medical Decisions Foundation (0100). Dr. Matlock was supported by the National Institutes on Aging (K23AG040696). No direct financial support was provided to authors for this manuscript. Revision accepted for publication 31 January 2014. NR 15 TC 3 Z9 3 U1 0 U2 7 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 2014 VL 34 IS 5 BP 560 EP 566 DI 10.1177/0272989X14528381 PG 7 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AJ3NB UT WOS:000337572300002 PM 24713692 ER PT J AU Caverly, TJ Prochazka, AV Binswanger, IA Kutner, JS Matlock, DD AF Caverly, Tanner J. Prochazka, Allan V. Binswanger, Ingrid A. Kutner, Jean S. Matlock, Daniel D. TI Confusing Relative Risk with Absolute Risk Is Associated with More Enthusiastic Beliefs about the Value of Cancer Screening SO MEDICAL DECISION MAKING LA English DT Article DE statistics; medical education; physicians; numeracy; risk communication ID 5-YEAR SURVIVAL RATES; UNITED-STATES; DOCTORS; IMPACT AB Background. Reviews of how data are presented in medical literature document that the benefit from an intervention is often exaggerated relative to the harm (e.g., relative risk for benefit and absolute risk for harm). Such mismatched presentations may create unwarranted enthusiasm, especially among those who misinterpret the statistics presented. The objective was to determine whether misinterpretation of risk data predicts enthusiasm for cancer screening. Methods. The authors administered a survey with 14 items assessing beliefs about cancer screening and 6 items measuring data interpretation ability. Multiple linear regression was used to evaluate the association between data interpretation and enthusiasm for cancer screening, with adjustment for gender and year graduated from medical school. Results. Eighty-eight of 139 physicians at a state-wide professional meeting returned completed surveys (63% response rate). Lower data interpretation scores were associated with higher enthusiasm for cancer screening scores (P = 0.004) in the adjusted primary analysis. Confusing relative risk with absolute risk appeared to drive the overall association. Conclusions. Biased presentations of risk data could affect general beliefs about the value of cancer screening, especially among physicians who uncritically accept mismatched presentations of data. C1 [Caverly, Tanner J.] Ann Arbor VA Hlth Syst, Ann Arbor, MI USA. [Caverly, Tanner J.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Prochazka, Allan V.; Binswanger, Ingrid A.; Kutner, Jean S.; Matlock, Daniel D.] Univ Colorado, Div Gen Internal Med, Aurora, CO USA. [Prochazka, Allan V.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Binswanger, Ingrid A.] Denver Hlth Med Ctr Denver, Denver, CO USA. RP Caverly, TJ (reprint author), Univ Michigan, Sch Med, VA Ctr Clin Management Res, Ann Arbor VA Hlth Syst, 2800 Plymouth Rd,Bldg 16,Room 326W, Ann Arbor, MI 48109 USA. EM tcaverly@med.umich.edu OI Binswanger, Ingrid/0000-0001-8862-8078 FU National Research Service Award [T32HP1006]; K23 [AG040696-01] FX Dr. Caverly was supported by a National Research Service Award T32HP1006 grant and Dr. Matlock was supported by a K23 (AG040696-01). This research was presented orally at the 2012 North American Annual Meeting for the Society for Medical Decision Making. Revision accepted for publication 5 February 2014. NR 17 TC 2 Z9 2 U1 0 U2 4 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 2014 VL 34 IS 5 BP 686 EP 692 DI 10.1177/0272989X14526641 PG 7 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AJ3NB UT WOS:000337572300012 PM 24732049 ER PT J AU Alba, GA Kelmenson, DA AF Alba, George A. Kelmenson, Daniel A. TI Optimising debriefing for technology-enhanced simulation SO MEDICAL EDUCATION LA English DT Editorial Material ID METAANALYSIS C1 [Kelmenson, Daniel A.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. RP Kelmenson, DA (reprint author), Massachusetts Gen Hosp, Dept Internal Med, 66 Myrtle St,Apartment 2, Boston, MA 02114 USA. EM dkelmenson@gmail.com NR 13 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0308-0110 EI 1365-2923 J9 MED EDUC JI Med. Educ. PD JUL PY 2014 VL 48 IS 7 BP 648 EP 650 DI 10.1111/medu.12481 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AJ4ZE UT WOS:000337688300001 PM 24909523 ER PT J AU Huh, JY Mougios, V Skraparlis, A Kabasakalis, A Mantzoros, CS AF Huh, Joo Young Mougios, Vassilis Skraparlis, Athanasios Kabasakalis, Athanasios Mantzoros, Christos S. TI Irisin in response to acute and chronic whole-body vibration exercise in humans SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Irisin; FNDC5; Whole body vibration exercise; Myokine ID CELL-PROLIFERATION; MESSENGER-RNA; FNDC5 GENE; FAT; METABOLISM; EXPRESSION; PROGRAM; SERUM; LINES; MEN AB Objective. Irisin is a recently identified myokine, suggested to mediate the beneficial effects of exercise by inducing browning of white adipocytes and thus increasing energy expenditure. In humans, the regulation of irisin by exercise is not completely understood. We investigated the effect of acute and chronic whole-body vibration exercise, a moderate-intensity exercise that resembles shivering, on circulating irisin levels in young healthy subjects. Materials/Methods. Healthy untrained females participated in a 6-week program of whole-body vibration exercise training. Blood was drawn before and immediately after an acute bout of exercise at baseline (week 0) and after 6 weeks of training. Results. The resting irisin levels were not different at baseline (week 0) and after 6 weeks of training. At both 0 and 6 weeks of training, an acute bout of vibration exercise significantly elevated circulating irisin levels by 9.5% and 18.1%, respectively (p = 0.05 for the percent change of irisin levels). Conclusions. Acute bouts of whole-body vibration exercise are effective in increasing circulating irisin levels but chronic training does not change levels of baseline irisin levels in humans. (c) 2014 Elsevier Inc. All rights reserved. C1 [Huh, Joo Young; Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02215 USA. [Mougios, Vassilis; Skraparlis, Athanasios; Kabasakalis, Athanasios] Aristotle Univ Thessaloniki, Sch Phys Educ & Sports Sci, GR-54006 Thessaloniki, Greece. RP Huh, JY (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. EM jhuh@bidmc.harvard.edu FU Clinical Science Research and Development Service of the VA Office of Research and Development FX Award from the Clinical Science Research and Development Service of the VA Office of Research and Development. NR 21 TC 22 Z9 22 U1 2 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD JUL PY 2014 VL 63 IS 7 BP 918 EP 921 DI 10.1016/j.metabol.2014.04.001 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ5ID UT WOS:000337715000006 PM 24814685 ER PT J AU Majmudar, S Wu, J Paganoni, S AF Majmudar, Salony Wu, Jason Paganoni, Sabrina TI Rehabilitation in amyotrophic lateral sclerosis: Why it matters SO MUSCLE & NERVE LA English DT Review DE braces; exercise; multidisciplinary care; physical therapy; rehabilitation ID QUALITY STANDARDS SUBCOMMITTEE; PRACTICE PARAMETER UPDATE; AMERICAN ACADEMY; MOUSE MODEL; CARE; ALS; EXERCISE; MANAGEMENT; SURVIVAL; PATIENT AB Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in a constellation of problematic symptoms and a high patient and caregiver burden. Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. Given the progressive nature of ALS, the clinician must be aware of the expected disease trajectory and apply appropriate interventions at each stage. This review will present rehabilitation strategies that can be utilized to maximize patient independence, function, safety, and quality of life, and to minimize disease-related symptoms. The role of bracing, exercise, assistive devices, and adaptive equipment will be discussed. At each disease stage, an experienced rehabilitation team is well positioned to make a significant impact on the life of ALS patients. Muscle Nerve 50: 4-13, 2014 C1 [Majmudar, Salony; Wu, Jason; Paganoni, Sabrina] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA 02163 USA. [Paganoni, Sabrina] Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA. RP Paganoni, S (reprint author), Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA 02163 USA. EM spaganoni@partners.org FU National Institutes of Health [2K12HD00 1097-16] FX This study was supported by a Career Development Award (2K12HD00 1097-16 to S. P.) from the National Institutes of Health. NR 41 TC 3 Z9 3 U1 2 U2 24 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 2014 VL 50 IS 1 BP 4 EP 13 DI 10.1002/mus.24202 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AJ4IU UT WOS:000337639600001 PM 24510737 ER PT J AU Woodruff, MC Turley, SJ AF Woodruff, Matthew C. Turley, Shannon J. TI Chemokine 'grooming' by cLECs directs DC migration SO NATURE IMMUNOLOGY LA English DT Editorial Material ID HIGH ENDOTHELIAL VENULES; LYMPH-NODE; STEADY-STATE; CELLS; ANTIGEN AB Migrating dendritic cells follow precise navigational chemokine gradients established by lymph node stromal cells through their asymmetric expression of the atypical chemokine receptor CCRL1. C1 [Woodruff, Matthew C.; Turley, Shannon J.] Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA 02163 USA. [Woodruff, Matthew C.] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Woodruff, Matthew C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. RP Woodruff, MC (reprint author), Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA 02163 USA. EM shannon_turley@dfci.harvard.edu NR 14 TC 1 Z9 2 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2014 VL 15 IS 7 BP 595 EP 596 PG 2 WC Immunology SC Immunology GA AJ5IJ UT WOS:000337715600003 PM 24940945 ER PT J AU Bhuvaneswar, CG Ruskin, JN Katzman, AR Wood, N Pitman, RK AF Bhuvaneswar, Chaya G. Ruskin, Jeremy N. Katzman, Anna Roglieri Wood, Nellie Pitman, Roger K. TI Pilot study of the effect of lipophilic vs. hydrophilic beta-adrenergic blockers being taken at time of intracardiac defibrillator discharge on subsequent PTSD symptoms SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE Stress disorders; Post-traumatic; Secondary prevention; Memory; Adrenergic beta-antagonists (all MeSH terms) ID POSTTRAUMATIC-STRESS-DISORDER; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; MEMORY CONSOLIDATION; PROPRANOLOL; PHARMACOTHERAPY; RECONSOLIDATION; ACTIVATION; PREVENTION; BLOCKADE; EVENTS AB A pathophysiological model of posttraumatic stress disorder (PTSD) posits that an overly strong stress response at the time of the traumatic event leads to overconsolidation of the event's memory in part through a central beta-adrenergic mechanism. We hypothesized that the presence of a beta-blocker in the patient's brain at the time of the traumatic event would reduce the PTSD outcome by blocking this effect. The unpredictable, uncontrollable discharge of an implantable intracardiac defibrillator (ICD) is experienced by most patients as highly stressful, and it has previously been shown to be capable of causing PTSD symptoms. The present pilot study evaluated a convenience sample of 18 male cardiac patients who had been taking either a lipophilic beta-blocker (which penetrates the blood-brain barrier) or a hydrophilic beta-blocker (which does not) at the time of a discharge of their ICD. The self- report PTSD Checklist-Specific Version quantified 17 PTSD symptoms pertaining to the ICD discharge during the month preceding the evaluation. There was a statistical trend for patients who had been taking a lipophilic beta-blocker at the time of the ICD discharge to have (35%) less severe PTSD symptoms than patients who had been taking a hydrophilic beta-blocker (one-tailed p = 0.07, g = 0.64). Further, prospective, randomized, controlled studies are suggested. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bhuvaneswar, Chaya G.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Ruskin, Jeremy N.] Massachusetts Gen Hosp, Div Cardiol, Dept Internal Med, Boston, MA 02114 USA. [Ruskin, Jeremy N.; Wood, Nellie; Pitman, Roger K.] Harvard Univ, Sch Med, Boston, MA USA. [Katzman, Anna Roglieri; Wood, Nellie; Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neurosci, Boston, MA 02114 USA. RP Pitman, RK (reprint author), MGH East, 120 Second Ave, Charlestown, MA 02129 USA. EM roger_pitman@hms.harvard.edu FU U.S. Public Health Service [MH068603-03S1] FX This project was supported by U.S. Public Health Service grant MH068603-03S1. The authors appreciate the assistance of Elaine Kay RN and Chris Feterowski RN. Theodore Stern MD provided helpful suggestions. NR 31 TC 4 Z9 5 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 EI 1095-9564 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD JUL PY 2014 VL 112 BP 248 EP 252 DI 10.1016/j.nlm.2013.12.013 PG 5 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AJ3FR UT WOS:000337552400028 PM 24389538 ER PT J AU Solovieff, N Roberts, AL Ratanatharathorn, A Haloosim, M De Vivo, I King, AP Liberzon, I Aiello, A Uddin, M Wildman, DE Galea, S Smoller, JW Purcell, SM Koenen, KC AF Solovieff, Nadia Roberts, Andrea L. Ratanatharathorn, Andrew Haloosim, Michelle De Vivo, Immaculata King, Anthony P. Liberzon, Israel Aiello, Allison Uddin, Monica Wildman, Derek E. Galea, Sandro Smoller, Jordan W. Purcell, Shaun M. Koenen, Karestan C. TI Genetic Association Analysis of 300 Genes Identifies a Risk Haplotype in SLCI8A2 for Post-traumatic Stress Disorder in Two Independent Samples SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; VESICULAR MONOAMINE TRANSPORTER; NATIONAL COMORBIDITY SURVEY; PSYCHIATRIC-DISORDERS; MENTAL-DISORDERS; TRAUMA EXPOSURE; DSM-IV; POPULATION; HEALTH; POLYMORPHISMS AB The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N = 2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR) = 1.4, p = 2.1E-05) in SLC I 8A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC I 8A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p = 0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p = 0.049; N = 748, men and women). SLC I 8A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p <0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects. C1 [Solovieff, Nadia; Smoller, Jordan W.; Purcell, Shaun M.] Massachusetts Gen Hosp, Dept Ctr Human Genet Res, Boston, MA 02114 USA. [Solovieff, Nadia; Smoller, Jordan W.; Purcell, Shaun M.] Broad Inst Harvard & MIT, Dept Stanley Ctr Psychiat Res, Cambridge, MA USA. [Solovieff, Nadia; Smoller, Jordan W.; Purcell, Shaun M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Roberts, Andrea L.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Ratanatharathorn, Andrew; Haloosim, Michelle; Galea, Sandro; Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [De Vivo, Immaculata] Harvard Univ, Sch Med, BWH, Channing Div Network Med, Boston, MA USA. [King, Anthony P.; Liberzon, Israel] VA Ann Arbor Hlth Syst, Mental Hlth Serv, Ann Arbor, MI 48105 USA. [Liberzon, Israel] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Aiello, Allison] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Uddin, Monica; Wildman, Derek E.] Wayne State Univ, Dept Psychiat & Behav Neurosci, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48207 USA. [Uddin, Monica] Wayne State Univ, Dept Psychiat & Behav Neurosci, Sch Med, Detroit, MI 48207 USA. [Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Purcell, Shaun M.] Mt Sinai Sch Med, Div Psychiat Genom, New York, NY USA. RP Koenen, KC (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 West 168th St,Room 720G, New York, NY 10032 USA. EM kck5@cumc.columbia.edu FU National Institute on Mental Health [RO1 MH093612, MH078928]; [DA022720]; [DA 022720-S1]; [MH088283]; [P51RR000165]; [RC4MH092707] FX This study was funded by National Institute on Mental Health awards RO1 MH093612, MH078928 to Karestan C Koenen. The Detroit Neighborhood Health Study (PI: Allison Aiello) is funded by DA022720, DA 022720-S1, and MH088283. Karestan C Koenen is also funded by grants, P51RR000165 and RC4MH092707. NR 51 TC 15 Z9 15 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2014 VL 39 IS 8 BP 1872 EP 1879 DI 10.1038/npp.2014.34 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AJ3EZ UT WOS:000337550600009 PM 24525708 ER PT J AU Song, Y Cho, G Chun, SI Baek, JH Cho, H Kim, YR Park, SB Kim, JK AF Song, Youngkyu Cho, Gyunggoo Chun, Song-I Baek, Jin Hee Cho, HyungJoon Kim, Young Ro Park, Sung Bin Kim, Jeong Kon TI Oxygen-induced frequency shifts in hyperoxia: a significant component of BOLD signal SO NMR IN BIOMEDICINE LA English DT Article DE oxygen; susceptibility; blood oxygen-level dependent (BOLD); hyperoxia; MRI ID CEREBRAL BLOOD-VOLUME; HUMAN BRAIN; CONTRAST; MRI; RELAXATION; RAT AB In comparison to the well-documented significance of intravascular deoxyhemoglobin (deoxyHgb), the effects of dissolved oxygen on the blood-oxygen-level-dependent (BOLD) signal have not been widely reported. Based on the fact that the prolonged inspiration of high oxygen fraction gas can result in up to a sixfold increase of the baseline tissue oxygenation, the current study focused on the influence of dissolved oxygen on the BOLD signal during hyperoxia. As results, our in vitro study revealed that the r(1) and r(2) (relaxivities) of the oxygen-treated serum were 0.22mM(-1) . s(-1) and 0.19 mM(-1) . s(-1), respectively. In an in vivo experiment, hyperoxic respiration induced negative BOLD contrast (i.e. signal decrease) in 18-42% of measured brain regions, voxels with accompanying significant decreases in both the T2 * (-12.1% to -19.4%) and T1 (-5.8% to -3.3%) relaxation times. In contrast, the T-2* relaxation time significantly increased (11.2% to 14.0%) for the voxels displaying positive BOLD contrast (in 41-50% of the measured brain), which reflected a hyperoxygenation-induced reduction in tissue deoxyHgb concentration. These data imply that hyperoxia-driven BOLD signal changes are primarily determined by the counteracting effects of extravascular oxygen and intravascular deoxyHgb. Oxygen-induced magnetic susceptibility was further demonstrated by the study of 1 min hypoxia, which induced BOLD signal changes opposite to those under hyperoxia. Vasoconstriction was more common in voxels with negative BOLD contrast than in voxels with positive contrast (% change of blood volume, -9.8% to -12.8% versus 2.0% to 2.2%), which further suggests that negative BOLD contrast is mainly evoked by an increase in extravascular oxygen concentration. Conclusively, frequency shifts, which are induced by the accumulation of oxygen molecules and associated magnetic field inhomogeneity, are a significant source of the negative BOLD contrast during hyperoxia. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Song, Youngkyu; Cho, Gyunggoo; Chun, Song-I; Baek, Jin Hee; Kim, Jeong Kon] Korea Basic Sci Inst, Div Magnet Resonance, Cheongwon, Chungbuk, South Korea. [Baek, Jin Hee; Kim, Jeong Kon] Univ Ulsan, Coll Med, Dept Radiol, Res Inst Radiol,Asan Med Ctr, Seoul, South Korea. [Cho, HyungJoon; Kim, Young Ro] Ulsan Natl Inst Sci & Technol, Ulsan, South Korea. [Kim, Young Ro] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Park, Sung Bin] Chung Ang Univ, Coll Med, Chung Ang Univ Hosp, Dept Radiol, Seoul 156756, South Korea. RP Kim, JK (reprint author), Univ Ulsan, Coll Med, Dept Radiol, Res Inst Radiol,Asan Med Ctr, Seoul, South Korea. EM kim.jeongkon@gmail.com FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2010-0025731, 2011-0028826]; Korea Basic Science Institute [E33600, D33404]; KOFST Brain Pool Program FX This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0025731 and 2011-0028826), by a grant from Korea Basic Science Institute (E33600 and D33404), and by the KOFST Brain Pool Program. NR 18 TC 3 Z9 3 U1 0 U2 12 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 2014 VL 27 IS 7 BP 835 EP 842 DI 10.1002/nbm.3128 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA AJ3XS UT WOS:000337601800011 PM 24828299 ER PT J AU Quackenbush, J AF Quackenbush, John TI Learning to share SO SCIENTIFIC AMERICAN LA English DT Editorial Material C1 Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. RP Quackenbush, J (reprint author), Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. EM johnq@jimmy.harvard.edu FU NHLBI NIH HHS [R01 HL111759]; NLM NIH HHS [R01 LM010129] NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD JUL PY 2014 VL 311 IS 1 BP S22 EP S22 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ5FX UT WOS:000337709200038 PM 24974706 ER PT J AU McMurtrey, C Harriff, M Liles, LM Swarbrick, G Bardet, W Canfield, ET Jackson, K Lewinsohn, D Lewinsohn, D Hildebrand, W AF McMurtrey, Curtis Harriff, Melanie Liles, Lauren M. Swarbrick, Gwendolyn Bardet, Wilfried Canfield, Elizabeth T. Jackson, Ken Lewinsohn, Deborah Lewinsohn, David Hildebrand, William TI M. TUBERCULOSIS PEPTIDE LIGAND PRESENTATION BY NON-CLASSICAL HLA-E SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 28th EFI European Immunogenetics and Histocompatibility Conference CY JUN 25-28, 2014 CL Stockholm, SWEDEN SP EFI C1 [McMurtrey, Curtis; Liles, Lauren M.; Bardet, Wilfried; Jackson, Ken; Hildebrand, William] Univ Oklahoma HSC, Oklahoma City, OK USA. [Harriff, Melanie; Swarbrick, Gwendolyn; Canfield, Elizabeth T.; Lewinsohn, Deborah; Lewinsohn, David] Portland VA Med Ctr, Portland, OR USA. EM william-hildebrand@ouhsc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-2815 EI 1399-0039 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2014 VL 84 IS 1 BP 6 EP 6 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA AJ3DN UT WOS:000337546000005 ER PT J AU Israeli, M Pollack, MS Shaut, CAE Youngs, D Halpin, A Saidman, SL AF Israeli, Moshe Pollack, Marilyn S. Shaut, Carley A. E. Youngs, Danny Halpin, Anne Saidman, Susan L. TI HARMONY AND DISHARMONY IN ANTI-HLA ANTIBODY TESTING (ON BEHALF OF THE ASHI PROFICIENCY TESTING PROGRAM) SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 28th EFI European Immunogenetics and Histocompatibility Conference CY JUN 25-28, 2014 CL Stockholm, SWEDEN SP EFI C1 [Israeli, Moshe] Leiden Univ, Med Ctr, Leiden, Netherlands. [Pollack, Marilyn S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Shaut, Carley A. E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Youngs, Danny] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Halpin, Anne] Univ Alberta Hosp, Edmonton, AB T6G 2B7, Canada. [Saidman, Susan L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM israelimoshe@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-2815 EI 1399-0039 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2014 VL 84 IS 1 BP 91 EP 92 PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA AJ3DN UT WOS:000337546000213 ER PT J AU Morrison, P Nikolajski, C Borrero, S Zickmund, S AF Morrison, Penelope Nikolajski, Cara Borrero, Sonya Zickmund, Susan TI Youth Perspectives on Risk and Resiliency: A Case Study From Juiz de Fora, Brazil SO YOUTH & SOCIETY LA English DT Article DE culture; health; risk behavior; resiliency ID PROTECTIVE FACTORS; SAO-PAULO; FAMILY-STRUCTURE; SEXUAL-BEHAVIOR; DRUG-USE; HEALTH; ADOLESCENTS; CHILDHOOD; ADULTHOOD; ATTITUDES AB The present work seeks to contribute to studies of cross-cultural risk and resiliency by presenting results from qualitative research with adolescents attending programs for at-risk youth in Juiz de Fora, Brazil. In 1990, Brazil introduced the Child and Adolescent Act (ECA), a significant piece of legislation that has had a direct impact on how at-risk youth are conceptualized both nationally and locally, through programs that target them. Little, however, is known about how youth in Brazil understand risk behaviors, what factors they believe contribute to risk taking or what they believe promotes resiliency. Furthermore, virtually no qualitative information exists on adolescents who are engaged in programs that use ECA as a prioritizing principle. By examining adolescent perspectives on risk and resiliency in such a context, we highlight the cultural differences in how youth negotiate their daily lives and the implications that continued exclusion of youth has on Brazilian society. C1 [Morrison, Penelope] Univ Pittsburgh, Hlth Inst, RAND, Pittsburgh, PA 15213 USA. [Nikolajski, Cara] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA 15213 USA. [Borrero, Sonya] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Zickmund, Susan] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Morrison, P (reprint author), Univ Pittsburgh, Hlth Inst, RAND, 230 McKeePl,Suite 600, Pittsburgh, PA 15213 USA. EM morrisonpk@upmc.edu NR 70 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 0044-118X EI 1552-8499 J9 YOUTH SOC JI Youth Soc. PD JUL PY 2014 VL 46 IS 4 BP 505 EP 528 DI 10.1177/0044118X12441614 PG 24 WC Social Issues; Social Sciences, Interdisciplinary; Sociology SC Social Issues; Social Sciences - Other Topics; Sociology GA AJ3ZG UT WOS:000337606900004 ER PT J AU Hanson, RF Gros, KS Davidson, TM Barr, S Cohen, J Deblinger, E Mannarino, AP Ruggiero, KJ AF Hanson, Rochelle F. Gros, Kirstin Stauffacher Davidson, Tatiana M. Barr, Simone Cohen, Judith Deblinger, Esther Mannarino, Anthony P. Ruggiero, Kenneth J. TI National Trainers' Perspectives on Challenges to Implementation of an Empirically-Supported Mental Health Treatment SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Treatment fidelity; Implementation of evidence-based treatment; Child mental health ID COGNITIVE-BEHAVIORAL THERAPY; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED-CONTROLLED-TRIAL; PSYCHOSOCIAL TREATMENTS; COMMUNITY TREATMENT; TRAUMATIC EVENTS; PTSD SYMPTOMS; CHILDREN; ADOLESCENTS; FIDELITY AB This study examined perceived challenges to implementation of an empirically supported mental health treatment for youth (Trauma-Focused Cognitive Behavioral Therapy; TF-CBT) and explored the potential use of technology-based resources in treatment delivery. Thematic interviews were conducted with 19 approved national TF-CBT trainers to assess their perspectives about challenges to implementation of TF-CBT and to explore their perceptions about the potential value of innovative, technology-based solutions to enhance provider fidelity and improve quality of care. These data offer some important insights and implications for training in evidence-based treatments, provider fidelity and competence, and patient engagement, particularly for those interventions targeting trauma-related symptoms among youth. C1 [Hanson, Rochelle F.; Gros, Kirstin Stauffacher; Davidson, Tatiana M.; Barr, Simone; Ruggiero, Kenneth J.] Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, Charleston, SC 29425 USA. [Gros, Kirstin Stauffacher; Ruggiero, Kenneth J.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Cohen, Judith; Mannarino, Anthony P.] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Deblinger, Esther] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. RP Hanson, RF (reprint author), Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, MSC 861, Charleston, SC 29425 USA. EM hansonrf@musc.edu FU CMHS SAMHSA HHS [1U79SM061269-01]; NCATS NIH HHS [UL1 TR000062]; NCRR NIH HHS [UL1 RR029882]; NIMH NIH HHS [R25 MH080916-01A2, R34 MH096907, R01 MH081056, R25 MH080916, 1 R34 MH096907-01] NR 50 TC 7 Z9 7 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD JUL PY 2014 VL 41 IS 4 BP 522 EP 534 DI 10.1007/s10488-013-0492-6 PG 13 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AI7OS UT WOS:000337083600009 PM 23605292 ER PT J AU Hayek, M Mackie, TI Mule, CM Bellonci, C Hyde, J Bakan, JS Leslie, LK AF Hayek, Munya Mackie, Thomas I. Mule, Christina M. Bellonci, Christopher Hyde, Justeen Bakan, Jennifer S. Leslie, Laurel K. TI A Multi-state Study on Mental Health Evaluation for Children Entering Foster Care SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Mental health; Screening; Assessment; Evaluation; Foster care; Child welfare ID YOUNG-CHILDREN; PSYCHOMETRIC PROPERTIES; NATIONAL PERSPECTIVE; STATE CUSTODY; SERVICE USE; WELFARE; SCALE; YOUTH; IMPLEMENTATION; IDENTIFICATION AB When compared with the general United States child population, children entering foster care have elevated rates of mental health problems. This study examines: (1) state approaches to mental health evaluations for children entering foster care for the first time, (2) the consistency of these approaches with professional guidelines, and (3) whether the specific instruments endorsed are supported by available evidence. Semi-structured qualitative interviews and a document review of available protocols/policies were conducted for 47 states and the District of Columbia. All states endorsed mental health evaluations; variation existed between states in approach, timeframe, administrator, and specific instruments endorsed. C1 [Hayek, Munya; Bellonci, Christopher; Leslie, Laurel K.] Tufts Med Ctr, Boston, MA USA. [Hayek, Munya; Leslie, Laurel K.] Floating Hosp Children, Tufts Med Ctr, Boston, MA USA. [Mackie, Thomas I.; Mule, Christina M.; Bakan, Jennifer S.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Mackie, Thomas I.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Mule, Christina M.] May Inst, Randolph, MA USA. [Mule, Christina M.] Northeastern Univ, Boston, MA 02115 USA. [Bellonci, Christopher] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Hyde, Justeen] Inst Community Hlth, Cambridge, MA USA. [Bakan, Jennifer S.] Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Leslie, Laurel K.] Tufts Clin & Translat Sci Inst, Ctr Aligning Researchers & Communities Hlth, Boston, MA 02111 USA. RP Leslie, LK (reprint author), Tufts Clin & Translat Sci Inst, Ctr Aligning Researchers & Communities Hlth, 800 Washington St,MC 345, Boston, MA 02111 USA. EM lleslie@tuftsmedicalcenter.org NR 79 TC 2 Z9 2 U1 6 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD JUL PY 2014 VL 41 IS 4 BP 552 EP 567 DI 10.1007/s10488-013-0495-3 PG 16 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AI7OS UT WOS:000337083600012 PM 23709285 ER PT J AU Bandla, S Peters, JH Ruff, D Chen, SM Li, CY Song, KC Thoms, K Litle, VR Watson, T Chapurin, N Lada, M Pennathur, A Luketich, JD Peterson, D Dulak, A Lin, L Bass, A Beer, DG Godfrey, TE Zhou, ZR AF Bandla, Santhoshi Peters, Jeffrey H. Ruff, David Chen, Shiaw-Min Li, Chieh-Yuan Song, Kunchang Thoms, Kimberly Litle, Virginia R. Watson, Thomas Chapurin, Nikita Lada, Michal Pennathur, Arjun Luketich, James D. Peterson, Derick Dulak, Austin Lin, Lin Bass, Adam Beer, David G. Godfrey, Tony E. Zhou, Zhongren TI Comparison of Cancer-Associated Genetic Abnormalities in Columnar-Lined Esophagus Tissues With and Without Goblet Cells SO ANNALS OF SURGERY LA English DT Article DE Barrett's esophagus; surveillance; DNA copy number alterations; esophageal metaplasia; mutation ID BARRETTS-ESOPHAGUS; INTESTINAL METAPLASIA; NEOPLASTIC PROGRESSION; SCREENING-TEST; ADENOCARCINOMA; GENOME; INSTABILITY; SURVEILLANCE; MANAGEMENT; DIAGNOSIS AB Objective: To determine and compare the frequency of cancer-associated genetic abnormalities in esophageal metaplasia biopsies with and without goblet cells. Background: Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma (EAC), but the appropriate histologic definition of Barrett's esophagus is debated. Intestinal metaplasia (IM) is defined by the presence of goblet cells whereas nongoblet cell metaplasia (NGM) lacks goblet cells. Both have been implicated in EAC risk but this is controversial. Although IM is known to harbor genetic changes associated with EAC, little is known about NGM. We hypothesized that if NGM and IM infer similar EAC risk, then they would harbor similar genetic aberrations in genes associated with EAC. Methods: Ninety frozen NGM, IM, and normal tissues from 45 subjects were studied. DNA copy number abnormalities were identified using microarrays and fluorescence in situ hybridization. Targeted sequencing of all exons from 20 EAC-associated genes was performed on metaplasia biopsies using Ion AmpliSeq DNA sequencing. Results: Frequent copy number abnormalities targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In 1 subject, fluorescence in situ hybridization confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing revealed 11 nonsynonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples. Conclusions: This study reports the largest and most comprehensive comparison of DNA aberrations in IM and NGM genomes. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM. C1 [Bandla, Santhoshi; Peters, Jeffrey H.; Thoms, Kimberly; Watson, Thomas; Chapurin, Nikita; Lada, Michal] Univ Rochester Med Ctr, Strong Mem Hosp, Dept Surg, Rochester, NY USA. [Song, Kunchang; Zhou, Zhongren] Univ Rochester Med Ctr, Strong Mem Hosp, Dept Pathol, Rochester, NY USA. [Peterson, Derick] Univ Rochester Med Ctr, Strong Mem Hosp, Dept Biostat, Rochester, NY USA. [Ruff, David; Chen, Shiaw-Min; Li, Chieh-Yuan] Life Technol, Foster City, CA USA. [Dulak, Austin; Bass, Adam] Dana Farber Canc Ctr, Boston, MA USA. [Lin, Lin; Beer, David G.] Univ Michigan, Ann Arbor, MI 48109 USA. [Pennathur, Arjun; Luketich, James D.] Univ Pittsburgh, Pittsburgh, PA USA. [Litle, Virginia R.; Godfrey, Tony E.] Boston Univ, Dept Surg, Boston, MA 02215 USA. RP Godfrey, TE (reprint author), Boston Univ Med Ctr, 700 Albany St,W408, Boston, MA 02118 USA. EM godfreyt@bu.edu; David_zhou@urmc.rochester.edu RI Godfrey, Tony/A-5572-2013; OI Godfrey, Tony/0000-0002-3283-6983; Chapurin, Nikita/0000-0002-3744-0451 FU Department of Cytogenetics FISH Core Facility at the University of Rochester Medical Center FX The authors gratefully acknowledge the support provided by the Department of Cytogenetics FISH Core Facility at the University of Rochester Medical Center and by Michael Thornton, Rob Bennett, Ben Kong, Iris Casuga, and David Joun at Life Technologies. NR 35 TC 8 Z9 8 U1 0 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 2014 VL 260 IS 1 BP 72 EP 80 DI 10.1097/SLA.0000000000000424 PG 9 WC Surgery SC Surgery GA AI9XD UT WOS:000337297900014 PM 24509200 ER PT J AU Rosario, M Reisner, SL Corliss, HL Wypij, D Frazier, AL Austin, SB AF Rosario, Margaret Reisner, Sari L. Corliss, Heather L. Wypij, David Frazier, A. Lindsay Austin, S. Bryn TI Disparities in Depressive Distress by Sexual Orientation in Emerging Adults: The Roles of Attachment and Stress Paradigms SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Sexual orientation; Depression; Attachment; Stress; Youth ID MENTAL-HEALTH; BISEXUAL YOUTHS; BUTCH/FEMME DIFFERENCES; INTERNALIZING SYMPTOMS; GENDER NONCONFORMITY; IDENTITY DEVELOPMENT; LONGITUDINAL DATA; SOCIAL SUPPORT; SUBSTANCE USE; YOUNG-ADULTS AB Lesbian, gay, and bisexual (BI) youth have elevated rates of depression compared to heterosexuals. We proposed and examined a theoretical model to understand whether attachment and stress paradigms explain disparities in depressive distress by sexual orientation, using the longitudinal Growing Up Today Study (GUTS) and Nurses' Health Study II (NHSII). GUTS participants eligible for this analysis reported sexual orientation, childhood gender nonconforming behaviors (GNBs), attachment to mother (all in 2005), and depressive symptoms (in 2007). Mothers of the GUTS participants who are the NHSII participants reported attitudes toward homosexuality (in 2004) and maternal affection (in 2006). The sample had 6,122 participants. Of GUTS youth (M = 20.6 years old in 2005; 64.4 % female), 1.7 % were lesbian/gay (LG), 1.7 % bisexual (BI), 10.0 % mostly heterosexual (MH), and 86.7 % completely heterosexual (CH). After adjusting for demographic characteristics and sibling clustering, LGs, BIs, and MHs reported more depressive distress than CHs. This relation was partially mediated (i.e., explained) for LGs, BIs, and MHs relative to CHs by less secure attachment. A conditional relation (i.e., interaction) indicated that BIs reported more distress than CHs as GNBs increased for BIs; no comparable relation was found for LGs versus CHs. Sibling comparisons found that sexual minorities (LGs, BIs, and MHs) reported more depressive distress, less secure attachment, and more childhood GNBs than CH siblings; the mothers reported less affection for their sexual-minority than CH offspring. The findings suggest that attachment and childhood gender nonconformity differentially pattern depressive distress by sexual orientation. Attachment and related experiences are more problematic for sexual minorities than for their CH siblings. C1 [Rosario, Margaret] CUNY City Coll, Dept Psychol, New York, NY 10031 USA. [Rosario, Margaret] Grad Ctr, New York, NY 10031 USA. [Reisner, Sari L.; Austin, S. Bryn] Harvard Univ, Sch Publ Hlth, Dept Soc & Behav Sci, Boston, MA 02115 USA. [Corliss, Heather L.; Austin, S. Bryn] Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA 02115 USA. [Wypij, David] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wypij, David] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Wypij, David; Frazier, A. Lindsay; Austin, S. Bryn] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. [Frazier, A. Lindsay] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Frazier, A. Lindsay; Austin, S. Bryn] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Rosario, M (reprint author), CUNY City Coll, Dept Psychol, Convent Ave & 138th St,NAC 7-120, New York, NY 10031 USA. EM mrosario@gc.cuny.edu FU NICHD NIH HHS [HD45763, R01 HD057368, HD57368, R01 HD045763]; NIDA NIH HHS [K01 DA023610]; PHS HHS [6T71-MC00009] NR 88 TC 10 Z9 10 U1 2 U2 21 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 2014 VL 43 IS 5 BP 901 EP 916 DI 10.1007/s10508-013-0129-6 PG 16 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA AI8FU UT WOS:000337146000006 PM 23780518 ER PT J AU Colak, S Zimberlin, CD Fessler, E Hogdal, L Prasetyanti, PR Grandela, CM Letai, A Medema, JP AF Colak, S. Zimberlin, C. D. Fessler, E. Hogdal, L. Prasetyanti, P. R. Grandela, C. M. Letai, A. Medema, J. P. TI Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID METASTATIC COLORECTAL-CANCER; ANTITUMOR-ACTIVITY; PLUS IRINOTECAN; BCL-2 PROTEIN; INHIBITOR; APOPTOSIS; LYMPHOMAS; ABT-199; BAX; TRANSLOCATION AB Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. Our data therefore point to a crucial role of BCLXL in protecting CSCs from chemotherapy and suggest that BH3 mimetics, in combination with chemotherapy, can be an efficient way to target chemotherapy-resistant CSCs. C1 [Colak, S.; Zimberlin, C. D.; Fessler, E.; Prasetyanti, P. R.; Grandela, C. M.; Medema, J. P.] Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med, LEXOR Lab Expt Oncol & Radiobiol, NL-1105 AZ Amsterdam, Netherlands. [Hogdal, L.; Letai, A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Medema, JP (reprint author), Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med, LEXOR Lab Expt Oncol & Radiobiol, CEMM Room G2-131,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM J.P.Medema@amc.uva.nl FU Netherlands Organisation for Scientific Research; Dutch Cancer Society (KWF Kankerbestrijding) grant [2009-4416, 2012-5612] FX We thank Louis Vermeulen, Felipe de Sousa e Melo, Michael Bots, Maarten Bijlsma and Jeremy Ryan for constructive discussion, and the surgeons Professor Bemelman, Professor Gulik, Dr. Tanis, Dr. Buskens and Dr. Van de Ven (AMC, Amsterdam) for providing colon cancer samples. We also thank Dr. Mien-Chie Hung (University of Texas) for providing MCL1-3a mutant construct and Dr. Rogier Rooswinkel and Professor Jannie Borst (The Netherlands Cancer Institute, Amsterdam) for providing all other pro-survival BCL2 family members, Dr. Laurie Ailles (University of Toronto) for providing Tcf/Lef reporter construct and Arjen Bakker and Dr. Bianca Blom (AMC Amsterdam) for providing pHEFTIG construct. Finally, we thank Berend Hooibrink, Toni van Capel and Kate Cameron (AMC, Amsterdam) for assistance with fluorescence-activated cell sorting experiments. This work was supported by a VICI grant from the Netherlands Organisation for Scientific Research and a Dutch Cancer Society (KWF Kankerbestrijding) grant (2009-4416 and 2012-5612; to JPM). NR 48 TC 27 Z9 28 U1 3 U2 11 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 2014 VL 21 IS 7 BP 1170 EP 1177 DI 10.1038/cdd.2014.37 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AI9EY UT WOS:000337234200014 PM 24682005 ER PT J AU Christov, M AF Christov, Marta TI Fibroblast growth factor 23 in acute kidney injury SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE FGF23; mineral metabolism; phosphate ID DOMINANT HYPOPHOSPHATEMIC RICKETS; LEFT-VENTRICULAR HYPERTROPHY; STAGE RENAL-DISEASE; PHOSPHATE HOMEOSTASIS; PARATHYROID-HORMONE; ADVERSE OUTCOMES; FGF23; FAILURE; CALCIUM; DEFICIENCY AB Purpose of review To review the emerging literature on changes in fibroblast growth factor 23 (FGF23) levels in the setting of acute kidney injury (AKI). Recent findings Studies suggest that FGF23 levels are elevated in patients with AKI and correlate with increased risk of death or need for dialysis in adults, or prolonged ventilation time and higher fluid gain in children. Animal studies have shown that the cause behind this FGF23 increase is multifactorial and includes increased production in bone and decreased clearance, but not vitamin D or parathyroid hormone (PTH) activated pathways. Interestingly, FGF23 levels are found to be mildly elevated even in hospitalized patients without kidney injury, although this observation may be limited to only c-terminal FGF23 fragments. The prognostic implications of an elevated FGF23 value in patients with AKI need to be confirmed in larger cohorts and evaluated for long-term outcomes such as the development of new chronic kidney disease (CKD) or CKD progression, as well as cardiovascular disease, similar to the studies of FGF23 in the prevalent CKD population. Summary FGF23 levels are elevated in patients with AKI and are associated with morbidity and mortality in small human studies. Mechanistic work in animals suggests that the elevation is independent of PTH or vitamin D signaling pathways. Much work remains to understand the physiology behind FGF23 elevation and the long-term effects of FGF23 in AKI. C1 [Christov, Marta] Beth Israel Deaconess Med Ctr, Div Nephrol, Dept Med, Boston, MA 02114 USA. [Christov, Marta] Massachusetts Gen Hosp, Dept Med, Div Endocrinol, Boston, MA 02114 USA. RP Christov, M (reprint author), Beth Israel Deaconess Med Ctr, Div Nephrol, Renal Unit Farr8, 185 Pilgrim Rd, Boston, MA 02114 USA. EM mchrist3@bidmc.harvard.edu FU NIDDK [DK93608] FX M.C. is supported by NIDDK DK93608. M. C. thanks H. Juppner for helpful comments on this article. NR 42 TC 4 Z9 4 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2014 VL 23 IS 4 BP 340 EP 345 DI 10.1097/01.mnh.0000447021.51722.2f PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA AI8HU UT WOS:000337153600003 PM 24848938 ER PT J AU DeCaprio, JA Duensing, A AF DeCaprio, James A. Duensing, Anette TI The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE DREAM complex; gastrointestinal stromal tumor; imatinib mesylate (Gleevec); quiescence ID CELL-CYCLE; SUBCELLULAR-LOCALIZATION; GENE-EXPRESSION; DOSE IMATINIB; QUIESCENCE; PROTEIN; KIT; DYRK1A; SENESCENCE; KINASE AB Purpose of review Although most gastrointestinal stromal tumors respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), complete remissions are rare and the majority of patients achieve disease stabilization. Furthermore, discontinuation of treatment in the presence of residual tumor mass almost inevitably leads to tumor progression. These observations suggest that a subset of tumor cells not only persists under imatinib treatment, but remains viable. The current article reviews the molecular basis for these findings and explores strategies to exploit them therapeutically. Recent findings Although imatinib induces apoptosis in a subset of gastrointestinal stromal tumor cells, it leads to a reversible exit from the cell division cycle and entry into G0, a cell cycle state called quiescence, in the remaining cells. Mechanistically, this process involves the DREAM complex (DP, p130/RBL2, E2F4 and MuvB), a newly identified key regulator of quiescence. Interfering with DREAM complex formation either by siRNA-mediated knockdown or by pharmacological inhibition of the regulatory kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A was shown to enhance imatinib-induced gastrointestinal stromal tumor cell death. Summary Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses. C1 [DeCaprio, James A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [DeCaprio, James A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [DeCaprio, James A.] Harvard Univ, Sch Med, Boston, MA USA. [Duensing, Anette] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Canc Therapeut Program, Pittsburgh, PA 15213 USA. [Duensing, Anette] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. RP Duensing, A (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Suite 1-8,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM aduensin@pitt.edu OI Duensing, Anette/0000-0002-0168-4067 FU U.S. Public Health Service [P01CA050661, R01CA63113]; American Cancer Society [RSG-08-092-01-CCG]; GIST Cancer Research Fund; Life Raft Group; UPCI; Pennsylvania Department of Health FX This work was supported in part by U.S. Public Health Service grants P01CA050661 and R01CA63113 (both to J.A.D.), a Research Scholar Grant from the American Cancer Society (RSG-08-092-01-CCG; to A. D.), the GIST Cancer Research Fund (to A. D.), The Life Raft Group (to A. D.) and a number of private donations (to A. D.). A. D. is supported by the UPCI and in part by a grant from the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. NR 49 TC 5 Z9 5 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JUL PY 2014 VL 26 IS 4 BP 415 EP 421 DI 10.1097/CCO.0000000000000090 PG 7 WC Oncology SC Oncology GA AI9UD UT WOS:000337283800009 PM 24840522 ER PT J AU Morales-Oyarvide, V Mino-Kenudson, M AF Morales-Oyarvide, Vicente Mino-Kenudson, Mari TI High-grade lung adenocarcinomas with micropapillary and/or solid patterns: a review SO CURRENT OPINION IN PULMONARY MEDICINE LA English DT Review DE histologic subtypes; lung adenocarcinoma; micropapillary; solid pattern ID RESPIRATORY SOCIETY CLASSIFICATION; PREDOMINANT HISTOLOGIC SUBTYPE; INTERNATIONAL-ASSOCIATION; IASLC/ATS/ERS CLASSIFICATION; PROGNOSTIC-SIGNIFICANCE; GENE ALTERATIONS; CHINESE PATIENTS; EGFR; RECURRENCE; MUTATIONS AB Purpose of review The purpose of this review is to discuss the most recent research findings on lung adenocarcinomas with solid and micropapillary patterns. Recent findings Multiple recent studies have confirmed that both patterns are associated with adverse clinicopathologic features such as lymphovascular and pleural invasion, as well as lymph node metastasis, and consequently with poor disease-free survival, overall survival, or both. Radiologic characteristics such as high F-18-fluorodeoxyglucose (FDG) uptake, a solid nodule, and size >2 cm have been found to be useful to detect solid and micropapillary patterns. A seminal study has shown that the presence of a micropapillary component (>5%) is a risk factor for early locoregional recurrence in patients undergoing limited resection for small (<2 cm) adenocarcinomas, but not for patients undergoing lobectomy. Several studies have demonstrated that micropapillary-predominant tumors are associated with EGFR mutations, whereas solid-predominant tumors are negatively associated with mutations of this gene and positively associated with KRAS mutations, indicative of the lack of response to EGFR tyrosine kinase inhibitors. The possible role of molecular events such as loss of BRG1/BRM and activation of c-Met has been identified in solid pattern and micropapillary pattern, respectively. Summary Micropapillary and solid patterns are markers for early recurrence and poor survival in lung adenocarcinomas. In order to overcome the unfavorable outcomes, the preoperative detection of these patterns, development of targeted therapy for KRAS mutants, and discovery of biomarkers that play a significant role in development or progression or both of these patterns are warranted to help in treating lung adenocarcinoma patients with micropapillary or solid patterns or both effectively. C1 [Morales-Oyarvide, Vicente] Inst Nacl Cancerol, Clin Thorac Oncol, Mexico City, DF, Mexico. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Boston, MA USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA. EM mminokenudson@partners.org NR 32 TC 9 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-5287 EI 1531-6971 J9 CURR OPIN PULM MED JI Curr. Opin. Pulm. Med. PD JUL PY 2014 VL 20 IS 4 BP 317 EP 323 DI 10.1097/MCP.0000000000000070 PG 7 WC Respiratory System SC Respiratory System GA AI9TN UT WOS:000337280500002 PM 24852329 ER PT J AU Berkowitz, SA Atlas, SJ Grant, RW Wexler, DJ AF Berkowitz, S. A. Atlas, S. J. Grant, R. W. Wexler, D. J. TI Individualizing HbA(1c) targets for patients with diabetes: impact of an automated algorithm within a primary care network SO DIABETIC MEDICINE LA English DT Article ID INTENSIVE GLUCOSE CONTROL; GLYCEMIC TARGETS; QUALITY MEASURES; TYPE-2; MELLITUS; COMPLICATIONS; MANAGEMENT; PERFORMANCE; DISPARITIES; GOALS AB Aims To develop glycaemic goal individualization algorithms and assess potential impact on a healthcare system and different segments of the population with diabetes. Methods A cross-sectional observational study of patients with diabetes in a primary care network age >18years with an HbA1c measured between 1 January and 31 December 2011. We applied diabetes guidelines to create targeted algorithms 1 and 2, which assigned HbA1c goals based on age, duration of diabetes (<15years or <10years), diabetes complications and Charlson co-morbidity score (<6 or <4) [targeted algorithm2 was designed to assign more patients a goal <64mmol/mol (8.0%) than targeted algorithm1]. Each patient's HbA1c was compared with these targeted goals and to the standard' goal <53mmol/mol (7.0%). Agreement was tested using McNemar's test. Results Overall, 55.7% of 12199 patients would be considered controlled under the standard' approach, 61.2% under targeted algorithm1 and 67.5% under targeted algorithm2. Targeted algorithm1 reclassified 1213 (23.6%) patients considered uncontrolled under the standard approach to controlled, P<0.001. Targeted algorithm2 reclassified 1844 (35.2%) patients, P<0.001. Compared with those controlled under the standard goal, there was no significant difference in the proportion of those controlled using targeted goals who had Medicaid, had less than a high school diploma or received primary care in a federally qualified health centre. Conclusions Two automated targeted algorithms would reclassify one quarter to one third of patients from uncontrolled to controlled within a primary care network without differentially affecting vulnerable patient subgroups. C1 [Berkowitz, S. A.; Atlas, S. J.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Berkowitz, S. A.; Atlas, S. J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Grant, R. W.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Wexler, D. J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Diabet Ctr,Dept Med, Boston, MA USA. RP Berkowitz, SA (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. EM SABerkowitz@partners.org OI Berkowitz, Seth/0000-0003-1030-4297; Grant, Richard/0000-0002-6164-8025 FU Institutional National Research Service Award [T32HP10251]; Ryoichi Sasakawa Fellowship Fund; General Medicine Division at Massachusetts General Hospital FX SAB was supported by an Institutional National Research Service Award no. T32HP10251, the Ryoichi Sasakawa Fellowship Fund and by the General Medicine Division at Massachusetts General Hospital. The funding organizations had no role in the design and conduct of the study; collection, management, analysis and interpretation of data; or preparation, review or approval of the manuscript, or decisions to submit for publication. NR 28 TC 6 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-3071 EI 1464-5491 J9 DIABETIC MED JI Diabetic Med. PD JUL PY 2014 VL 31 IS 7 BP 839 EP 846 DI 10.1111/dme.12427 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ4DL UT WOS:000337621100013 PM 24606323 ER PT J AU Bind, MA Zanobetti, A Gasparrini, A Peters, A Coull, B Baccarelli, A Tarantini, L Koutrakis, P Vokonas, P Schwartz, J AF Bind, Marie-Abele Zanobetti, Antonella Gasparrini, Antonio Peters, Annette Coull, Brent Baccarelli, Andrea Tarantini, Letizia Koutrakis, Petros Vokonas, Pantel Schwartz, Joel TI Effects of Temperature and Relative Humidity on DNA Methylation SO EPIDEMIOLOGY LA English DT Article ID APPARENT TEMPERATURE; AMBIENT-TEMPERATURE; AIR-TEMPERATURE; HEART-DISEASE; CARDIOVASCULAR-DISEASE; OUTDOOR TEMPERATURE; HOSPITAL ADMISSIONS; CASE-CROSSOVER; INFLAMMATION; COAGULATION AB Background: Previous studies have found relationships between DNA methylation and various environmental contaminant exposures. Associations with weather have not been examined. Because temperature and humidity are related to mortality even on non-extreme days, we hypothesized that temperature and relative humidity may affect methylation. Methods: We repeatedly measured methylation on long interspersed nuclear elements (LINE-1), Alu, and 9 candidate genes in blood samples from 777 elderly men participating in the Normative Aging Study (1999-2009). We assessed whether ambient temperature and relative humidity are related to methylation on LINE-1 and Alu, as well as on genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. We examined intermediate-term associations of temperature, relative humidity, and their interaction with methylation, using distributed lag models. Results: Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5 degrees C increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (-8% to -1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days. Conclusions: DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may also interact to produce stronger effects. C1 [Bind, Marie-Abele; Zanobetti, Antonella; Peters, Annette; Baccarelli, Andrea; Koutrakis, Petros; Schwartz, Joel] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Bind, Marie-Abele; Coull, Brent] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gasparrini, Antonio] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. [Peters, Annette] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol, Neuherberg, Germany. [Tarantini, Letizia] Univ Milan, Ctr Mol & Genet Epidemiol, Milan, Italy. [Vokonas, Pantel] Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02118 USA. [Vokonas, Pantel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Bind, MA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Landmark Ctr, 401 Pk Dr,Suite 415, Boston, MA 02115 USA. EM ma.bind@mail.harvard.edu RI Gasparrini, Antonio/F-7627-2012; Peters, Annette/A-6117-2011; OI Gasparrini, Antonio/0000-0002-2271-3568; Baccarelli, Andrea/0000-0002-3436-0640 FU US EPA [RD-827353, RD-832416]; NIEHS [RO1-ES015172, 2RO1-ES015172, R21 AG0H0027, ES014663, ES00002]; Clean Air Act grant [RD83479701]; Medical Research Council-UK [G1002296]; Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs, Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA FX This work was supported by the following US EPA grants RD-827353 and RD-832416; NIEHS grants RO1-ES015172, 2RO1-ES015172, R21 AG0H0027, ES014663, ES00002, and Clean Air Act grant RD83479701, and by a grant from Medical Research Council-UK G1002296. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA. NR 40 TC 10 Z9 11 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2014 VL 25 IS 4 BP 561 EP 569 DI 10.1097/EDE.0000000000000120 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AJ0CM UT WOS:000337316700014 PM 24809956 ER PT J AU Sallaway, L Magee, S Shi, J Lehmann, O Quivira, F Tgavalekos, K Brooks, DH Muftu, S Meleis, W Moore, RH Kopans, D Wan, KT AF Sallaway, L. Magee, S. Shi, J. Lehmann, O. Quivira, F. Tgavalekos, K. Brooks, D. H. Muftu, S. Meleis, W. Moore, R. H. Kopans, D. Wan, K. -T. TI Detecting Solid Masses in Phantom Breast Using Mechanical Indentation SO EXPERIMENTAL MECHANICS LA English DT Article DE Palpation; Indentation; Breast cancer; Phantom gel; Lesion detection ID CANCER MORTALITY; CARCINOMA MORTALITY; MAMMOGRAPHY; WOMEN; ELASTOGRAPHY; REDUCTION; TRIALS; TISSUE AB Palpation is an economical, safe and effective method to detect breast cancer among other expensive and sometimes limited diagnostic tools such as mammography and magnetic resonance imaging (MRI). To understand the mechanics of palpation, a rigid inclusion was embedded in a phantom gel to simulate the lesion. An array of indents using a rigid indenter was made over an assigned area of the phantom surface, while the applied load, F, was measured as a function of instantaneous indentation depth, w. When the local stress field interacted with a sufficiently shallow inclusion, the mechanical response F(w) yielded an augmented apparent stiffness C. A 2-dimensional spatial map of C shows the presence, depth, and geometry of the simulated lesion. A camcorder was used to capture the in-situ movement of the inclusion during indentation, which showed consistency with the finite element (FEA) prediction. Results provide preliminary confirmation that mechanical indentation is a good tool to complement existing imaging techniques and has the potential to guide design and fabrication of an automatic palpation device. C1 [Sallaway, L.; Magee, S.; Shi, J.; Lehmann, O.; Quivira, F.; Tgavalekos, K.; Brooks, D. H.; Muftu, S.; Meleis, W.; Wan, K. -T.] Northeastern Univ, Boston, MA 02115 USA. [Moore, R. H.; Kopans, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wan, KT (reprint author), Northeastern Univ, Boston, MA 02115 USA. EM ktwan@coe.neu.edu FU Massachusetts General Hospital; Northeastern University Gordon Scholars Program; US National Science Foundation FX Massachusetts General Hospital is acknowledged for funding LS, SM, FQ, and KT, and the Northeastern University Gordon Scholars Program for providing a stipend for SM. Partial support for JS and KTW by the US National Science Foundation is also acknowledged. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of NSF. NR 27 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4851 EI 1741-2765 J9 EXP MECH JI Exp. Mech. PD JUL PY 2014 VL 54 IS 6 BP 935 EP 942 DI 10.1007/s11340-013-9786-6 PG 8 WC Materials Science, Multidisciplinary; Mechanics; Materials Science, Characterization & Testing SC Materials Science; Mechanics GA AI8JJ UT WOS:000337159200002 ER PT J AU Zietman, A AF Zietman, Anthony TI Bringing Radiation Therapy to Underserved Nations: An Increasingly Global Responsibility in an Ever-Shrinking World SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Zietman, A (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM azietman@partners.org NR 7 TC 13 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2014 VL 89 IS 3 BP 440 EP 442 DI 10.1016/j.ijrobp.2014.03.046 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI9AX UT WOS:000337219400001 PM 24929151 ER PT J AU Efstathiou, JA Bvochora-Nsingo, M Gierga, DP Kayembe, MKA Mmalane, M Russell, AH Paly, JJ Brown, C Musimar, Z Abramson, JS Bruce, KA Karumekayi, T Clayman, R Hodgeman, R Kasese, J Makufa, R Bigger, E Suneja, G Busse, PM Randall, TC Chabner, BA Dryden-Peterson, S AF Efstathiou, Jason A. Bvochora-Nsingo, Memory Gierga, David P. Kayembe, Mukendi K. Alphonse Mmalane, Mompati Russell, Anthony H. Paly, Jonathan J. Brown, Carolyn Musimar, Zola Abramson, Jeremy S. Bruce, Kathy A. Karumekayi, Talkmore Clayman, Rebecca Hodgeman, Ryan Kasese, Joseph Makufa, Remigio Bigger, Elizabeth Suneja, Gita Busse, Paul M. Randall, Thomas C. Chabner, Bruce A. Dryden-Peterson, Scott TI Addressing the Growing Cancer Burden in the Wake of the AIDS Epidemic in Botswana: The BOTSOGO Collaborative Partnership SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID PART I AB Botswana has experienced a dramatic increase in HIV-related malignancies over the past decade. The BOTSOGO collaboration sought to establish a sustainable partnership with the Botswana oncology community to improve cancer care. This collaboration is anchored by regular tumor boards and on-site visits that have resulted in the introduction of new approaches to treatment and perceived improvements in care, providing a model for partnership between academic oncology centers and high-burden countries with limited resources. (C) 2014 Elsevier Inc. C1 [Efstathiou, Jason A.; Gierga, David P.; Russell, Anthony H.; Paly, Jonathan J.; Bruce, Kathy A.; Clayman, Rebecca; Busse, Paul M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Abramson, Jeremy S.; Bigger, Elizabeth; Chabner, Bruce A.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Suneja, Gita; Randall, Thomas C.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Bvochora-Nsingo, Memory; Karumekayi, Talkmore; Makufa, Remigio] Univ Botswana, Gaborone Private Hosp, Sch Med, Gaborone, Botswana. [Kayembe, Mukendi K. Alphonse] Univ Botswana, Sch Med, Dept Anat Pathol, Natl Hlth Lab, Gaborone, Botswana. [Kayembe, Mukendi K. Alphonse] Univ Botswana, Sch Med, Dept Pathol, Gaborone, Botswana. [Mmalane, Mompati; Brown, Carolyn; Hodgeman, Ryan; Dryden-Peterson, Scott] Botswana Harvard AIDS Inst, Gaborone, Botswana. [Musimar, Zola; Bigger, Elizabeth] Princess Marina Hosp, Gaborone, Botswana. [Kasese, Joseph] Bokamoso Private Hosp, Gaborone, Botswana. [Suneja, Gita; Randall, Thomas C.] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Suneja, Gita; Randall, Thomas C.] Univ Penn, Leonard David Inst Hlth Econ, Philadelphia, PA 19104 USA. [Dryden-Peterson, Scott] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Efstathiou, JA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM jefstathiou@partners.org FU MGH Center for Global Health Travel Awards; MGH Department of Radiation Oncology; Ira J. Spiro Award; Paul G. Allen Family Foundation [11689]; Mick Radio-Nuclear Instruments; NCI Federal Share of program - Massachusetts General Hospital [C06 CA059267] FX Supported by MGH Center for Global Health Travel Awards, MGH Department of Radiation Oncology, Ira J. Spiro Award, Paul G. Allen Family Foundation (grant 11689), American Society of Clinical Oncology, in-kind donations from Mick Radio-Nuclear Instruments, and the NCI Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267. NR 19 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2014 VL 89 IS 3 BP 468 EP 475 DI 10.1016/j.ijrobp.2014.03.033 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI9AX UT WOS:000337219400007 PM 24929156 ER PT J AU Mayr, NA Hu, KS Liao, ZX Viswanathan, AN Wall, TJ Amendola, BE Calaguas, MJ Palta, JR Yue, NJ Rengan, R Williams, TR AF Mayr, Nina A. Hu, Kenneth S. Liao, Zhongxing Viswanathan, Akila N. Wall, Terry J. Amendola, Beatriz E. Calaguas, Miriam J. Palta, Jatinder R. Yue, Ning J. Rengan, Ramesh Williams, Timothy R. TI International Outreach: What Is the Responsibility of ASTRO and the Major International Radiation Oncology Societies? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CANCER AB In this era of globalization and rapid advances in radiation oncology worldwide, the American Society for Radiation Oncology (ASTRO) is committed to help decrease profound regional disparities through the work of the International Education Subcommittee (IES). The IES has expanded its base, reach, and activities to foster educational advances through a variety of educational methods with broad scope, in addition to committing to the advancement of radiation oncology care for cancer patients around the world, through close collaboration with our sister radiation oncology societies and other educational, governmental, and organizational groups. (C) 2014 Elsevier Inc. C1 [Mayr, Nina A.; Rengan, Ramesh] Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA 98195 USA. [Hu, Kenneth S.] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, New York, NY 10003 USA. [Liao, Zhongxing] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Viswanathan, Akila N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Canc Ctr,Dept Radiat Oncol, Boston, MA 02115 USA. [Wall, Terry J.] St Lukes Canc Inst, Kansas City, MO USA. [Amendola, Beatriz E.] Innovat Canc Inst, Miami, FL USA. [Calaguas, Miriam J.] St Lukes Med Ctr, Dept Radiat Oncol, Quezon City, Philippines. [Palta, Jatinder R.] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. [Yue, Ning J.] Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA. [Williams, Timothy R.] Boca Raton Reg Hosp, Lynn Canc Inst, Boca Raton, FL USA. RP Mayr, NA (reprint author), Univ Washington, Sch Med, Dept Radiat Oncol, ASTRO Int Educ Subcomm, 1959 NE Pacific St, Seattle, WA 98195 USA. EM ninamayr@uw.edu NR 7 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2014 VL 89 IS 3 BP 481 EP 484 DI 10.1016/j.ijrobp.2013.12.052 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI9AX UT WOS:000337219400009 PM 24929158 ER PT J AU Damato, AL Townamchai, K Albert, M Bair, RJ Cormack, RA Jang, J Kovacs, A Lee, LJ Mak, KS Mirabeau-Beale, KL Mouw, KW Phillips, JG Pretz, JL Russo, AL Lewis, JH Viswanathan, AN AF Damato, Antonio L. Townamchai, Kanopkis Albert, Michele Bair, Ryan J. Cormack, Robert A. Jang, Joanne Kovacs, Arpad Lee, Larissa J. Mak, Kimberley S. Mirabeau-Beale, Kristina L. Mouw, Kent W. Phillips, John G. Pretz, Jennifer L. Russo, Andrea L. Lewis, John H. Viswanathan, Akila N. TI Dosimetric Consequences of Interobserver Variability in Delineating the Organs at Risk in Gynecologic Interstitial Brachytherapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID GUIDED ADAPTIVE BRACHYTHERAPY; CERVICAL-CANCER BRACHYTHERAPY; RADIATION-THERAPY; PARAMETERS; MALIGNANCIES; RADIOTHERAPY; ENDOMETRIAL; GUIDELINES; OBSERVERS; CONTOURS AB Purpose: To investigate the dosimetric variability associated with interobserver organat- risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy. Methods and Materials: The rectum, bladder, and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using k statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D-0.1cc and D-2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SD TOT) was calculated. Results: The population mean +/- 1 standard deviation of k, CIgen, and volume CV were, respectively: 0.77 +/- 0.06, 0.70 +/- 0.08, and 20% +/- 6% for bladder; 0.74 +/- 06, 0.67 +/- 0.08, and 20% +/- 5% for rectum; and 0.33 +/- 0.20, 0.26 +/- 0.17, and 82% +/- 42% for sigmoid. Dosimetric variability was as follows: for bladder, CV = 31% +/- 19% (SD TOT = 72 +/- 64 Gy) for D-0.1cc and CV = 16% +/- 10% ( SDTOT = 9 +/- 6 Gy) for D-2cc; for rectum, CV=11% +/- 5%( SD TOT=16 +/- 17 Gy) forD(0.1cc) and CV=7% +/- 2% (SD TOT = 4 +/- 3 Gy) for D-2cc; for sigmoid, CV = 39% +/- 28% (SD TOT = 12 +/- 18 Gy) for D-0.1cc and CV = 34% +/- 19% ( SD TOT = 4 +/- 4 Gy) for D-2cc. Conclusions: Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose- volume histogram parameters except bladder D-0.1cc. Small delineation differences in high- dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study. (c) 2014 Elsevier Inc. C1 [Damato, Antonio L.; Townamchai, Kanopkis; Cormack, Robert A.; Lee, Larissa J.; Lewis, John H.; Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Albert, Michele] St Annes Hosp, Reg Canc Ctr, Dept Radiat Oncol, Fall River, MA USA. [Bair, Ryan J.; Kovacs, Arpad] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Jang, Joanne] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Mak, Kimberley S.; Mirabeau-Beale, Kristina L.; Mouw, Kent W.; Phillips, John G.; Pretz, Jennifer L.; Russo, Andrea L.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. RP Damato, AL (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1,L2, Boston, MA 02115 USA. EM adamato@lroc.harvard.edu FU National Institutes of Health grant [R21 CA167800] FX This work was partially funded by National Institutes of Health grant R21 CA167800 (Principal Investigator, A.N.V.). NR 25 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2014 VL 89 IS 3 BP 674 EP 681 DI 10.1016/j.ijrobp.2014.03.005 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI9AX UT WOS:000337219400036 PM 24803035 ER PT J AU Azimi, E Lerner, EA AF Azimi, Ehsan Lerner, Ethan A. TI The 7th World Congress on Itch SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article C1 [Azimi, Ehsan; Lerner, Ethan A.] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Lerner, EA (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, 149,13th St, Charlestown, MA 02129 USA. EM elerner@partners.org FU NIAMS [R13 AR065371]; Abbvie; Cosemderm; Creabilis; Leo Pharma; Mitsubishi Tanabe; Regeneron; Sanofi-Aventis; Taro; Toray; Trevi; Valeant FX The meeting was supported by a generous gift from Charles Stiefel, a conference grant from NIAMS, R13 AR065371, and additional support from the following pharmaceutical companies: Abbvie, Cosemderm, Creabilis, Leo Pharma, Mitsubishi Tanabe, Regeneron, Sanofi-Aventis, Taro, Toray, Trevi, and Valeant. NR 0 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2014 VL 134 IS 7 BP 1786 EP 1788 DI 10.1038/jid.2014.91 PG 3 WC Dermatology SC Dermatology GA AJ0IA UT WOS:000337333000001 PM 24924756 ER PT J AU Dziunycz, PJ Lefort, K Wu, XW Freiberger, SN Neu, J Djerbi, N Iotzowa-Weiss, G French, LE Dotto, GP Hofbauer, GFL AF Dziunycz, Piotr J. Lefort, Karine Wu, Xunwei Freiberger, Sandra N. Neu, Johannes Djerbi, Nadia Iotzowa-Weiss, Guergana French, Lars E. Dotto, Gian-Paolo Hofbauer, Guenther F. L. TI The Oncogene ATF3 Is Potentiated by Cyclosporine A and Ultraviolet Light A SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID ORGAN TRANSPLANT RECIPIENTS; SQUAMOUS-CELL CARCINOMA; SKIN-CANCER; DNA-DAMAGE; IMMUNOSUPPRESSION; KERATINOCYTES; AZATHIOPRINE; CALCINEURIN; RADIATION; PATHWAY AB Cutaneous squamous cell carcinoma (SCC) represents the most important cutaneous complication following organ transplantation. It develops mostly on sun-exposed areas. A recent study showed the role of activating transcription factor 3 (ATF3) in SCC development following treatment with calcineurin inhibitors. It has been reported that ATF3, which may act as an oncogene, is under negative calcineurin/nuclear factor of activated T cells (NFAT) control and is upregulated by calcineurin inhibitors. Still, these findings do not fully explain the preferential appearance of SCC on chronically sun-damaged skin. We analyzed the influence of UV radiation on ATF3 expression and its potential role in SCC development. We found that ATF3 is a specifically induced AP1 member in SCC of transplanted patients. Its expression was strongly potentiated by combination of cyclosporine A and UVA treatment. UVA induced ATF3 expression through reactive oxygen species-mediated nuclear factor erythroid 2-related factor 2 (NRF2) activation independently of calcineurin/NFAT inhibition. Activated NRF2 directly binds to ATF3 promoter, thus inducing its expression. These results demonstrate two mechanisms that independently induce and, when combined together, potentiate the expression of ATF3, which may then force SCC development. Taking into account the previously defined role of ATF3 in the SCC development, these findings may provide an explanation and a mechanism for the frequently observed burden on SCCs on sunexposed areas of the skin in organ transplant recipients treated by calcineurin inhibitors. C1 [Dziunycz, Piotr J.; Freiberger, Sandra N.; Neu, Johannes; Djerbi, Nadia; Iotzowa-Weiss, Guergana; French, Lars E.; Hofbauer, Guenther F. L.] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Lefort, Karine; Dotto, Gian-Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Wu, Xunwei; Dotto, Gian-Paolo] Harvard Univ, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Dziunycz, PJ (reprint author), Univ Zurich Hosp, Dept Dermatol, Gloriastr 31, CH-8091 Zurich, Switzerland. EM piotr.dziunycz@usz.ch RI Hofbauer, Gunther/B-2671-2010 OI Hofbauer, Gunther/0000-0003-0542-7989 NR 24 TC 9 Z9 9 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2014 VL 134 IS 7 BP 1998 EP 2004 DI 10.1038/jid.2014.77 PG 7 WC Dermatology SC Dermatology GA AJ0IA UT WOS:000337333000029 PM 24509533 ER PT J AU Goddard, A LeBoeuf, N O'Farrell, D Cormack, R Hansen, J Kupper, T Devlin, P AF Goddard, A. LeBoeuf, N. O'Farrell, D. Cormack, R. Hansen, J. Kupper, T. Devlin, P. TI Palliative therapy for recalcitrant cutaneous T-cell lymphoma of the hands and feet with low-dose HDR custom surface mold brachytherapy SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Medical-Dermatology-Society CY MAR 20, 2014 CL Denver, CO SP Med Dermatol Soc C1 [Goddard, A.; LeBoeuf, N.; O'Farrell, D.; Cormack, R.; Hansen, J.; Kupper, T.; Devlin, P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Goddard, A.; LeBoeuf, N.; Kupper, T.; Devlin, P.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2014 VL 134 IS 7 MA 4 BP 2059 EP 2059 PG 1 WC Dermatology SC Dermatology GA AJ0IA UT WOS:000337333000045 ER PT J AU Strazzula, L Vedak, P Hoang, M Sober, A Tsao, H Kroshinsky, D AF Strazzula, L. Vedak, P. Hoang, M. Sober, A. Tsao, H. Kroshinsky, D. TI Mildly and moderately dysplastic nevi: A retrospective analysis of re-excision utility SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Medical-Dermatology-Society CY MAR 20, 2014 CL Denver, CO SP Med Dermatol Soc C1 [Strazzula, L.; Vedak, P.; Hoang, M.; Sober, A.; Tsao, H.; Kroshinsky, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2014 VL 134 IS 7 MA 6 BP 2060 EP 2060 PG 1 WC Dermatology SC Dermatology GA AJ0IA UT WOS:000337333000048 ER PT J AU McIntosh, N Burgess, JF Meterko, M Restuccia, JD Alt-White, AC Kaboli, P Charns, M AF McIntosh, Nathalie Burgess, James F., Jr. Meterko, Mark Restuccia, Joseph D. Alt-White, Anna C. Kaboli, Peter Charns, Martin TI Impact of Provider Coordination on Nurse and Physician Perceptions of Patient Care Quality SO JOURNAL OF NURSING CARE QUALITY LA English DT Article DE interprofessional coordination; intraprofessional coordination; multidisciplinary rounding; patient care quality; relational coordination ID LENGTH-OF-STAY; HEALTH-CARE; TEAMWORK; SAFETY; COMMUNICATION; COLLABORATION; WORK; ENVIRONMENT; ATTITUDES; PATTERNS AB The objective of this study was to assess the role of provider coordination on nurse manager and physician perceptions of care quality, while controlling for organizational factors. Findings indicated that nurse-nurse coordination was positively associated with nurse manager perceptions of care quality; neither physician-physician nor physician-nurse coordination was associated with physician perceptions. Organizational factors associated with positive perceptions of care quality included facility support of education for nurses and physicians, and the use of multidisciplinary rounding. C1 [McIntosh, Nathalie; Burgess, James F., Jr.; Meterko, Mark; Restuccia, Joseph D.; Charns, Martin] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. [Alt-White, Anna C.] VA Off Nursing Serv, Washington, DC USA. [Kaboli, Peter] Iowa City VA Healthcare Syst, Comprehens Access & Delivery Res & Evaluat CADRE, Iowa City, IA USA. [Kaboli, Peter] Univ Iowa Carver Coll Med, Dept Internal Med, Iowa City, IA USA. [Burgess, James F., Jr.; Meterko, Mark; Charns, Martin] Boston Univ Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Restuccia, Joseph D.] Boston Univ Sch Management, Boston, MA USA. RP McIntosh, N (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave 152-M, Boston, MA 02130 USA. EM mcintnm@gmail.com FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Services [HSRD IIR 08-067] FX This study was based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Services (HSR&D IIR 08-067). The views and conclusions expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs of the US government. NR 42 TC 2 Z9 2 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1057-3631 EI 1550-5065 J9 J NURS CARE QUAL JI J. Nurs. Care Qual. PD JUL-SEP PY 2014 VL 29 IS 3 BP 269 EP 279 DI 10.1097/NCQ.0000000000000055 PG 11 WC Nursing SC Nursing GA AI9VS UT WOS:000337290600014 PM 24509244 ER PT J AU Schieffer, M Jessen, HK Oster, AF Pissani, F Soghoian, DZ Lu, R Jessen, AB Zedlack, C Schultz, BT Davis, I Ranasinghe, S Rosenberg, ES Alter, G Schumann, RR Streeck, H AF Schieffer, Miriam Jessen, Heiko K. Oster, Alexander F. Pissani, Franco Soghoian, Damien Z. Lu, Richard Jessen, Arne B. Zedlack, Carmen Schultz, Bruce T. Davis, Isaiah Ranasinghe, Srinika Rosenberg, Eric S. Alter, Galit Schumann, Ralf R. Streeck, Hendrik TI Induction of Gag-Specific CD4 T Cell Responses during Acute HIV Infection Is Associated with Improved Viral Control SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO; VIRUS; SUPERINFECTION; MAINTENANCE; PROTECTION; INFLUENZA; KINETICS; DISEASE; VIREMIA AB Effector CD4 T cell responses have been shown to be critically involved in the containment and clearance of viral pathogens. However, their involvement in the pathogenesis of HIV infection is less clear, given their additional role as preferred viral targets. We previously demonstrated that the presence of HIV-specific CD4 T cell responses is somewhat associated with HIV control and that specific CD4 T cell functions, such as direct cytolytic activity, can contribute to control of HIV viremia. However, little is known about how the induction of HIV-specific CD4 T cell responses during acute HIV infection influences disease progression and whether responses induced during the early phase of infection are preferentially depleted. We therefore longitudinally assessed, in a cohort of 55 acutely HIV-infected individuals, HIV-specific CD4 T cell responses from acute to chronic infection. Interestingly, we found that the breadth, magnitude, and protein dominance of HIV-specific CD4 T cell responses remained remarkably stable over time. Moreover, we found that the epitopes targeted at a high frequency in acute HIV infection were recognized at the same frequency by HIV-specific CD4 T cells in chronic HIV infection. Interestingly the induction of Gag-specific CD4 T cell responses in acute HIV infection was significantly inversely correlated with viral set point in chronic HIV infection (R = -0.5; P = 0.03), while the cumulative contribution of Env-specific CD4 T cell responses showed the reverse effect. Moreover, individuals with HIV-specific CD4 T cell responses dominantly targeting Gag over Env in acute HIV infection remained off antiretroviral therapy significantly longer (P = 0.03; log rank). Thus, our data suggest that the induction of HIV-specific CD4 T cell responses during acute HIV infection is beneficial overall and does not fuel disease progression. C1 [Schieffer, Miriam; Jessen, Heiko K.; Jessen, Arne B.; Zedlack, Carmen; Davis, Isaiah] HIV Clin Praxis Jessen, Berlin, Germany. [Oster, Alexander F.; Pissani, Franco; Lu, Richard; Schultz, Bruce T.; Streeck, Hendrik] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Oster, Alexander F.; Pissani, Franco; Lu, Richard; Schultz, Bruce T.; Streeck, Hendrik] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Soghoian, Damien Z.; Ranasinghe, Srinika; Alter, Galit; Streeck, Hendrik] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Soghoian, Damien Z.; Ranasinghe, Srinika; Alter, Galit; Streeck, Hendrik] Harvard Univ, Cambridge, MA 02138 USA. [Rosenberg, Eric S.] Massachussetts Gen Hosp, Boston, MA USA. [Schieffer, Miriam; Schumann, Ralf R.] Charite Univ Med Ctr, Inst Microbiol & Hyg, Berlin, Germany. RP Streeck, H (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. EM hstreeck@hivresearch.org FU U.S. National Institutes of Health (NIH) [R01 AI091450-01, R01 AI094602-01, P01 AI074415]; Bill and Melinda Gates Foundation FX This study was funded by the U.S. National Institutes of Health (NIH) (R01 AI091450-01, R01 AI094602-01, and P01 AI074415) and supported by the Bill and Melinda Gates Foundation. NR 36 TC 10 Z9 10 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 13 BP 7357 EP 7366 DI 10.1128/JVI.00728-14 PG 10 WC Virology SC Virology GA AI9GN UT WOS:000337240700022 PM 24741089 ER PT J AU Quadeer, AA Louie, RHY Shekhar, K Chakraborty, AK Hsing, IM McKay, MR AF Quadeer, Ahmed A. Louie, Raymond H. Y. Shekhar, Karthik Chakraborty, Arup K. Hsing, I-Ming McKay, Matthew R. TI Statistical Linkage Analysis of Substitutions in Patient-Derived Sequences of Genotype 1a Hepatitis C Virus Nonstructural Protein 3 Exposes Targets for Immunogen Design SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; COORDINATED EVOLUTION; ESCAPE MUTATIONS; CD8 EPITOPE; NS3 PROTEIN; HCV NS3; INFECTION; CD4(+); REPLICATION; IDENTIFICATION AB Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4(+) and cytotoxic CD8(+) T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing diverse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. C1 [Quadeer, Ahmed A.; Louie, Raymond H. Y.; McKay, Matthew R.] HKUST, Dept Elect & Comp Engn, Kowloon, Hong Kong, Peoples R China. [Shekhar, Karthik; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Shekhar, Karthik; Chakraborty, Arup K.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Shekhar, Karthik; Chakraborty, Arup K.] Harvard Univ, Boston, MA 02115 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] HKUST, Inst Adv Study, Kowloon, Hong Kong, Peoples R China. [Hsing, I-Ming] HKUST, Dept Chem & Biomol Engn, Kowloon, Hong Kong, Peoples R China. [Hsing, I-Ming; McKay, Matthew R.] HKUST, Div Biomed Engn, Kowloon, Hong Kong, Peoples R China. RP McKay, MR (reprint author), HKUST, Dept Elect & Comp Engn, Kowloon, Hong Kong, Peoples R China. EM eemckay@ust.hk OI Hsing, I-Ming/0000-0002-3326-3021 FU Hong Kong PhD Fellowship Scheme, Research Grants Council, Hong Kong; HKUST [IGN13EG02]; Ragon Institute of Massachusetts General Hospital, MIT and Harvard; Hari Harilela endowment fund [R8002] FX This work was supported by the Hong Kong PhD Fellowship Scheme, Research Grants Council, Hong Kong (A.A.Q.), HKUST research grant IGN13EG02 (R.H.Y.L.), the Ragon Institute of Massachusetts General Hospital, MIT and Harvard (K.S. and A.K.C.), and the Hari Harilela endowment fund, R8002 (M.R.M.). NR 74 TC 9 Z9 9 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 13 BP 7628 EP 7644 DI 10.1128/JVI.03812-13 PG 17 WC Virology SC Virology GA AI9GN UT WOS:000337240700044 PM 24760894 ER PT J AU Cen, B Xiong, Y Song, JH Mahajan, S DuPont, R McEachern, K DeAngelo, DJ Cortes, JE Minden, MD Ebens, A Mims, A LaRue, AC Kraft, AS AF Cen, Bo Xiong, Ying Song, Jin H. Mahajan, Sandeep DuPont, Rachel McEachern, Kristen DeAngelo, Daniel J. Cortes, Jorge E. Minden, Mark D. Ebens, Allen Mims, Alice LaRue, Amanda C. Kraft, Andrew S. TI The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INITIATION-FACTOR 4B; ACUTE MYELOID-LEUKEMIA; PROSTATE-CANCER; LUNG-CANCER; CELL; INHIBITORS; PHOSPHORYLATION; AMPLIFICATION; PROGRESSION; METASTASIS AB MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology. C1 [Cen, Bo; Mims, Alice; Kraft, Andrew S.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Song, Jin H.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Cen, Bo; Song, Jin H.; Mahajan, Sandeep; LaRue, Amanda C.; Kraft, Andrew S.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Xiong, Ying; LaRue, Amanda C.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [LaRue, Amanda C.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. [DuPont, Rachel; McEachern, Kristen] AstraZeneca, Oncol iMed, Waltham, MA USA. [DeAngelo, Daniel J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Cortes, Jorge E.] Univ Texas Hlth Sci Ctr Houston, Dept Leukemia, Houston, TX 77030 USA. [Minden, Mark D.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Ebens, Allen] Genentech Inc, San Francisco, CA 94080 USA. RP Cen, B (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM cen@musc.edu; kraft@musc.edu FU NIH [1K01DK085196, 1R01CA173200, W81XWH-12-10560]; HCC [5P30CA138313]; Conquer Cancer Foundation of ASCO Young Investigator Award FX This work is supported by NIH grants 1K01DK085196 (to B.C.), 1R01CA173200 (to A.S.K.), and W81XWH-12-10560 (to A.S.K.) and the HCC support grant 5P30CA138313. This work was funded by a Conquer Cancer Foundation of ASCO Young Investigator Award (to A.M.). NR 29 TC 16 Z9 16 U1 1 U2 5 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 2014 VL 34 IS 13 BP 2517 EP 2532 DI 10.1128/MCB.00147-14 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AI9GG UT WOS:000337239800013 PM 24777602 ER PT J AU Nicolay, NH Sommer, E Perez, RL Wirkner, U Bostel, T Askoxylakis, V Debus, J Saffrich, R Huber, PE AF Nicolay, N. H. Sommer, E. Perez, Lopez R. Wirkner, U. Bostel, T. Askoxylakis, V. Debus, J. Saffrich, R. Huber, P. E. TI Sensitivity of mesenchymal Stem Cells compared with Combination Treatments of Radiation and Receptor Kinase Inhibition SO STRAHLENTHERAPIE UND ONKOLOGIE LA German DT Meeting Abstract CT 20th Annual Congress of the German-Society-for-Radiation-Oncology CY JUL 03-06, 2014 CL Dusseldorf, GERMANY SP German Soc Radiat Oncol C1 [Nicolay, N. H.; Sommer, E.; Perez, Lopez R.; Wirkner, U.; Bostel, T.; Askoxylakis, V.; Debus, J.; Huber, P. E.] Deutsch Krebsforschungszentrum, Heidelberg, Germany. [Nicolay, N. H.; Bostel, T.; Debus, J.; Saffrich, R.; Huber, P. E.] Univ Klin Heidelberg, Heidelberg, Germany. [Askoxylakis, V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0179-7158 EI 1439-099X J9 STRAHLENTHER ONKOL JI Strahlenther. Onkol. PD JUL PY 2014 VL 190 SU 1 BP 36 EP 36 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI7GF UT WOS:000337052500080 ER PT J AU Merritt, MA Poole, EM Hankinson, SE Willett, WC Tworoger, SS AF Merritt, Melissa A. Poole, Elizabeth M. Hankinson, Susan E. Willett, Walter C. Tworoger, Shelley S. TI Dairy food and nutrient intake in different life periods in relation to risk of ovarian cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Ovarian cancer; Dairy; Milk; Lactose; Calcium; Fat ID BREAST-CANCER; FREQUENCY QUESTIONNAIRE; PREMENOPAUSAL WOMEN; PROSPECTIVE COHORT; ADOLESCENT DIET; POOLED ANALYSIS; NURSES HEALTH; VITAMIN-D; ENDOMETRIOSIS; CONSUMPTION AB High lactose intake has been suggested to increase epithelial ovarian cancer (EOC) risk. We evaluated the association between lactose consumed during specific life periods (high school, premenopause, and postmenopause) and later risk of EOC. We assessed the association of dairy food and nutrient intake with risk of EOC during 28 years of follow-up including 764 cases in the Nurses' Health Study (NHS) and NHSII. Cox proportional hazards regression was used to model the hazard ratios (HRs) and 95 % confidence intervals (CIs) for EOC across categories of dairy food or nutrient intake. We examined dietary intake in adulthood overall, as well as during premenopausal/postmenopausal years and high school. In analyses of the highest versus lowest cumulative average intake in adulthood, we observed a non-significant inverse association with skim milk intake (HR 0.76, 95 % CI 0.54-1.06, p (trend) = 0.05), a non-significant inverse association with lactose intake (HR 0.87, 95 % CI 0.69-1.11, p (trend) = 0.22) and no association with consumption of whole milk, dairy calcium, or dairy fat. Similar risk estimates were observed for dairy food/nutrient intake during high school, premenopause or postmenopause. Lactose intake in adulthood was inversely associated with risk of endometrioid EOC (HR 0.32, 95 % CI 0.16-0.65, p (trend) < 0.001). These findings do not support the hypothesis that higher lactose intake increases EOC risk. The inverse association with endometrioid tumors deserves further study. C1 [Merritt, Melissa A.; Poole, Elizabeth M.; Hankinson, Susan E.; Willett, Walter C.; Tworoger, Shelley S.] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Merritt, Melissa A.] Harvard Univ, OB GYN Epidemiol Ctr, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Merritt, Melissa A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Poole, Elizabeth M.; Hankinson, Susan E.; Willett, Walter C.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Hankinson, Susan E.; Willett, Walter C.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Merritt, MA (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, Norfolk Pl, London W2 1PG, England. EM m.merritt@imperial.ac.uk OI Merritt, Melissa A./0000-0002-5067-6119; Tworoger, Shelley/0000-0002-6986-7046 FU National Cancer Institute, National Institutes of Health [P01 CA87969, R01 CA50385, R25 CA098566, T32 CA009001] FX The authors thank the participants and staff of the NHS and NHSII cohorts for their dedication to these studies and their contribution to this research. The authors thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. This research was supported by the National Cancer Institute, National Institutes of Health Grants P01 CA87969 and R01 CA50385 and training Grants to M. A. M. (R25 CA098566) and E. M. P. (T32 CA009001). NR 46 TC 5 Z9 5 U1 1 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUL PY 2014 VL 25 IS 7 BP 795 EP 808 DI 10.1007/s10552-014-0381-7 PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AI6XM UT WOS:000337020700003 PM 24722953 ER PT J AU Stevenson, M Christensen, J Shoemaker, D Foster, T Barry, WT Tong, BC Wahidi, M Shofer, S Datto, M Ginsburg, G Crawford, J D'Amico, T Ready, N AF Stevenson, Marvaretta Christensen, Jared Shoemaker, Debra Foster, Traci Barry, William T. Tong, Betty C. Wahidi, Momen Shofer, Scott Datto, Michael Ginsburg, Geoffrey Crawford, Jeffrey D'Amico, Thomas Ready, Neal TI Tumor Acquisition for Biomarker Research in Lung Cancer SO CANCER INVESTIGATION LA English DT Article DE Lung cancer; Gene profiling; Bioinformatics ID NEEDLE-BIOPSY; RNA INTEGRITY; PHASE-III; TISSUE; EXTRACTION; TRIAL; MICRODISSECTION; COMPLICATIONS; PNEUMOTHORAX; CHEMOTHERAPY AB The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N = 30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing. C1 [Stevenson, Marvaretta; Christensen, Jared; Shoemaker, Debra; Foster, Traci; Tong, Betty C.; Wahidi, Momen; Shofer, Scott; Datto, Michael; Crawford, Jeffrey; D'Amico, Thomas; Ready, Neal] Duke Canc Inst, Durham, NC 27707 USA. [Barry, William T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ginsburg, Geoffrey] Duke Inst Genome Sci & Policy, Durham, NC USA. RP Stevenson, M (reprint author), Duke Canc Inst, 3100 Tower Blvd,Suite 600, Durham, NC 27707 USA. EM steve041@mc.duke.edu RI Christensen, Jared/A-2376-2016 OI Christensen, Jared/0000-0001-9347-4720 FU Lilly pharmaceutical company FX There are no acknowledgements to be made. Funding for the trials described was provided by the Lilly pharmaceutical company. NR 37 TC 1 Z9 1 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0735-7907 EI 1532-4192 J9 CANCER INVEST JI Cancer Invest. PD JUL PY 2014 VL 32 IS 6 BP 291 EP 298 DI 10.3109/07357907.2014.911880 PG 8 WC Oncology SC Oncology GA AI6YX UT WOS:000337025900011 PM 24810245 ER PT J AU Hsieh, CT Chuang, JH Yang, WC Yin, Y Lin, YS AF Hsieh, Chang-Ting Chuang, Jen-Hua Yang, Wen-Chin Yin, Yi Lin, Yenshou TI Ceramide inhibits insulin-stimulated Akt phosphorylation through activation of Rheb/mTORC1/S6K signaling in skeletal muscle SO CELLULAR SIGNALLING LA English DT Article DE C2-ceramide; Insulin resistance; mTORC1; mTORC2; Myotubes ID PROTEIN-KINASE-B; RECEPTOR SUBSTRATE-1; RESISTANCE; CELLS; MTOR; APOPTOSIS; PALMITATE; RICTOR; EXPRESSION; PATHWAY AB Ceramide is a negative regulator of insulin activity. At the molecular level, it causes a decrease in insulin-stimulated Akt Ser473 phosphorylation in C2C12 myotubes. Interestingly, we found that the phosphorylation of S6K at Thr389 was increased under the same conditions. Utilizing both rapamycin to inhibit mTORC1 activity and shRNA to knock down Rheb, we demonstrated that the decrease in Akt Ser473 phosphorylation stimulated by insulin after C2-ceramide incubation can be prevented. The mechanism by which C2-ceramide impairs signaling would seem to involve a negative feedback of activated S6K via phosphorylation of insulin receptor substrate-1 at Ser636/639, since S6K inhibitor can block this phenomenon. Finally, rapamycin treatment was found not to affect C2-ceramide-induced PKC zeta activation, suggesting that the pathway revealed in this study is parallel to the one involving PKC zeta activation. We proposed a novel pathway/mechanism involving Rheb/mTORC1/S6K signaling to explain how C2-cerarnide impairs insulin signaling via Ala phosphorylation. The existence of multiple pathways involved in insulin signaling impairment by C2-ceramide treatment implies that different strategies might be needed to ameliorate insulin resistance caused by C2-ceramide. (C) 2014 Elsevier Inc. All rights reserved. C1 [Hsieh, Chang-Ting; Chuang, Jen-Hua; Lin, Yenshou] Natl Taiwan Normal Univ, Dept Life Sci, Taipei 116, Taiwan. [Yang, Wen-Chin] Acad Sinica, Agr Biotechnol Res Ctr, Taipei 115, Taiwan. [Yin, Yi] Massachusetts Gen Hosp, Dept Mol Biol, Diabet Unit, Med Serv, Boston, MA 02114 USA. RP Lin, YS (reprint author), Natl Taiwan Normal Univ, Dept Life Sci, 88 Ting Chou Rd,Sect 4, Taipei 116, Taiwan. EM yenshoulin@ntnu.edu.tw RI Yang, Wen-Chin/D-3441-2015 FU National Science Council [NSC101-2311-B-003-005/NSC102-2311-B-003-003]; National Taiwan Normal University (NTNU), Taiwan [103T3040B06] FX This work was supported by Grants NSC101-2311-B-003-005/NSC102-2311-B-003-003 and Grant 103T3040B06 to Y. Lin from the National Science Council and National Taiwan Normal University (NTNU), Taiwan, respectively. We are grateful for the help from the English Editing Service, the Office of Research and Development, NTNU and from National RNAi Core Facility Platform of Academia Sinica (Taipei, Taiwan). We would also like to thank Dr. Neil Ruderman and Mr. Theodore Kurowski of Boston University Medical Center (Boston, MA, USA) for the technical assistance. NR 40 TC 6 Z9 7 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD JUL PY 2014 VL 26 IS 7 BP 1400 EP 1408 DI 10.1016/j.cellsig.2014.03.004 PG 9 WC Cell Biology SC Cell Biology GA AI4FB UT WOS:000336820000005 PM 24650522 ER PT J AU Ring, D AF Ring, David TI Editorial Comment: Traumatic Elbow Instability and its Sequelae SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Yawkey 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2035 EP 2036 DI 10.1007/s11999-014-3599-5 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300008 PM 24711132 ER PT J AU Boretto, JG Sammartino, MR Gallucci, G De Carli, P Ring, D AF Boretto, Jorge G. Sammartino, Mario Rodriguez Gallucci, Gerardo De Carli, Pablo Ring, David TI Comparative Study of Simple and Complex Open Elbow Dislocations SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID RADIAL HEAD; FRACTURE; JOINT; INJURIES AB Open elbow dislocations are rare injuries. Most of the evidence related to these dislocations is found in case reports or in series with closed injuries. We reviewed the experiences of three centers in the treatment of open elbow dislocations. We compared the results after operative treatment of simple and complex open dislocations in terms of (1) ROM, (2) functional score, and (3) complications. Eighteen patients were retrospectively included in this study: 11 with simple open elbow dislocations and seven with complex open elbow dislocations. Mean age was 40 years. Thirteen were men. Eight patients presented neurovascular injuries. Evaluation included ROM of the elbow and forearm as measured by hand-held goniometer. We then classified the results using the 100-point Broberg and Morrey functional rating index based on ROM, grip strength, elbow stability, and pain. Scores of 95 to 100 were considered excellent, 80 to 94 good, 60 to 79 fair, and less than 60 poor. Complications were recorded. Minimum followup was 6 months (mean, 25 months; range, 6-72 months). We found no differences between simple and complex open elbow dislocations related to ROM (median flexion/extension: 117A degrees versus 110A degrees, p = 0.12; forearm rotation: 160A degrees versus 170A degrees, p = 0.67). According to the Broberg and Morrey score, four patients had excellent results, five good, and one fair in the simple dislocation group, whereas in the complex dislocation group, four patients had excellent results, two good, and one fair (p = 0.8). No difference in complication rate was found between groups (p = 0.63). All complications in the simple dislocation group were neurovascular. In the complex dislocation group, there was one case of brachial artery occlusion, two cases of heterotopic ossification, one case of infection and nonunion, and one case of infection. No patients had recurrent elbow instability. No differences between simple and complex open elbow dislocations were found in terms of ROM, functional results, and rate of complications. Complications in the simple dislocation group were related to neurovascular injuries in contrast to the complex dislocation group where complications were associated with the bony injury. Level IV, prognostic study. See Instructions for Authors for a complete description of levels of evidence. C1 [Boretto, Jorge G.; Gallucci, Gerardo; De Carli, Pablo] Hosp Italiano Buenos Aires, Inst Ortopedia & Traumatol Dr Prof Carlos Ottolen, Dept Hand & Upper Extrem, Buenos Aires, DF, Argentina. [Sammartino, Mario Rodriguez] Clin Fracturas & Ortopedia, Orthoped & Traumatol Serv, Mar Del Plata, Buenos Aires, Argentina. [Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, Boston, MA USA. RP Boretto, JG (reprint author), Hosp Italiano Buenos Aires, Inst Ortopedia & Traumatol Dr Prof Carlos Ottolen, Dept Hand & Upper Extrem, Buenos Aires, DF, Argentina. EM jboretto@hotmail.com OI Boretto, Jorge G./0000-0001-7701-3852 NR 25 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2037 EP 2043 DI 10.1007/s11999-014-3491-3 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300009 PM 24515405 ER PT J AU Ring, D Bruinsma, WE Jupiter, JB AF Ring, David Bruinsma, Wendy E. Jupiter, Jesse B. TI Complications of Hinged External Fixation Compared With Cross-pinning of the Elbow for Acute and Subacute Instability SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID FRACTURE-DISLOCATION; RADIAL HEAD AB Elbows that are unstable after injury or reconstructive surgery often are stabilized using external fixation or cross-pinning of the joint supplemented by cast immobilization. The superiority of one approach or the other remains a matter of debate. We compared patients treated with external fixation or cross-pinning in terms of (1) adverse events, (2) Broberg and Morrey scores, and (3) ROM. Between 1998 and 2010, 19 patients (19 elbows) had hinged external fixation and 10 patients (11 elbows) cross-pinning and casting for subacute or acute posttraumatic elbow instability. Our general indications for both techniques were persistent elbow instability after usual treatment. Initially, we used external fixation for delayed treatment of fracture-dislocations and cross-pinning for simple elbow dislocations in patients who could not tolerate surgery, but more recently we have used cross-pinning for both indications. Adverse events, elbow scores, and ROM were retrospectively evaluated by chart review, with the latter two end points being calculated at a mean of 31 months (range, 5-83 months) and 10 months (range, 5-21 months) after index procedure for the patients treated with external fixation and cross-pinning, respectively. Seven of 19 patients treated with external fixation experienced nine device-related adverse events: three pin tract infections, two nerve problems, one broken pin, one residual subluxation, one suture abscess, and one pin tract fracture of the ulna resulting in a nonunion. Of the 10 patients (11 elbows) treated with cross-pinning, one patient had pin tract inflammation that resolved with pin removal. Mean Broberg and Morrey score was 90 (95% CI, 84-95) after external fixation and 90 (95% CI, 84-96) after cross-pinning (p = 0.88). There were no differences between the external fixation and cross-pinning groups in mean flexion (123A degrees versus 128A degrees, p = 0.49), extension (29A degrees versus 29A degrees, p = 0.97), forearm pronation (68A degrees versus 74A degrees, p = 0.56), and forearm supination (47A degrees versus 68A degrees, p = 0.15). When the elbow remains unstable after reduction and usual treatment for fractures and dislocations or has been out of place for more than 2 weeks, both cross-pinning and external fixation can help maintain elbow alignment while structures heal. Hinged external fixation is associated with more adverse events related to the device, but Broberg and Morrey score and ROM are similar between techniques. Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. C1 [Ring, David; Jupiter, Jesse B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, Boston, MA USA. [Bruinsma, Wendy E.] Acad Med Ctr, Dept Surg, Trauma Unit, NL-1100 DD Amsterdam, Netherlands. RP Bruinsma, WE (reprint author), Acad Med Ctr, Dept Surg, Trauma Unit, Meibergdreef 9, NL-1100 DD Amsterdam, Netherlands. EM w.e.bruinsma@amc.nl NR 8 TC 7 Z9 8 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2044 EP 2048 DI 10.1007/s11999-014-3510-4 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300010 PM 24554456 ER PT J AU Yi, PH Weening, AA Shin, SR Hussein, KI Tornetta, P Jawa, A AF Yi, Paul H. Weening, Alexander A. Shin, Sangmin R. Hussein, Khalil I. Tornetta, Paul, III Jawa, Andrew TI Injury Patterns and Outcomes of Open Fractures of the Proximal Ulna Do Not Differ From Closed Fractures SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID DISTAL HUMERUS; EPIDEMIOLOGY; MANAGEMENT; FIXATION; RISK AB The incidence and injury patterns of open fractures of the proximal ulna are poorly elucidated and little evidence exists to guide management. The purpose of this study was to compare the (1) bony injury patterns; (2) range of motion (ROM) and frequency of union; and (3) postoperative complications between open and closed fractures of the proximal ulna. Seventy-nine consecutive open fractures of the proximal ulna were identified. After excluding fracture-dislocations, penetrating injuries, and pediatric injuries, 60 were compared in a retrospective case-control study with an age- and sex-matched group of 91 closed fractures to compare the bony injury patterns based on radiographic review. In a subset of 39 open and 39 closed fractures with sufficient followup, chart and radiographic review was performed by someone other than the operating surgeon to compare differences in final ROM, union, and postoperative complication rates at a minimum followup of 3 months (mean, 22 and 15 months; range, 3-86 months and 3-51 months for open and closed fractures, respectively). A total of 12% of the fractures were open (79 of 671) at the three study centers, and the majority of fractures were intraarticular (45 of 60 [75%]) with Gustilo-Anderson Type I and II wounds (54 of 60 [90%]). Overall, open fractures of the proximal ulna overall did not have more complex bony injury patterns, but there were more anterior olecranon fracture-dislocations among the open fracture group (nine of 60 [15%] versus two of 91 [2%]; p = 0.004) and more posterior olecranon fracture-dislocations in the closed fracture group (31 of 91 [34%] versus seven of 60 [12%]; p = 0.002). Final ROM was not different in both groups and all fractures healed. There was no difference in wound infection rate but a higher secondary procedure rate among open fractures of the proximal ulna (39% versus 23%, p = 0.014). In contrast to open fractures of the distal humerus, open fractures of the proximal ulna present with mild soft tissue injuries and do not have more complex bony injury patterns than closed fractures. Our findings suggest that open fractures of the proximal ulna are the result of tension failure of the skin secondary to the limited soft tissue envelope around the proximal ulna. Open fractures of the proximal ulna should be regarded as relatively mild injuries that are not different in severity and prognosis compared with closed fractures. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Yi, Paul H.; Shin, Sangmin R.; Hussein, Khalil I.; Tornetta, Paul, III; Jawa, Andrew] Boston Univ, Med Ctr, Boston, MA USA. [Weening, Alexander A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yi, PH (reprint author), 23 Wigglesworth St, Boston, MA 02120 USA. EM paulyi88@gmail.com NR 15 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2100 EP 2104 DI 10.1007/s11999-014-3489-x PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300017 PM 24504649 ER PT J AU Bruinsma, WE Guitton, T Ring, D AF Bruinsma, Wendy E. Guitton, Thierry Ring, David CA Sci Variation Grp TI Radiographic Loss of Contact Between Radial Head Fracture Fragments Is Moderately Reliable SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID PROXIMAL HUMERAL FRACTURES; COMPUTED-TOMOGRAPHY; HIGH AGREEMENT; LOW KAPPA; RELIABILITY; CLASSIFICATION; DISPLACEMENT; PARADOXES AB Loss of contact between radial head fracture fragments is strongly associated with other elbow or forearm injuries. If this finding has adequate interobserver reliability, it could help examiners identify and treat associated ligament injuries and fractures (eg, forearm interosseous ligament injury or elbow dislocation). (1) What is the interobserver agreement on radiographic loss of contact between radial head fracture fragments? (2) Are there factors associated with the observer such as location of practice or subspecialization that increase interobserver reliability? Fully trained practicing orthopaedic and trauma surgeons from around the world evaluated 27 anteroposterior and lateral radiographs of radial head fractures on a web-based platform for the following characteristics: (1) loss of contact between at least one radial head fracture fragment and the remaining radial head and neck; (2) a gap between fragments of 2 mm or greater; (3) anticipated fracture instability (mobility) on operative exposure; (4) anticipated associated ligament injuries; and (5) recommendation for treatment. Agreement among observers was measured using the multirater kappa measure. Kappas for various observer characteristics were compared using 95% confidence intervals. The overall interobserver agreement was moderate (range, 0.49-0.55) for each question except associated ligament injury, which was fair (0.33). Shoulder and elbow surgeons had substantial agreement (range, 0.51-0.61) in many areas, but kappas were generally in the moderate range (0.41-0.59) based on number of years in practice, radial head fractures treated per year, and trainee supervision. Radiographic signs of radial head fracture instability such as loss of contact have moderate reliability. This characteristic seems clinically useful, because loss of contact between at least one radial head fracture fragment and the remaining radial head and neck is strongly associated with associated ligament injury or other fractures. Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Bruinsma, Wendy E.] Acad Med Ctr, Dept Surg, Trauma Unit, NL-1100 DD Amsterdam, Netherlands. [Guitton, Thierry] Acad Med Ctr, Dept Orthopaed Surg, Orthopaed Res Ctr Amsterdam, NL-1100 DD Amsterdam, Netherlands. [Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Bruinsma, WE (reprint author), Acad Med Ctr, Dept Surg, Trauma Unit, Meibergdreef 9, NL-1100 DD Amsterdam, Netherlands. EM w.e.bruinsma@amc.nl RI Page, Richard/K-6327-2015; OI Page, Richard/0000-0002-2225-7144; Frihagen, Frede/0000-0002-4811-669X; Guitton, Thierry/0000-0002-2599-1985; Borris, Lars/0000-0002-0527-1518; Swiontkowski, Marc/0000-0001-7036-1782 NR 20 TC 3 Z9 3 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2113 EP 2119 DI 10.1007/s11999-014-3592-z PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300019 PM 24711128 ER PT J AU Watters, TS Garrigues, GE Ring, D Ruch, DS AF Watters, Tyler Steven Garrigues, Grant E. Ring, David Ruch, David S. TI Fixation Versus Replacement of Radial Head in Terrible Triad: Is There a Difference in Elbow Stability and Prognosis? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID INTRAARTICULAR FRACTURES; CORONOID PROCESS; DISLOCATIONS; ARTHROPLASTY; SIZE AB Surgical treatment for terrible triad injuries of the elbow (defined as elbow dislocations with concomitant fractures of the radial head and coronoid) remains a challenging clinical problem. Specifically, the question of whether to repair or replace the radial head remains controversial. We compared patients with terrible triad injuries of the elbow whose radial head fracture was treated with either internal fixation and internal fixation (ORIF) or radial head arthroplasty in terms of (1) clinical outcome measures (DASH and Broberg-Morrey scores, ROM), (2) elbow stability and radiographic signs of arthrosis, and (3) complications and reoperation rates. Retrospective review identified 39 patients with terrible triad injuries and minimum 18-month complete clinical and radiographic followup (mean, 24 months; range, 18-53 months). Patients were managed with a standard algorithm consisting of (1) repair (n = 9) or replacement (n = 30) of the radial head, (2) repair of the lateral ulnar collateral ligament, and (3) repair of the coronoid fracture. During the study period, the radial head generally was internally fixed when there were fewer than four articular fragments; otherwise, it was replaced. Evaluation included the DASH score, the Broberg-Morrey index, measurements of elbow stability and motion, and radiographic assessment for signs of arthrosis; chart review was performed for complications and reoperations. Complete followup was available on 87% (39 of 45 patients). There were no differences between groups in terms of ROM or elbow scores. All patients who underwent radial head arthroplasty at the index procedure had a stable elbow at final followup whereas three of nine patients who underwent ORIF were unstable (p = 0.009). However, 11 patients who underwent arthroplasty demonstrated radiographic signs of arthrosis compared to none in the ORIF group (p = 0.04). Eleven patients (28%) underwent reoperation (seven arthroplasty, four ORIF) for various reasons. With the numbers available, there was no difference in reoperation rate between groups (p = 0.45). For terrible triad injuries, radial head arthroplasty afforded the ability to obtain elbow stability with comparable overall outcomes when compared to ORIF. As these injuries commonly occur in younger patients, longer-term studies will be required to ascertain whether the apparent benefits of radial head arthroplasty are offset by late complications of arthroplasty, such as loosening. Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. C1 [Watters, Tyler Steven; Garrigues, Grant E.; Ruch, David S.] Duke Univ, Med Ctr, Dept Orthopaed Surg, Durham, NC 27710 USA. [Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Watters, TS (reprint author), Duke Univ, Med Ctr, Dept Orthopaed Surg, DUMC 3000, Durham, NC 27710 USA. EM tyler.watters@dm.duke.edu NR 24 TC 18 Z9 20 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2128 EP 2135 DI 10.1007/s11999-013-3331-x PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300021 PM 24136807 ER PT J AU Wiggers, JK Helmerhorst, GTT Brouwer, KM Niekel, MC Nunez, F Ring, D AF Wiggers, Jimme K. Helmerhorst, Gijs T. T. Brouwer, Kim M. Niekel, Maarten C. Nunez, Fiesky Ring, David TI Injury Complexity Factors Predict Heterotopic Ossification Restricting Motion After Elbow Trauma SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TOTAL HIP-ARTHROPLASTY; RISK-FACTORS; FRACTURES; BURNS; BONE AB Heterotopic ossification (HO) is a common extrinsic cause of elbow stiffness after trauma. However, factors associated with the development of HO are incompletely understood. We retrospectively identified (1) patient-related demographic factors, (2) injury-related factors, and (3) treatment-related factors associated with the development of HO severe enough to restrict motion after surgery for elbow trauma. We also determined what percentage of the variation in HO restricting motion was explained by the variables studied. Between 2001 and 2007, we performed surgery on 417 adult patients for elbow fractures; of these, 284 (68%) were available for radiographs at a minimum of 4 months and clinical review at a minimum of 6 months after surgery (mean, 7.9 months; range, 6-31 months). HO was classified according to the Hastings and Graham system. Patients with HO restricting motion (defined as a Hastings and Graham Class II or III) were compared with patients without HO restricting motion in terms of demographics, fracture location, elbow dislocation, open wound, mechanism of injury, ipsilateral fracture, head trauma, time from injury to surgery, number of surgeries within 4 weeks, total number of surgeries, bone graft, and infection, using bivariate and multivariable analyses. A total of 96 patients had radiographic HO, and in 27 (10% of those available for followup), it restricted motion. There were no patient-related demographic factors that predicted the formation of symptomatic HO. Ulnohumeral dislocation in addition to fracture (odds ratio, 2.38; 95% CI, 1.01-5.64; p = 0.048) but not fracture location was associated with HO. Longer time from injury to definitive surgery and number of surgical procedures in the first 4 weeks were also independent predictors of HO (p = 0.01 and 0.004, respectively). These factors explained 20% of the variance in risk for HO restricting motion. HO restricting motion after operative elbow fracture treatment associates with factors that seem related to injury complexity, in particular, ulnohumeral dislocation, delay, and number of early surgeries; however, a substantial portion of the variation among patients with elbow fracture who develop restrictive HO remains unexplained. Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. C1 [Wiggers, Jimme K.; Helmerhorst, Gijs T. T.; Brouwer, Kim M.; Niekel, Maarten C.; Nunez, Fiesky; Ring, David] Harvard Univ, Sch Med, Orthopaed Hand & Upper Extrem Serv, Massachusetts Gen Hosp,Yawkey Ctr, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Sch Med, Orthopaed Hand & Upper Extrem Serv, Massachusetts Gen Hosp,Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM j.k.wiggers@amc.nl; dring@partners.org NR 17 TC 8 Z9 9 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2162 EP 2167 DI 10.1007/s11999-013-3304-0 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300025 PM 24078170 ER PT J AU Teunis, T Nota, SPFT Hornicek, FJ Schwab, JH Lozano-Calderon, SA AF Teunis, Teun Nota, Sjoerd P. F. T. Hornicek, Francis J. Schwab, Joseph H. Lozano-Calderon, Santiago A. TI Outcome After Reconstruction of the Proximal Humerus for Tumor Resection: A Systematic Review SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Review ID PROSTHESIS COMPOSITE RECONSTRUCTION; VASCULARIZED FIBULAR GRAFT; SOFT-TISSUE TUMORS; SHOULDER GIRDLE; LIMB SALVAGE; MALIGNANT BONE; ENDOPROSTHETIC RECONSTRUCTION; OSTEOARTICULAR ALLOGRAFTS; SURGICAL-TREATMENT; REPLACEMENT AB Tumors of the appendicular skeleton commonly affect the proximal humerus, but there is no consensus regarding the best reconstructive technique after proximal humerus resection for tumors of the shoulder. We wished to perform a systematic review to determine which surgical reconstruction offers the (1) best functional outcome as measured by the Musculoskeletal Tumor Society (MSTS) score, (2) longest construct survival, and (3) lowest complication rate after proximal humerus resection for malignant or aggressive benign tumors of the shoulder. We searched the literature up to June 1, 2013, from MEDLINE, EMBASE, and the Cochrane Library. Only studies reporting results in English, Dutch, or German and with followups of 80% or more of the patients at a minimum of 2 years were included. Twenty-nine studies with 693 patients met our criteria, seven studies (24%) were level of evidence III and the remainder were level IV. Studies reported on reconstruction with prostheses (n = 17), osteoarticular allografts (n = 10), and allograft-prosthesis composites (n = 11). Owing to substantial heterogeneity and bias, we narratively report our results. Functional scores in prosthesis studies ranged from 61% to 77% (10 studies, 141 patients), from 50% to 78% (eight studies, 84 patients) in osteoarticular graft studies, and from 57% to 91% (10 studies, 141 patients) in allograft-prosthesis composite studies. Implant survival ranged from 0.38 to 1.0 in the prosthesis group (341 patients), 0.33 to 1.0 in the osteoarticular allograft group (143 patients), and 0.33 to 1.0 in allograft-prosthesis group (132 patients). Overall complications per patient varied between 0.045 and 0.85 in the prosthesis group, 0 and 1.5 in the osteoarticular graft group, and 0.19 and 0.79 in the prosthesis-composite graft group. We observed a higher fracture rate for osteoarticular allografts, but other specific complication rates were similar. Owing to the limitations of our systematic review, we found that allograft-prosthesis composites and prostheses seem to have similar functional outcome and survival rates, and both seem to avoid fractures that are observed with osteoarticular allografts. Further collaboration in the field of surgical oncology, using randomized controlled trials, is required to establish the superiority of any particular treatment. C1 [Teunis, Teun; Nota, Sjoerd P. F. T.; Hornicek, Francis J.; Schwab, Joseph H.; Lozano-Calderon, Santiago A.] Harvard Univ, Musculoskeletal Oncol Serv, Massachusetts Gen Hosp, Dept Orthopaed Surg,Med Sch, Boston, MA 02163 USA. [Hornicek, Francis J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA USA. [Schwab, Joseph H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Spine Surg Serv, Boston, MA USA. RP Teunis, T (reprint author), Harvard Univ, Musculoskeletal Oncol Serv, Massachusetts Gen Hosp, Dept Orthopaed Surg,Med Sch, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02163 USA. EM teunteunis@gmail.com FU National Center for Research Resources, Center for advancing Translational Sciences, NIH [8UL1TR000170-05]; Harvard University FX Help was received from the Harvard Catalyst, who is funded by: National Center for Research Resources, Center for advancing Translational Sciences, NIH award 8UL1TR000170-05, and financial contributions from Harvard University. NR 62 TC 6 Z9 8 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2014 VL 472 IS 7 BP 2245 EP 2253 DI 10.1007/s11999-014-3474-4 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AI6XP UT WOS:000337021300038 PM 24469551 ER PT J AU Lee, JW Norden, AD Ligon, KL Golby, AJ Beroukhim, R Quackenbush, J Wells, W Oelschlager, K Maetzold, D Wen, PY AF Lee, Jong Woo Norden, Andrew D. Ligon, Keith L. Golby, Alexandra J. Beroukhim, Rameen Quackenbush, John Wells, William Oelschlager, Kristen Maetzold, Derek Wen, Patrick Y. TI Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study SO EPILEPSY RESEARCH LA English DT Article DE Brain tumor; Seizure; Gene expression; Imaging ID LOW-GRADE GLIOMAS; DIAGNOSED BRAIN-TUMORS; MULTIVARIATE-ANALYSIS; EPILEPSY; LOCALIZATION; MULTIFORME; RESECTION; PERMUTATION; DISORDERS; GLUTAMATE AB Tumor associated seizures (TAS) are common and cause significant morbidity. Both imaging and gene expression features play significant roles in determining TAS, with strong interactions between them. We describe gene expression imaging tools which allow mapping of brain regions where gene expression has significant influence on TAS, and apply these methods to study 77 patients who underwent surgical evaluation for supratentorial glioblastomas. Tumor size and location were measured from MRI scans. A 9-set gene expression profile predicting long-term survivors was obtained from RNA derived from formalin-fixed paraffin embedded tissue. A total of 32 patients (42%) experienced preoperative TAS. Tumor volume was smaller (31.1 vs. 58.8 cubic cm, p < 0.001) and there was a trend toward median survival being higher (48.4 vs. 32.7 months, p = 0.055) in patients with TAS. Although the expression of only OLIG2 was significantly lower in patients with TAS in a groupwise analysis, gene expression imaging analysis revealed regions with significantly lower expression of OLIG2 and RTN1 in patients with TAS. Gene expression imaging is a powerful technique that demonstrates that the influence of gene expression on TAS is highly region specific. Regional variability should be evaluated with any genomic or molecular markers of solid brain lesions. (C) 2014 Elsevier B.V. All rights reserved. C1 [Lee, Jong Woo] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Norden, Andrew D.; Beroukhim, Rameen; Wen, Patrick Y.] Harvard Univ, Sch Med, Ctr Neurooncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ligon, Keith L.] Boston Childrens Hosp, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ligon, Keith L.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02115 USA. [Golby, Alexandra J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Quackenbush, John] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Wells, William] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Oelschlager, Kristen; Maetzold, Derek] Castle Biosci Inc, Phoenix, AZ 85012 USA. RP Lee, JW (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM jlee38@partners.org FU National Center for Image Guided Therapy [U41 RR019703]; National Institutes of Health [P41RR13218]; Castle Biosciences Inc. FX This study was supported by funding from the National Center for Image Guided Therapy (U41 RR019703), National Institutes of Health (P41RR13218), and Castle Biosciences Inc. NR 50 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 EI 1872-6844 J9 EPILEPSY RES JI Epilepsy Res. PD JUL PY 2014 VL 108 IS 5 BP 843 EP 852 DI 10.1016/j.eplepsyres.2014.02.021 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AI6VJ UT WOS:000337014800003 PM 24690158 ER PT J AU Valkovic, L Gajdosik, M Traussnigg, S Wolf, P Chmelik, M Kienbacher, C Bogner, W Krebs, M Trauner, M Trattnig, S Krssak, M AF Valkovic, Ladislav Gajdosik, Martin Traussnigg, Stefan Wolf, Peter Chmelik, Marek Kienbacher, Christian Bogner, Wolfgang Krebs, Michael Trauner, Michael Trattnig, Siegfried Krssak, Martin TI Application of localized P-31 MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease SO EUROPEAN RADIOLOGY LA English DT Article DE Liver metabolism; P-31 MRS saturation transfer; Reproducibility; NASH; NAFL ID MAGNETIC-RESONANCE-SPECTROSCOPY; STEATOHEPATITIS; QUANTIFICATION; ABNORMALITIES; CIRRHOSIS; LESIONS AB Saturation transfer (ST) phosphorus MR spectroscopy (P-31 MRS) enables in vivo insight into energy metabolism and thus could identify liver conditions currently diagnosed only by biopsy. This study assesses the reproducibility of the localized P-31 MRS ST in liver at 7 T and tests its potential for noninvasive differentiation of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). After the ethics committee approval, reproducibility of the localized P-31 MRS ST at 7 T and the biological variation of acquired hepato-metabolic parameters were assessed in healthy volunteers. Subsequently, 16 suspected NAFL/NASH patients underwent MRS measurements and diagnostic liver biopsy. The Pi-to-ATP exchange parameters were compared between the groups by a Mann-Whitney U test and related to the liver fat content estimated by a single-voxel proton (H-1) MRS, measured at 3 T. The mean exchange rate constant (k) in healthy volunteers was 0.31 +/- 0.03 s(-1) with a coefficient of variation of 9.0 %. Significantly lower exchange rates (p < 0.01) were found in NASH patients (k = 0.17 +/- 0.04 s(-1)) when compared to healthy volunteers, and NAFL patients (k = 0.30 +/- 0.05 s(-1)). Significant correlation was found between the k value and the liver fat content (r = 0.824, p < 0.01). Our data suggest that the P-31 MRS ST technique provides a tool for gaining insight into hepatic ATP metabolism and could contribute to the differentiation of NAFL and NASH. aEuro cent 1D localized (31) P MRS saturation transfer in the liver is reproducible at 7 T aEuro cent NASH patients have decreased hepatic Pi-to-ATP exchange rate aEuro cent In this study, hepatic metabolic activity correlates with liver fat content. C1 [Valkovic, Ladislav; Gajdosik, Martin; Chmelik, Marek; Bogner, Wolfgang; Trattnig, Siegfried; Krssak, Martin] Med Univ Vienna, High Field MR Ctr, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Valkovic, Ladislav] Slovak Acad Sci, Inst Measurement Sci, Dept Imaging Methods, Bratislava, Slovakia. [Traussnigg, Stefan; Kienbacher, Christian; Trauner, Michael] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Vienna, Austria. [Wolf, Peter; Krebs, Michael; Krssak, Martin] Med Univ Vienna, Dept Internal Med 3, Div Endocrinol & Metab, Vienna, Austria. [Bogner, Wolfgang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Boston, MA USA. RP Krssak, M (reprint author), Med Univ Vienna, Dept Internal Med 3, Div Endocrinol & Metab, Vienna, Austria. EM martin.krssak@meduniwien.ac.at OI Valkovic, Ladislav/0000-0003-2567-3642; Bogner, Wolfgang/0000-0002-0130-3463 FU Vienna Spots of Excellence des Wiener Wissenschafts- und Technologie-Fonds (WWTF) - Vienna Advanced Imaging Center (VIACLIC) [FA102A0017]; OeNB Jubilaeumsfond [13629, 13834, 15455]; Slovak Grant Agency (VEGA) [2/0013/14]; Slovak Grant Agency (APVV) [0513-10] FX The scientific guarantor of this publication is Assistant Professor Martin Krssak, Ph.D. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This study has received funding by the Vienna Spots of Excellence des Wiener Wissenschafts- und Technologie-Fonds (WWTF) - Vienna Advanced Imaging Center (VIACLIC #FA102A0017) and the OeNB Jubilaeumsfond (grant #13629, #13834, #15455) and the Slovak Grant Agency (VEGA grant #2/0013/14 and APVV grant #0513-10). No complex statistical methods were necessary for this paper. Institutional review board approval was obtained. Written informed consent was obtained from all subjects (patients) in this study. Methodology: prospective, experimental, performed at one institution. NR 30 TC 6 Z9 6 U1 1 U2 9 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 2014 VL 24 IS 7 BP 1602 EP 1609 DI 10.1007/s00330-014-3141-x PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI7DH UT WOS:000337041900021 PM 24647824 ER PT J AU Neverova, N Teerlink, JR AF Neverova, Natalia Teerlink, John R. TI Serelaxin: a potential new drug for the treatment of acute heart failure SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Article DE acute heart failure; dyspnea; relaxin; serelaxin; vasodilator ID RANDOMIZED CONTROLLED TRIAL; CARDIAC MYOSIN ACTIVATOR; DOUBLE-BLIND; RELAX-AHF; INTRAVENOUS NESIRITIDE; TISSUE DISTRIBUTION; OMECAMTIV MECARBIL; HORMONE RELAXIN; FUTURE-RESEARCH; NITRIC-OXIDE AB Introduction: The incidence and mortality related to acute heart failure (AHF) have increased in the recent decades despite clinical trials of multiple agents and considerable progress in cardiovascular disease overall. Areas covered: This article reviews serelaxin, a new investigational drug in the treatment of AHF. It provides the background of the available treatments and focuses on serelaxin mechanisms, pharmacology, clinical features and its potential role in AHF. Expert opinion: Recent clinical trials of serelaxin (Pre-RELAX-AHF; RELAX-AHF) have provided a new hope in AHF. They have demonstrated significant serelaxin-related improvement in heart failure symptoms, length of hospital stay as well as mortality reduction in AHF patients. These findings were in the context of early administration in the course of AHF presentation in patients with normal or high blood pressures, thus highlighting the drug's strengths based on its molecular mechanisms of action. Overall, serelaxin is a promising therapy, and further studies aimed at reproducibility of prior results, safety and hemodynamic effects of serelaxin, as well as investigation of the molecular reasons for such effects are currently under way. C1 [Neverova, Natalia; Teerlink, John R.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94117 USA. [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94131 USA. RP Teerlink, JR (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94117 USA. EM john.teerlink@ucsf.edu FU Amgen, Inc; Cytokinetics; Novartis; Trevena Inc. FX JR Teerlink has received research grants and consultancy fees from Amgen, Inc, Cytokinetics, Novartis and Trevena Inc. 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 66 TC 7 Z9 7 U1 3 U2 19 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3784 EI 1744-7658 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUL PY 2014 VL 23 IS 7 BP 1017 EP 1026 DI 10.1517/13543784.2014.924504 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AI7QF UT WOS:000337089000011 PM 24865798 ER PT J AU Park, JM Small, BJ Geller, DA Murphy, TK Lewin, AB Storch, EA AF Park, Jennifer M. Small, Brent J. Geller, Daniel A. Murphy, Tanya K. Lewin, Adam B. Storch, Eric A. TI Does D-Cycloserine Augmentation of CBT Improve Therapeutic Homework Compliance for Pediatric Obsessive-Compulsive Disorder? SO JOURNAL OF CHILD AND FAMILY STUDIES LA English DT Article DE Obsessive-compulsive disorder; D-Cycloserine; Exposure and response prevention; Homework compliance; Children ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; SOCIAL ANXIETY DISORDER; EXPOSURE THERAPY; CONDITIONED FEAR; TREATMENT EXPECTANCY; FOLLOW-UP; EXTINCTION; CHILDREN; ADOLESCENTS AB Clinical studies in adults and children with obsessive-compulsive disorder (OCD) have shown that d-cycloserine (DCS) can improve treatment response by enhancing fear extinction learning during exposure-based psychotherapy. Some have hypothesized that improved treatment response is a function of increased compliance and engagement in therapeutic homework tasks, a core component of behavioral treatment. The present study examined the relationship between DCS augmented cognitive-behavioral therapy (CBT) and homework compliance in a double-blind, placebo controlled trial with 30 youth with OCD. All children received 10 CBT sessions, the last seven of which included exposure and response prevention paired with DCS or placebo dosed 1 h before the session started. Results suggested that DCS augmented CBT did not predict improved homework compliance over the course of treatment, relative to the placebo augmented CBT group. However, when groups were collapsed, homework compliance was directly associated with treatment outcome. These findings suggest that while DCS may not increase homework compliance over time, more generally, homework compliance is an integral part of pediatric OCD treatment outcome. C1 [Park, Jennifer M.] Univ S Florida, Dept Psychol, Tampa, FL 33611 USA. [Small, Brent J.] Univ S Florida, Sch Aging Studies, Tampa, FL 33611 USA. [Geller, Daniel A.] Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, Boston, MA 02114 USA. [Murphy, Tanya K.; Lewin, Adam B.; Storch, Eric A.] Univ S Florida, Dept Pediat, St Petersburg, FL 33701 USA. [Murphy, Tanya K.; Lewin, Adam B.; Storch, Eric A.] Univ S Florida, Dept Psychiat, St Petersburg, FL 33701 USA. RP Park, JM (reprint author), Univ S Florida, Dept Psychol, 4202 E Fowler Ave,PCD 4118G, Tampa, FL 33611 USA. EM jmpark@mail.usf.edu RI Murphy, Tanya/J-7079-2013; OI Small, Brent/0000-0002-7444-4689 FU NIMH NIH HHS [R03 MH076775, L40 MH081950] NR 66 TC 11 Z9 11 U1 3 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1062-1024 EI 1573-2843 J9 J CHILD FAM STUD JI J. Child Fam. Stud. PD JUL PY 2014 VL 23 IS 5 BP 863 EP 871 DI 10.1007/s10826-013-9742-1 PG 9 WC Family Studies; Psychology, Developmental; Psychiatry SC Family Studies; Psychology; Psychiatry GA AI7PC UT WOS:000337085000010 PM 24999301 ER PT J AU Yang, JC Aronson, JP Dunn, GP Codd, PJ Buchbinder, BR Eskandar, EN AF Yang, Jimmy C. Aronson, Joshua P. Dunn, Gavin P. Codd, Patrick J. Buchbinder, Bradley R. Eskandar, Emad N. TI Three-dimensional brain surface visualization for epilepsy surgery of focal cortical dysplasia SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Brain imaging; Epilepsy; Focal cortical dysplasia; 3D imaging ID INTRACTABLE EPILEPSY; SURGICAL-TREATMENT; CLASSIFICATION; ADULTS; TUMORS; SHIFT; EEG AB Focal cortical dysplasia (FCD) causes medically intractable seizures in 5-10% of adult epilepsy patients, but patients can become seizure free through surgical resection. The authors present the utility of three-dimensional surface visualization (3DSV) that expands on existing imaging datasets to highlight surface vasculature as a tool for achieving more successful resections in patients with FCD. In this prospective series of six patients, preoperative 3DSV was performed for planning the surgical approach to the lesion and for intraoperative guidance. Reconstructions involved volume rendering of a contrast-enhanced dataset to visualize surface venous vasculature. Postoperatively, five of the six patients had complete resections, with one patient having a subtotal resection due to proximity to crucial vasculature. We report that 3DSV is a useful tool for surgical planning, since topographical relationships between lesion location and surface vasculature landmarks are less likely to change with surgical progress. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Yang, Jimmy C.; Aronson, Joshua P.; Dunn, Gavin P.; Codd, Patrick J.; Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Yang, Jimmy C.; Aronson, Joshua P.; Dunn, Gavin P.; Codd, Patrick J.; Buchbinder, Bradley R.; Eskandar, Emad N.] Harvard Univ, Sch Med, Boston, MA USA. [Buchbinder, Bradley R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Eskandar, EN (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White 502, Boston, MA 02114 USA. EM eeskandar@partners.org NR 16 TC 1 Z9 1 U1 1 U2 7 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 2014 VL 21 IS 7 BP 1230 EP 1232 DI 10.1016/j.jocn.2013.12.004 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AI7ZB UT WOS:000337120400028 PM 24485033 ER PT J AU Bell, DL Stapleton, CJ Terry, AR Stone, JR Ogilvy, CS AF Bell, Donnie L. Stapleton, Christopher J. Terry, Anna R. Stone, James R. Ogilvy, Christopher S. TI Clinical presentation and treatment considerations of a ruptured posterior spinal artery pseudoaneurysm SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Endovascular neurosurgery; Posterior spinal artery; Pseudoaneurysm; Spinal subarachnoid hemorrhage; Vascular neurosurgery ID OF-THE-LITERATURE; ANEURYSM AB Spinal artery pseudoaneurysms are rare vascular lesions with poorly defined natural history, diagnostic paradigms, and treatment strategies. We present a 68-year-old woman with severe back pain and left lower extremity weakness with spinal subarachnoid hemorrhage due to a ruptured T5 region posterior spinal artery pseudoaneurysm, and review issues related to radiologic diagnosis and endovascular and open neurosurgical interventions. (c) 2014 Elsevier Ltd. All rights reserved. C1 [Bell, Donnie L.] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Neuroradiol Endovasc Neurosurg, Boston, MA 02114 USA. [Bell, Donnie L.; Stapleton, Christopher J.; Terry, Anna R.; Stone, James R.; Ogilvy, Christopher S.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Stapleton, Christopher J.; Terry, Anna R.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ogilvy, Christopher S.] Beth Israel Deaconess Med Ctr, Dept Surg, Div Neurosurg, Boston, MA 02215 USA. RP Stapleton, CJ (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,ACC 745, Boston, MA 02114 USA. EM cstapleton@partners.org NR 7 TC 1 Z9 1 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 2014 VL 21 IS 7 BP 1273 EP 1276 DI 10.1016/j.jocn.2014.01.002 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AI7ZB UT WOS:000337120400043 PM 24572933 ER PT J AU Shibli-Rahhal, A Paturi, B AF Shibli-Rahhal, A. Paturi, B. TI Variations in parathyroid hormone concentration in patients with low 25 hydroxyvitamin D SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Hyperparathyroidism; PTH; Vitamin D ID VITAMIN-D STATUS; SERUM 25-HYDROXYVITAMIN D; SECONDARY HYPERPARATHYROIDISM; MAGNESIUM-DEFICIENCY; D INSUFFICIENCY; CALCIUM INTAKE; BONE TURNOVER; WOMEN; OSTEOPOROSIS; AGE AB Although 25 hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) levels are inversely related, less than half of the patients with a low vitamin D level have an elevated PTH, and, in most of these patients, the PTH does not immediately normalize with correction of the vitamin D. Despite the inverse relationship between 25OHD and PTH, patients with vitamin D deficiency seen in clinical practice do not always have an elevated PTH, and, in those with secondary hyperparathyroidism, the PTH does not always normalize with correction of vitamin D deficiency. We examined variations in PTH concentrations in patients with low 25OHD and studied changes in the PTH concentration with restoration of vitamin D sufficiency. This was a retrospective cohort study of patients with a 25OHD < 30 ng/mL and a concomitant PTH measurement seen at the Metabolic Bone Disease Clinic at a tertiary care center between July 1, 2007 and May 31, 2011. Patients with conditions associated with alterations in PTH were excluded. The study population consisted of 104 patients. The mean age was 55.5 years, and 83 % were female. The 25OHD and PTH were negatively correlated, but only 30 % of patients with a 25OHD < 30 ng/mL and 40 % of those with a 25OHD < 20 ng/mL had an elevated PTH. As the 25OHD increased to 30 ng/mL or higher, the PTH decreased significantly in the group of patients who had an elevated PTH at baseline, but only 44 % reached a normal PTH. Of patients with a normal PTH at baseline, 59 % experienced a drop in their PTH while the PTH remained unchanged or increased in 41 %. PTH has a limited role in defining vitamin D status in individual patients and in guiding vitamin D therapy in clinical practice. C1 [Shibli-Rahhal, A.] Univ Iowa, Div Endocrinol Diabet & Metab, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Paturi, B.] St Francis Med Ctr, Div Endocrinol Diabet & Metab, Dept Internal Med, Peoria, IL USA. [Paturi, B.] Joslin Diabet Ctr, Peoria, IL USA. [Shibli-Rahhal, A.] Univ Iowa, Div Endocrinol, Carver Coll Med, Iowa City, IA 52242 USA. RP Shibli-Rahhal, A (reprint author), Univ Iowa, Div Endocrinol, Carver Coll Med, E 426 GH,200 Hawkins Dr, Iowa City, IA 52242 USA. EM amal-rahhal@uiowa.edu NR 26 TC 4 Z9 4 U1 1 U2 6 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUL PY 2014 VL 25 IS 7 BP 1931 EP 1936 DI 10.1007/s00198-014-2687-4 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AI7BI UT WOS:000337034600012 PM 24647889 ER PT J AU Batsis, M Wright, D Souter, I AF Batsis, M. Wright, D. Souter, I. TI The effect of ovarian reserve parameters on biomarkers identified with time-lapse imaging SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 30th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE) CY JUN 29-JUL 02, 2014 CL Munich, GERMANY SP European Soc Human Reprod & Embryol C1 [Batsis, M.; Wright, D.; Souter, I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Fertil Ctr,Dept Obstet Gynecol Reprod Endocrinol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2014 VL 29 SU 1 MA P-173 BP 189 EP 189 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CP2YZ UT WOS:000359745300441 ER PT J AU Souter, I Afeiche, M Batsis, M Williams, P Hauser, R Chavarro, J AF Souter, I. Afeiche, M. Batsis, M. Williams, P. Hauser, R. Chavarro, J. TI Hair mercury concentrations and ovarian reserve parameters in women undergoing fertility treatments SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 30th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE) CY JUN 29-JUL 02, 2014 CL Munich, GERMANY SP European Soc Human Reprod & Embryol C1 [Souter, I.] Harvard Univ, Med School Massachusetts, Obstet Gynecol Reprod Endocrinol & Infertilit, Gen Hosp,Fertil Ctr, Boston, MA 02115 USA. [Afeiche, M.] Harvard Univ, Sch Publ Hlth, Nutr, Boston, MA 02115 USA. [Batsis, M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Batsis, M.] Massachusetts Gen Hosp, Fertil Ctr, Environm Hlth & Obstet Gynecol Reprod Endocrinol, Boston, MA 02114 USA. [Williams, P.] Harvard Univ, Sch Publ Hlth, Biostat, Boston, MA 02115 USA. [Hauser, R.] Harvard Univ, Sch Publ Hlth, Environm Hlth & Obstet Gynecol Reprod Endocrinol, Sch Med, Boston, MA 02115 USA. [Chavarro, J.] Harvard Univ, Sch Publ Hlth, Epidemiol & Dept Nutr, Sch Med, Boston, MA 02115 USA. [Chavarro, J.] Dept Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2014 VL 29 SU 1 MA P-576 BP 355 EP 355 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CP2YZ UT WOS:000359745300833 ER PT J AU Chow, JDY Lawrence, RT Healy, ME Dominy, JE Liao, JA Breen, DS Byrne, FL Kenwood, BM Lackner, C Okutsu, S Mas, VR Caldwell, SH Tomsig, JL Cooney, GJ Puigserver, PB Turner, N James, DE Villen, J Hoehn, KL AF Chow, Jenny D. Y. Lawrence, Robert T. Healy, Marin E. Dominy, John E. Liao, Jason A. Breen, David S. Byrne, Frances L. Kenwood, Brandon M. Lackner, Carolin Okutsu, Saeko Mas, Valeria R. Caldwell, Stephen H. Tomsig, Jose L. Cooney, Gregory J. Puigserver, Pere B. Turner, Nigel James, David E. Villen, Judit Hoehn, Kyle L. TI Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation SO MOLECULAR METABOLISM LA English DT Article DE Lipid metabolism; Liver; Steatosis: Acetylation AB Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extramitochondrial space. (C) 2014 The Authors. Published by Elsevier GmbH. Open access under CC BY-NC-ND Iscense. C1 [Hoehn, Kyle L.] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. Harvard Univ, Sch Med, Dana Faber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Faber Canc Inst, Dept Cell Biol, Boston, MA 02115 USA. Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. Med Univ Graz, Inst Pathol, Graz, Austria. Garvan Inst Med Res, Diabet & Obes Program, Darlinghurst, NSW 2010, Australia. Univ New S Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW, Australia. Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia. RP Hoehn, KL (reprint author), Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. EM jvillen@uw.edu RI Turner, Nigel/H-7176-2013; OI Turner, Nigel/0000-0002-0119-9328; Villen, Judit/0000-0002-1005-1739; Byrne, Frances/0000-0002-8897-8438; Hoehn, Kyle/0000-0002-0214-3238 FU NCI NIH HHS [T32 CA009109] NR 55 TC 22 Z9 23 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2212-8778 J9 MOL METAB JI Mol. Metab. PD JUL PY 2014 VL 3 IS 4 BP 419 EP 431 DI 10.1016/j.molmet.2014.02.004 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V42UI UT WOS:000209638300016 PM 24944901 ER PT J AU Buckley, EM Parthasarathy, AB Grant, PE Yodh, AG Franceschini, MA AF Buckley, Erin M. Parthasarathy, Ashwin B. Grant, P. Ellen Yodh, Arjun G. Franceschini, Maria Angela TI Diffuse correlation spectroscopy for measurement of cerebral blood flow: future prospects SO NEUROPHOTONICS LA English DT Article DE cerebral blood flow; biomedical optics; spectroscopy; medical imaging AB Diffuse correlation spectroscopy (DCS) is an emerging optical modality used to measure cortical cerebral blood flow. This outlook presents a brief overview of the technology, summarizing the advantages and limitations of the method, and describing its recent applications to animal, adult, and infant cohorts. At last, the paper highlights future applications where DCS may play a pivotal role individualizing patient management and enhancing our understanding of neurovascular coupling, activation, and brain development. (C) The Authors. C1 [Buckley, Erin M.; Franceschini, Maria Angela] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Parthasarathy, Ashwin B.; Yodh, Arjun G.] Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. [Grant, P. Ellen] Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. RP Buckley, EM (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. EM buckley@nmr.mgh.harvard.edu NR 59 TC 12 Z9 12 U1 1 U2 1 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2014 VL 1 IS 1 AR 011009 DI 10.1117/1.NPh.1.1.011009 PG 7 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA V45SO UT WOS:000209836500008 ER PT J AU Devor, A Roe, AW Mahadevan-Jansen, A Boas, DA AF Devor, Anna Roe, Anna W. Mahadevan-Jansen, Anita Boas, David A. TI The BRAIN Initiative SO NEUROPHOTONICS LA English DT Editorial Material C1 [Devor, Anna] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Devor, Anna] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Devor, Anna; Boas, David A.] Harvard Med Sch, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Roe, Anna W.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Mahadevan-Jansen, Anita] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37240 USA. RP Devor, A (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. EM adevor@ucsd.edu; anna.roe@vanderbilt.edu; anita.mahadevan-jansen@vanderbilt.edu; dboas@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2014 VL 1 IS 1 AR 011001 DI 10.1117/1.NPh.1.1.011001 PG 2 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA V45ZM UT WOS:000209854500001 ER PT J AU Selb, J Boas, DA Chan, ST Evans, KC Buckley, EM Carp, SA AF Selb, Juliette Boas, David A. Chan, Suk-Tak Evans, Karleyton C. Buckley, Erin M. Carp, Stefan A. TI Sensitivity of near-infrared spectroscopy and diffuse correlation spectroscopy to brain hemodynamics: simulations and experimental findings during hypercapnia SO NEUROPHOTONICS LA English DT Article DE near-infrared spectroscopy; diffuse correlation spectroscopy; functional brain imaging; hypercapnia AB Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) are two diffuse optical technologies for brain imaging that are sensitive to changes in hemoglobin concentrations and blood flow, respectively. Measurements for both modalities are acquired on the scalp, and therefore hemodynamic processes in the extracerebral vasculature confound the interpretation of cortical hemodynamic signals. The sensitivity of NIRS to the brain versus the extracerebral tissue and the contrast-to-noise ratio (CNR) of NIRS to cerebral hemodynamic responses have been well characterized, but the same has not been evaluated for DCS. This is important to assess in order to understand their relative capabilities in measuring cerebral physiological changes. We present Monte Carlo simulations on a head model that demonstrate that the relative brain-to-scalp sensitivity is about three times higher for DCS (0.3 at 3 cm) than for NIRS (0.1 at 3 cm). However, because DCS has higher levels of noise due to photon-counting detection, the CNR is similar for both modalities in response to a physiologically realistic simulation of brain activation. Even so, we also observed higher CNR of the hemodynamic response during graded hypercapnia in adult subjects with DCS than with NIRS. (C) 2014 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Selb, Juliette; Boas, David A.; Chan, Suk-Tak; Buckley, Erin M.; Carp, Stefan A.] Massachusetts Gen Hosp, Dept Radiol, Opt Div, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. [Evans, Karleyton C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, 149 13th St, Charlestown, MA 02129 USA. RP Selb, J (reprint author), Massachusetts Gen Hosp, Dept Radiol, Opt Div, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM juliette@nmr.mgh.harvard.edu NR 85 TC 14 Z9 14 U1 0 U2 1 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2014 VL 1 IS 1 AR 015005 DI 10.1117/1.NPh.1.1.015005 PG 15 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA V45SO UT WOS:000209836500015 ER PT J AU Rounsaville, D O'Farrell, TJ Andreas, JB Murphy, CM Murphy, MM AF Rounsaville, Daniel O'Farrell, Timothy J. Andreas, Jasmina Burdzovic Murphy, Christopher M. Murphy, Marie M. TI Children's exposure to parental conflict after father's treatment for alcoholism SO ADDICTIVE BEHAVIORS LA English DT Article DE Children of alcoholics (COAs); Parental conflict ID INTIMATE PARTNER VIOLENCE; BEHAVIOR PROBLEMS; MARITAL DISCORD; PSYCHOSOCIAL ADJUSTMENT; HEAVY DRINKING; SAMPLE; DISORDERS; PATTERNS; GIRLS AB Objective: This study investigated children of alcoholics' (COAs) exposure to inter-parental conflict before and after their fathers received alcohol treatment and compared exposure levels to a community comparison sample. Method: This study included 67 couples with a treatment-seeking male alcoholic partner and children aged 4-16. The alcoholic fathers and their relationship partners provided data at baseline and at six and twelve month follow-ups. A community comparison sample of 78 couples with children in the target age range completed similar longitudinal assessments. It was hypothesized that treatment of paternal alcoholism would be associated with a decrease in COAs' exposure to conflict, and that among remitted patients exposure to conflict would decrease to the level found in the community sample. Results: Prior to the father's alcohol treatment, the children of the treatment sample were exposed to significantly more conflict between their parents than in the community comparison sample. After the fathers received alcohol treatment, COAs' exposure to conflict significantly decreased at both the six and twelve month follow-ups compared to baseline. Children of remitted alcoholics did not differ significantly in levels of exposure to conflict at six months follow-up compared to the community sample as predicted. However, at twelve months remitted alcoholics reported significantly more exposure to conflict compared to the community sample. Conclusions: Decreased child exposure to parental conflict is a benefit associated with the father's treatment for alcoholism, and it may lead to improvements in COAs' functioning after parental treatment. Published by Elsevier Ltd. C1 [Rounsaville, Daniel; O'Farrell, Timothy J.; Murphy, Marie M.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02301 USA. [Andreas, Jasmina Burdzovic] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Murphy, Christopher M.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. RP O'Farrell, TJ (reprint author), Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, VAMC 116B1,940 Belmont St, Brockton, MA 02301 USA. EM timothy_ofarrell@hms.harvard.edu FU NIAAA [R01AA10796, T32 AA007459]; U.S. Department of Veterans Affairs FX Funding for this study was provided by NIAAA grant R01AA10796 to the second author, NIAAA grant T32 AA007459 to Brown University's Center for Alcohol and Addiction Studies to support the first author in preparing this manuscript, and by the U.S. Department of Veterans Affairs. NIAAA and the VA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 17 TC 6 Z9 6 U1 1 U2 16 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 2014 VL 39 IS 7 BP 1168 EP 1171 DI 10.1016/j.addbeh.2014.03.017 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA AI3OO UT WOS:000336772000006 PM 24727114 ER PT J AU Chiang, S Haneef, Z AF Chiang, Sharon Haneef, Zulfi TI Graph theory findings in the pathophysiology of temporal lobe epilepsy SO CLINICAL NEUROPHYSIOLOGY LA English DT Review DE Graph theory; Temporal lobe epilepsy; Pathophysiology; Functional connectivity; Diffusion tensor imaging; Small-world networks ID SMALL-WORLD NETWORKS; RESTING-STATE FMRI; COMPLEX BRAIN NETWORKS; DEFAULT MODE NETWORK; FUNCTIONAL CONNECTIVITY; THEORETICAL ANALYSIS; STRUCTURAL CONNECTIVITY; HIPPOCAMPAL ATROPHY; COGNITIVE DECLINE; CEREBRAL-CORTEX AB Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Chiang, Sharon] Rice Univ, Dept Stat, Houston, TX 77251 USA. [Haneef, Zulfi] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Haneef, Zulfi] VA Med Ctr, Houston, TX USA. RP Haneef, Z (reprint author), Baylor Coll Med, Dept Neurol, Peter Kellaway Sect Neurophysiol, One Baylor Plaza,MS NB302, Houston, TX 77030 USA. EM zulfi.haneef@bcm.edu FU Epilepsy Foundation of America; National Library of Medicine Training Fellowship in Biomedical Informatics; Gulf Coast Consortia for Quantitative Biomedical Sciences [2T15LM007093-21]; National Institute of Health [5T32CA09652007]; Epilepsy Foundation of America and the Baylor College of Medicine Computational; Integrative Biomedical Research Center (CIBR) FX Funding for this study was provided by the Epilepsy Foundation of America. Ms. Chiang's contributions to this article include writing of the review and the decision to submit the article for publication. She is funded by the National Library of Medicine Training Fellowship in Biomedical Informatics, Gulf Coast Consortia for Quantitative Biomedical Sciences (Grant # 2T15LM007093-21) and by the National Institute of Health (Grant # 5T32CA09652007). Ms. Chiang reports no disclosures, commercial considerations, or financial conflicts of interest. Dr. Haneef's contributions to this article include writing of the review and the decision to submit the article for publication. He is funded by the Epilepsy Foundation of America and the Baylor College of Medicine Computational and Integrative Biomedical Research Center (CIBR) seed grant awards. Dr. Haneef reports no disclosures, commercial considerations, or financial conflicts of interest. NR 85 TC 27 Z9 28 U1 4 U2 26 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 2014 VL 125 IS 7 BP 1295 EP 1305 DI 10.1016/j.clinph.2014.04.004 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AI0AC UT WOS:000336507100004 PM 24831083 ER PT J AU Chu, CJ Leahy, J Pathmanathan, J Kramer, MA Cash, SS AF Chu, C. J. Leahy, J. Pathmanathan, J. Kramer, M. A. Cash, S. S. TI The maturation of cortical sleep rhythms and networks over early development SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Development; Brain rhythms; Brain networks; Functional connectivity; Sleep; EEG ID GAMMA-BAND ACTIVITY; GABAERGIC INTERNEURONS; REGIONAL DIFFERENCES; FUNCTIONAL NETWORKS; SPECTRAL-ANALYSIS; VISUAL-CORTEX; EEG COHERENCE; OSCILLATIONS; ELECTROENCEPHALOGRAM; CIRCUITS AB Objective: Although neuronal activity drives all aspects of cortical development, how human brain rhythms spontaneously mature remains an active area of research. We sought to systematically evaluate the emergence of human brain rhythms and functional cortical networks over early development. Methods: We examined cortical rhythms and coupling patterns from birth through adolescence in a large cohort of healthy children (n = 384) using scalp electroencephalogram (EEG) in the sleep state. Results: We found that the emergence of brain rhythms follows a stereotyped sequence over early development. In general, higher frequencies increase in prominence with striking regional specificity throughout development. The coordination of these rhythmic activities across brain regions follows a general pattern of maturation in which broadly distributed networks of low-frequency oscillations increase in density while networks of high frequency oscillations become sparser and more highly clustered. Conclusion: Our results indicate that a predictable program directs the development of key rhythmic components and physiological brain networks over early development. Significance: This work expands our knowledge of normal cortical development. The stereotyped neurophysiological processes observed at the level of rhythms and networks may provide a scaffolding to support critical periods of cognitive growth. Furthermore, these conserved patterns could provide a sensitive biomarker for cortical health across development. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Chu, C. J.; Leahy, J.; Pathmanathan, J.; Cash, S. S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02144 USA. [Chu, C. J.; Pathmanathan, J.; Cash, S. S.] Harvard Univ, Sch Med, Boston, MA 02144 USA. [Kramer, M. A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Chu, CJ (reprint author), Massachusetts Gen Hosp, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM cjchu@hms.harvard.edu RI Kramer, Mark/A-1291-2014 FU NIH Neurological Sciences Academic Development Award [K12]; Harvard/MIT Health Sciences and Technology; Beth Israel Deaconess Medical Center Clinical Investigator Training Program; Pfizer, Inc.; Merck Co.; Career Award at the Scientific Interface from the Burroughs Wellcome Fund; US NIH, NINDS [NS062092] FX This work was supported by the NIH K12 Neurological Sciences Academic Development Award (C.J.C.), Harvard/MIT Health Sciences and Technology, Beth Israel Deaconess Medical Center Clinical Investigator Training Program in collaboration with Pfizer, Inc. and Merck Co. (C.J.C.), a Career Award at the Scientific Interface from the Burroughs Wellcome Fund (M.A.K.), and a grant from the US NIH, NINDS NS062092 (S.S.C.). NR 84 TC 7 Z9 7 U1 0 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 2014 VL 125 IS 7 BP 1360 EP 1370 DI 10.1016/j.clinph.2013.11.028 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AI0AC UT WOS:000336507100011 PM 24418219 ER PT J AU Ostergaard, SD Bech, P Trivedi, MH Wisniewski, SR Rush, AJ Fava, M AF Ostergaard, Soren D. Bech, Per Trivedi, Madhukar H. Wisniewski, Stephen R. Rush, A. John Fava, Maurizio TI Brief, unidimensional melancholia rating scales are highly sensitive to the effect of citalopram and may have biological validity: Implications for the Research Domain Criteria (RDoC) SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depression; Psychometrics; Research Domain Criteria ID STAR-ASTERISK-D; HAMILTON DEPRESSION SCALE; SHORT-TERM TREATMENT; MAJOR DEPRESSION; PSYCHOTIC DEPRESSION; CONTROLLED-TRIALS; PLACEBO; SEVERITY; DISORDER; CORE AB Background: Most depression rating scales are multidimensional and the resulting heterogeneity may impede identification of coherent biomarkers. The aim of this study was to compare the psychometric performance of the multidimensional 17 item Hamilton Depression Rating Scale (HAM-D-17) and the 30 item Inventory of Depressive Symptomatology (IDS-C-30) to that of their unidimensional six item melancholia subscales (HAM-D-6 and IDS-C-6). Methods: A total of 2242 subjects from level 1 (citalopram) of the Sequenced Treatment Alternatives to Relieve Depression (STAVE)) study were included in the analysis. Symptom change, response and remission rates were compared for HAM-D-6 versus HAM-D17 and for IDS-C-6 versus IDS-C-30. The changes in total scores on these scales were compared to the change in Quality of Life Enjoyment and Satisfaction Questionnaire (QLES-Q) score using correlation analysis. Results: The response to treatment was significantly greater according to the HAM-D-6 and IDS-C-6. Furthermore, the correlation of changes in depression-ratings with changes in QLES-Q scores were comparable for the subscales and full scales. Limitations: STAR*D was not designed to answer the research questions addressed in this analysis. Conclusions: Our findings indicate that the HAM-D-6 and IDS-C-6 melancholia scales capture a coherent construct in depression. The syndrome reflected in these scales is unidimensional, sensitive to specific pharmacological intervention, and therefore likely to have biological validity. We therefore believe that "melancholia" thus defined could be a valuable construct under the Research Domain Criteria (RDoC), which specifically aims at identifying the neurobiology underlying mental disorders and providing drugable targets. (C) 2014 Elsevier B.V. All rights reserved. C1 [Ostergaard, Soren D.] Aarhus Univ Hosp, Res Unit, Dept P, DK-8240 Risskov, Denmark. [Ostergaard, Soren D.] Aalborg Univ Hosp, Aalborg Psychiat Hosp, Unit Psychiat Res, Aalborg, Denmark. [Ostergaard, Soren D.; Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Bech, Per] Copenhagen Univ Hosp, Psychiat Ctr North Zealand, Psychiat Res Unit, Hillerod, Denmark. [Trivedi, Madhukar H.] Univ Texas Southwestern Med Sch, Dallas, TX USA. [Wisniewski, Stephen R.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Rush, A. John] Duke NUS, Clin Sci, Singapore, Singapore. RP Ostergaard, SD (reprint author), Aarhus Univ Hosp, Res Unit, Dept P, Skovagervej 2, DK-8240 Risskov, Denmark. EM soeoes@rm.dk OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382; Ostergaard, Soren Dinesen/0000-0002-8032-6208 FU Janssen-Cilag; Agency for Healthcare Research and Quality (AHRQ); Corcept Therapeutics, Inc.; Cyberonics, Inc.; National Alliance for Research in Schizophrenia and Depression; National Institute of Mental Health; National Institute on Drug Abuse; Novartis; Pharmacia , Upjohn; Predix Pharmaceuticals (Epix); Solvay Pharmaceuticals, Inc.; Eli Lilly and Company; Brain Resource Ltd.; H. Lundbeck A/S; Medavante, Inc.; CINP; Duke National University of Singapore; Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb Foundation; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Laboratories; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen Research and Development, LLC; Jed Foundation; Johnson & Johnson Services, Inc.; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; MedAvante; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates, Inc.; Pharmavite(R) LLC; PharmoRx Therapeutics; Photothera; Roche Pharmaceuticals; RCT Logic, LLC; Sanofi-Aventis US LLC; Shire; Synthelabo; Wyeth-Ayerst Laboratories FX Soren D. Ostergaard: (last 3 years) Has received speaking fees, consultant honoraria and travel support from Janssen-Cilag until April 2011.; Madhukar H. Trivedi: (lifetime) is or has been an advisor/consultant to: Abbott Laboratories, Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc.), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb Company, Cephalon, Inc., Cerecor, Concert Pharmaceuticals, Inc, Eli Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals, Inc, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Global Services, LLC, Janssen Pharmaceutica Products, LP, Johnson & Johnson PRD, Libby, Lundbeck, Meade Johnson, MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America, Inc., Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals, Inc., Pfizer Inc., PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd., Sepracor, SHIRE Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, Vantage Point, Vivus, and Wyeth-Ayerst Laboratories. In addition, he has received research support from: Agency for Healthcare Research and Quality (AHRQ), Corcept Therapeutics, Inc., Cyberonics, Inc., National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health, National Institute on Drug Abuse, Novartis, Pharmacia &, Upjohn, Predix Pharmaceuticals (Epix), and Solvay Pharmaceuticals, Inc.; Stephen R. Wisniewski: (last 3 years) Has received grant support from Eli Lilly and Company.; A. John Rush: (last 3 years) Has received consulting fees from Brain Resource Ltd., H. Lundbeck A/S, and Medavante, Inc.; royalties from Guilford Publications, a travel grant from CINP and research support from Duke National University of Singapore.; Maurizio Fava: (lifetime) Research Support: Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb Foundation; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Laboratories; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen Research and Development, LLC; Jed Foundation; Johnson & Johnson Services, Inc.; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; MedAvante; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates, Inc.; Pharmavite (R) LLC; PharmoRx Therapeutics; Photothera; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories. Advisory/Consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Rioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research 8, Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc; Merck & Co. Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite (R) LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.: Vanda Pharmaceuticals, Inc. Speaking/Publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; ; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Acaclemy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories. Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: Patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to RUE Logic, LLC; and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD). NR 50 TC 10 Z9 11 U1 0 U2 4 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 PY 2014 VL 163 BP 18 EP 24 DI 10.1016/j.jad.2014.03.049 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AH9BS UT WOS:000336435000003 PM 24836083 ER PT J AU Edelman, EA Lin, BK Doksum, T Drohan, B Edelson, V Dolan, SM Hughes, K O'Leary, J Vasquez, L Copeland, S Galvin, SL DeGroat, N Pardanani, S Feero, WG Adams, C Jones, R Scott, J AF Edelman, Emily A. Lin, Bruce K. Doksum, Teresa Drohan, Brian Edelson, Vaughn Dolan, Siobhan M. Hughes, Kevin O'Leary, James Vasquez, Lisa Copeland, Sara Galvin, Shelley L. DeGroat, Nicole Pardanani, Setul Feero, W. Gregory Adams, Claire Jones, Renee Scott, Joan TI Evaluation of a Novel Electronic Genetic Screening and Clinical Decision Support Tool in Prenatal Clinical Settings SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Family health history; Personalized risk assessment; Clinical decision support; Prenatal care; Genetic screening ID FAMILY-HISTORY; PRIMARY-CARE; PERSONALIZED MEDICINE; RISK-ASSESSMENT; CANCER; GUIDELINES; ALERTS AB "The Pregnancy and Health Profile" (PHP) is a free prenatal genetic screening and clinical decision support (CDS) software tool for prenatal providers. PHP collects family health history (FHH) during intake and provides point-of-care risk assessment for providers and education for patients. This pilot study evaluated patient and provider responses to PHP and effects of using PHP in practice. PHP was implemented in four clinics. Surveys assessed provider confidence and knowledge and patient and provider satisfaction with PHP. Data on the implementation process were obtained through semi-structured interviews with administrators. Quantitative survey data were analyzed using Chi square test, Fisher's exact test, paired t tests, and multivariate logistic regression. Open-ended survey questions and interviews were analyzed using qualitative thematic analysis. Of the 83 % (513/618) of patients that provided feedback, 97 % felt PHP was easy to use and 98 % easy to understand. Thirty percent (21/71) of participating physicians completed both pre- and post-implementation feedback surveys [13 obstetricians (OBs) and 8 family medicine physicians (FPs)]. Confidence in managing genetic risks significantly improved for OBs on 2/6 measures (p values a parts per thousand currency sign0.001) but not for FPs. Physician knowledge did not significantly change. Providers reported value in added patient engagement and reported mixed feedback about the CDS report. We identified key steps, resources, and staff support required to implement PHP in a clinical setting. To our knowledge, this study is the first to report on the integration of patient-completed, electronically captured and CDS-enabled FHH software into primary prenatal practice. PHP is acceptable to patients and providers. Key to successful implementation in the future will be customization options and interoperability with electronic health records. C1 [Edelman, Emily A.; Scott, Joan] Natl Coalit Hlth Profess Educ Genet, Lutherville Timonium, MD 21093 USA. [Lin, Bruce K.; Dolan, Siobhan M.] March Dimes, White Plains, NY 10605 USA. [Doksum, Teresa] Doksum Consulting, Stoneham, MA 02180 USA. [Drohan, Brian; Hughes, Kevin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Edelson, Vaughn; O'Leary, James] Genet Alliance, Washington, DC 20008 USA. [Dolan, Siobhan M.; Pardanani, Setul] Montefiore Med Ctr, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. [Vasquez, Lisa; Copeland, Sara] Hlth Resources & Serv Adm, Genet Serv Branch, Rockville, MD 20857 USA. [Galvin, Shelley L.] Mt Area Hlth Educ Ctr, Dept Obstet & Gynecol, Asheville, NC 28803 USA. [DeGroat, Nicole] Montefiore Med Ctr, Bronx, NY 10461 USA. [Feero, W. Gregory; Adams, Claire] Maine Dartmouth Family Med Residency, Augusta, ME 04330 USA. [Jones, Renee] Ariosa Diagnost, San Jose, CA 95138 USA. RP Edelman, EA (reprint author), Natl Coalit Hlth Profess Educ Genet, 2360 W Joppa Rd,Suite 320, Lutherville Timonium, MD 21093 USA. EM eedelman@nchpeg.org OI Hughes, Kevin/0000-0003-4084-6484 FU PHS HHS [U33MC12786] NR 34 TC 4 Z9 4 U1 2 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JUL PY 2014 VL 18 IS 5 BP 1233 EP 1245 DI 10.1007/s10995-013-1358-y PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AI3CF UT WOS:000336735800020 PM 24101435 ER PT J AU Louie, PK Sangeorzan, BJ Fassbind, MJ Ledoux, WR AF Louie, Philip K. Sangeorzan, Bruce J. Fassbind, Michael J. Ledoux, William R. TI Talonavicular Joint Coverage and Bone Morphology between Different Foot Types SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE pes planus; pes cavus; talonavicular joint; talus; navicular ID POSTERIOR TIBIAL TENDON; PES PLANUS; FLAT FOOT; PREVALENCE; RUPTURE; ADULTS; WOLFF; TALAR; LAW AB This study explored three dimensional (3D) talonavicular joint (TNJ) coverage/orientation and bone morphology to reveal parameters that could classify and identify predispositions to cavus and planus feet. 3D models of 65 feet from 40 subjects were generated from computed tomography images classified as pes cavus, neutrally aligned, or asymptomatic/symptomatic pes planus. We calculated the talar and navicular overlap (TNJ coverage). We also measured orientation of the navicular, morphological parameters of the talus and navicular, and angular position of the talar head to body. Pes cavus showed significantly less talonavicular coverage (58 +/- 2% talus and 86 +/- 2% navicular) compared to asymptomatic pes planus (63 +/- 2% and 95 +/- 2%) and neutrally aligned feet (98 +/- 2% navicular), and significantly more navicular dorsiflexion and adduction relative to the talus (p<0.0083). The talar head in cavus feet was inverted relative to the body compared to planus feet (p<0.0083). For symptomatic pes planus, significant abduction was measured for the navicular relative to the talus and the talar head was plantar flexed relative to the body (p<0.0083). The talar head in planus feet was everted relative to the body compared to neutrally aligned feet. Both intrinsic (bone morphology) and extrinsic (bone position) differences exist in groups of feet described as cavus and planus. (c) 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:958-966, 2014. C1 [Louie, Philip K.; Sangeorzan, Bruce J.; Fassbind, Michael J.; Ledoux, William R.] VA Puget Sound, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA 98108 USA. [Louie, Philip K.] Univ Washington, Sch Med, Seattle, WA 98195 USA. [Sangeorzan, Bruce J.; Ledoux, William R.] Univ Washington, Dept Orthopaed Surg & Sports Med, Seattle, WA 98195 USA. [Ledoux, William R.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. RP Sangeorzan, BJ (reprint author), VA Puget Sound, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA 98108 USA. EM bsangeor@uw.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 NR 26 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JUL PY 2014 VL 32 IS 7 BP 958 EP 966 DI 10.1002/jor.22612 PG 9 WC Orthopedics SC Orthopedics GA AG5ST UT WOS:000335479700015 PM 24719271 ER PT J AU Bandopadhayay, P Bergthold, G London, WB Goumnerova, LC La Madrid, A Marcus, KJ Guo, DJ Ullrich, NJ Robison, NJ Chi, SN Beroukhim, R Kieran, MW Manley, PE AF Bandopadhayay, Pratiti Bergthold, Guillaume London, Wendy B. Goumnerova, Liliana C. La Madrid, Andres Morales Marcus, Karen J. Guo, Dongjing Ullrich, Nicole J. Robison, Nathan J. Chi, Susan N. Beroukhim, Rameen Kieran, Mark W. Manley, Peter E. TI Long-Term Outcome of 4,040 Children Diagnosed With Pediatric Low-Grade Gliomas: An Analysis of the Surveillance Epidemiology and End Results (SEER) Database SO PEDIATRIC BLOOD & CANCER LA English DT Article DE BRAF V600E; pediatric BRAF mutation; pediatric thyroid carcinoma; BRAF mutation ID PILOCYTIC ASTROCYTOMAS; SPONTANEOUS REGRESSION; MALIGNANT-TRANSFORMATION; CHILDHOOD; ONCOLOGY; SURVIVAL; MULTICENTER; HEMATOLOGY; MUTATIONS; SOCIETY AB Background Clinical outcome of papillary thyroid carcinoma (PTC) in children differs significantly from that of adults. There is no clear explanation of this difference although previous studies have demonstrated a lower prevalence of the BRAF(V600E) mutation in PTC of children. However, data are limited due to the rarity of this diagnosis. BRAF(V600E) mutation prevalence and its relationship with outcome in pediatric PTC remain unclear. Procedure BRAF(V600E) mutational status was determined in 27 PTC patients less than 22 years of age using restriction fragment length polymorphism (RFLP) analysis. The relationship between BRAF(V600E) mutation status, patient and tumor characteristics as well as progression-free survival (PFS) were analyzed. Results BRAF(V600E) was present in 63% of patients and occurred more often in male patients versus females (P = 0.033). Presence of the mutation did not correlate with any difference in extent of disease at diagnosis, tumor size, capsular invasion, vascular invasion, soft tissue invasion, or margin status. At 10 years, PFS for BRAF(V600E) positive versus negative patients was 55.5% versus 70.0%, respectively (P = 0.48). Overall survival was 100% and median follow-up was 13.9 years. Conclusions This study of pediatric PTC demonstrates that BRAF(V600E) mutations occur in children at a rate comparable to adults. We found a correlation of BRAF(V600E) with the male gender, but no evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that differences in disease course of PTC in children versus adults are not strongly dependent upon the presence of the BRAF(V600E) mutation. Pediatr Blood Cancer 2014;61:1168-1172. (c) 2014 Wiley Periodicals, Inc. C1 [Bandopadhayay, Pratiti; Goumnerova, Liliana C.; La Madrid, Andres Morales; Ullrich, Nicole J.; Chi, Susan N.; Kieran, Mark W.; Manley, Peter E.] Boston Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Dept Pediat Oncol, Boston, MA USA. [Bandopadhayay, Pratiti; Bergthold, Guillaume; Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [London, Wendy B.; Guo, Dongjing] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Goumnerova, Liliana C.] Boston Childrens Hosp, Dept Pediat Neurosurg, Boston, MA USA. [Marcus, Karen J.] Boston Childrens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Marcus, Karen J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ullrich, Nicole J.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Robison, Nathan J.] Univ So Calif, Keck Sch Med, Childrens Ctr Canc & Blood Dis, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA. RP Manley, PE (reprint author), Dana Farber Canc Inst, Pediat Neurooncol Program, D3148,450 Brookline Ave, Boston, MA 02215 USA. EM Peter_Manley@dfci.harvard.edu OI Kieran, Mark/0000-0003-2184-7692 FU Stop&Shop Pediatric Brain Tumor Program; Andrysiak Fund for LGG, Pediatric Low-Grade Astrocytoma Foundation; Friends of DFCI; Nuovo-Soldati Foundation; Philippe Foundation; St Baldrick's Foundation FX Grant sponsor: Stop&Shop Pediatric Brain Tumor Program; Grant sponsor: Andrysiak Fund for LGG, Pediatric Low-Grade Astrocytoma Foundation; Grant sponsor: Friends of DFCI; Grant sponsor: Nuovo-Soldati Foundation; Grant sponsor: Philippe Foundation; Grant sponsor: St Baldrick's Foundation NR 28 TC 32 Z9 32 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2014 VL 61 IS 7 BP 1173 EP 1179 DI 10.1002/pbc.24935 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AG1TG UT WOS:000335198400011 PM 24482038 ER PT J AU Plourde, PV Jeha, S Hijiya, N Keller, FG Silverman, LB Rheingold, SR Dreyer, ZE Dahl, GV Mercedes, T Lai, CL Corn, T AF Plourde, Paul V. Jeha, Sima Hijiya, Nobuko Keller, Frank G. Silverman, Lewis B. Rheingold, Susan R. Dreyer, ZoAnn E. Dahl, Gary V. Mercedes, Taheri Lai, Chinglin Corn, Tim TI Safety Profile of Asparaginase Erwinia chrysanthemi in a Large Compassionate-Use Trial SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cell cycle; PLK1 expression; childhood acute lymphoblastic leukemia; BI 2536 ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ESCHERICHIA-COLI-ASPARAGINASE; CHILDRENS CANCER GROUP; ONCOLOGY GROUP; YOUNG-ADULTS; E. COLI; ADOLESCENTS; THERAPY; PROTOCOLS; GLYCOL AB Background Polo-like kinase 1 (PLK1) is a conserved kinase that mediates various mitotic events. Compelling data have repeatedly demonstrated its upregulation in different neoplasia, being frequently associated with poor prognosis. However, in childhood acute lymphoblastic leukemia (ALL), no studies have yet been conducted. Procedure PLK1 expression and association with biological features were evaluated in 65 consecutively diagnosed childhood ALL samples by quantitative real-time PCR. Moreover, the effects of a specific PLK1 inhibitor, BI 2536, was tested against a panel of nine ALL cell lines at nanomolar concentrations (10, 50, 100 nM). Results The mRNA expression of PLK1 showed great variability in pediatric ALL, but no difference was evidenced compared to normal bone marrow. Additionally, no association was found between PLK1 mRNA expression with any clinical or biological features. Alternatively, high mRNA expression of PLK1 was present in ALL cell lines. In vitro treatment with BI 2536 strongly diminished growth, while presenting significant reduction in colony formation capacity and increased apoptosis rates. Moreover, strong G2/M arrest was detected suggesting important impaired proliferation after treatment. Conclusions PLK1 mRNA expression level is not associated with prognosis in childhood ALL; however, considering the great variability observed in the sample and the in vitro experiments presented herein, BI 2536 treatment might serve as a promising therapeutic to enhance the efficacy of conventional treatment modalities in some childhood ALL cases. Pediatr Blood Cancer 2014;61:1227-1231. (c) 2014 Wiley Periodicals, Inc. C1 [Plourde, Paul V.; Mercedes, Taheri; Lai, Chinglin] Jazz Pharmaceut Inc, Palo Alto, CA USA. [Jeha, Sima] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Hijiya, Nobuko] Lurie Childrens Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Chicago, IL USA. [Hijiya, Nobuko] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Keller, Frank G.] Emory Univ, Dept Pediat Hematol Oncol, Aflac Canc & Blood Disorders Ctr, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Silverman, Lewis B.] Boston Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Dept Pediat Oncol, Boston, MA USA. [Rheingold, Susan R.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Dreyer, ZoAnn E.] Texas Childrens Hosp, Dept Pediat Med Hematol Oncol, Houston, TX 77030 USA. [Dahl, Gary V.] Stanford Univ, Sch Med, Dept Pediat Hematol Oncol, Palo Alto, CA 94304 USA. [Corn, Tim] EUSA Pharma, Dept Clin Oncol, Oxford, England. RP Plourde, PV (reprint author), Jazz Pharmaceut Inc, Dept Clin Oncol, 1818 Market St,Suite 2350, Philadelphia, PA 19103 USA. EM paul.plourde@jazzpharma.com FU EUSA Pharma (an international division of Jazz Pharmaceuticals, plc); Jazz Pharmaceuticals, plc FX Grant sponsor: EUSA Pharma (an international division of Jazz Pharmaceuticals, plc); Grant sponsor: Jazz Pharmaceuticals, plc NR 37 TC 16 Z9 16 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2014 VL 61 IS 7 BP 1232 EP 1238 DI 10.1002/pbc.24978 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AG1TG UT WOS:000335198400021 PM 24436152 ER PT J AU McGuinn, C Geyer, MB Jin, ZZ Garvin, JH Satwani, P Bradley, MB Bhatia, M George, D Duffy, D Morris, E van de Ven, C Schwartz, J Baxter-Lowe, LA Cairo, MS AF McGuinn, Catherine Geyer, Mark B. Jin, Zhezhen Garvin, James H. Satwani, Prakash Bradley, M. Brigid Bhatia, Monica George, Diane Duffy, Deirdre Morris, Erin van de Ven, Carmella Schwartz, Joseph Baxter-Lowe, Lee Ann Cairo, Mitchell S. TI Pilot Trial of Risk-Adapted Cyclophosphamide Intensity Based Conditioning and HLA Matched Sibling and Unrelated Cord Blood Stem Cell Transplantation in Newly Diagnosed Pediatric and Adolescent Recipients with Acquired Severe Aplastic Anemia SO PEDIATRIC BLOOD & CANCER LA English DT Article DE pediatric oncology; cluster analysis; patient-reported outcomes; multiple symptoms; latent profile analysis ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; GRAFT-REJECTION; IMMUNOSUPPRESSIVE THERAPY; REDUCED-INTENSITY; MYCOPHENOLATE-MOFETIL; NONMALIGNANT DISEASES; CHILDREN; DONORS; PROPHYLAXIS AB Background Children with cancer experience multiple symptoms due to their disease and as a result of treatment. The purpose of this study was to demonstrate the feasibility and potential utility of using latent profile analysis (LPA), a type of cluster analysis, in children with cancer to identify groups of patients who experience similar levels of symptom severity and impairment of physical function. Procedure We analyzed patient-reported symptom and functional data previously collected using the Pediatric Patient Reported Outcomes Measurement Information System (PROMIS). LPA was used to identify and characterize groups of patients who reported similar levels of symptom severity and functional impairment. We then used the multinomial logit model to examine demographic and disease characteristics associated with symptom/function profile membership. Results The analysis included 200 patients in treatment or in survivorship. We identified four symptom/function profiles; children currently receiving cancer treatment and those with at least one other medical problem were more likely to be members of the profile with the highest levels of symptom severity and functional impairment. Gender, age, race/ethnicity, and tumor type were not associated with profile membership. Conclusions LPA is a cluster research methodology that provides clinically useful results in pediatric oncology patients. Future studies of children with cancer using LPA could potentially lead to development of clinical scoring systems that predict patients' risk of developing more severe symptoms and functional impairments, allowing clinicians, patients, and parents to better anticipate and prevent the multiple symptoms that occur during and after treatment for childhood cancer. Pediatr Blood Cancer 2014;61:1282-1288. (c) 2014 Wiley Periodicals, Inc. C1 [McGuinn, Catherine] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Geyer, Mark B.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Jin, Zhezhen] Columbia Univ, Dept Biostat, New York, NY USA. [Garvin, James H.; Satwani, Prakash; Bradley, M. Brigid; Bhatia, Monica; George, Diane] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Duffy, Deirdre; Morris, Erin; van de Ven, Carmella; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Schwartz, Joseph] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Baxter-Lowe, Lee Ann] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Cairo, MS (reprint author), New York Med Coll, Children & Adolescent Canc & Blood Dis Ctr, Valhalla, NY 10595 USA. EM mitchell_cairo@nymc.edu OI Geyer, Mark/0000-0001-5248-9117 FU Pediatric Cancer Research Foundation (PCRF); Brittany Barron Fund; Marisa Fund; Paul Luisi Foundation FX Grant sponsor: Pediatric Cancer Research Foundation (PCRF); Grant sponsor: Brittany Barron Fund; Grant sponsor: Marisa Fund; Grant sponsor: Paul Luisi Foundation NR 47 TC 4 Z9 4 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2014 VL 61 IS 7 BP 1289 EP 1294 DI 10.1002/pbc.25029 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AG1TG UT WOS:000335198400030 PM 24623601 ER PT J AU Sun, PZ Wang, Y Dai, ZZ Xiao, G Wu, RH AF Sun, Phillip Zhe Wang, Yu Dai, ZhuoZhi Xiao, Gang Wu, Renhua TI Quantitative chemical exchange saturation transfer (qCEST) MRI - RF spillover effect-corrected omega plot for simultaneous determination of labile proton fraction ratio and exchange rate SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE amide proton transfer; chemical exchange saturation transfer (CEST); omega plot ID TRANSFER CEST MRI; ACUTE CEREBRAL-ISCHEMIA; IN-VIVO; 7 T; MAGNETIZATION-TRANSFER; CONTRAST AGENTS; REPETITION TIME; PARACEST AGENTS; ENZYME-ACTIVITY; HUMAN BRAIN AB Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute proteins and peptides as well as microenvironmental properties. However, the complexity of the CEST MRI effect, which varies with the labile proton content, exchange rate and experimental conditions, underscores the need for developing quantitative CEST (qCEST) analysis. Towards this goal, it has been shown that omega plot is capable of quantifying paramagnetic CEST MRI. However, the use of the omega plot is somewhat limited for diamagnetic CEST (DIACEST) MRI because it is more susceptible to direct radio frequency (RF) saturation (spillover) owing to the relatively small chemical shift. Recently, it has been found that, for dilute DIACEST agents that undergo slow to intermediate chemical exchange, the spillover effect varies little with the labile proton ratio and exchange rate. Therefore, we postulated that the omega plot analysis can be improved if RF spillover effect could be estimated and taken into account. Specifically, simulation showed that both labile proton ratio and exchange rate derived using the spillover effect-corrected omega plot were in good agreement with simulated values. In addition, the modified omega plot was confirmed experimentally, and we showed that the derived labile proton ratio increased linearly with creatine concentration (p<0.01), with little difference in their exchange rate (p=0.32). In summary, our study extends the conventional omega plot for quantitative analysis of DIACEST MRI. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Sun, Phillip Zhe; Wang, Yu] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sun, Phillip Zhe; Wang, Yu] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Dai, ZhuoZhi; Xiao, Gang; Wu, Renhua] Shantou Univ, Coll Med, Dept Radiol, Affiliated Hosp 2, Shantou, Guangdong, Peoples R China. [Xiao, Gang] Hanshan Normal Univ, Dept Math & Appl Math, Chaozhou, Peoples R China. RP Sun, PZ (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM pzhesun@nmr.mgh.harvard.edu; rhwu@stu.edu.cn FU NIH/NIBIB [K01EB009771]; NIH/NINDS [1R01NS083654]; NIH/NCRR [P41RR14075]; NSFC [30930027] FX This study was supported in part by grants from NIH/NIBIB K01EB009771, NIH/NINDS 1R01NS083654, NIH/NCRR P41RR14075 and NSFC 30930027. The authors would like to thank Ms Nichole Eusemann for editorial assistance. NR 58 TC 13 Z9 15 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 EI 1555-4317 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JUL PY 2014 VL 9 IS 4 BP 268 EP 275 DI 10.1002/cmmi.1569 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AE2TG UT WOS:000333825300002 PM 24706610 ER PT J AU Figge, L Appler, F Chen, HH Sosnovik, DE Schnorr, J Seitz, O Taupitz, M Hamm, B Schellenberger, E AF Figge, Lena Appler, Franziska Chen, Howard H. Sosnovik, David E. Schnorr, Joerg Seitz, Oliver Taupitz, Matthias Hamm, Bernd Schellenberger, Eyk TI Direct coupling of annexin A5 to VSOP yields small, protein-covered nanoprobes for MR imaging of apoptosis SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE apoptosis; Annexin A5; VSOP; very small iron oxide particles; magnetic resonance imaging ID NANOPARTICLE; BINDING; DEATH; MODEL AB Annexin A5 (Anx) has been extensively used for imaging apoptosis by single-photon emission computed tomography, positron emission tomography, optical imaging and MRI. Recently we introduced ultrasmall Anx-VSOP (very small iron oxide particles) - the smallest high-relaxivity probe for MRI of apoptosis. Here we present a simplified method for the direct coupling of Anx to VSOP, which resulted in nanoparticles that are nearly completely covered with human Anx. These superparamagnetic nanoparticles are only 14.4 +/- 2.3 nm in diameter and have higher T-2* relaxivity. Compared with existing probes, the small size and the Anx shielding provide prerequisites for good biocompatibility and bioavailability in target tissues. In vitro characterization showed specific binding of Anx-VSOP to apoptotic cells, which led to a signal loss in T-2*-weighted MR measurements, while control probe M1324-VSOP produced no such change. Exploratory MRI was done in vivo in a cardiac model of ischemia-reperfusion damage illustrating the potential of the probe for future studies. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Figge, Lena; Appler, Franziska; Schnorr, Joerg; Taupitz, Matthias; Hamm, Bernd; Schellenberger, Eyk] Charite, D-13353 Berlin, Germany. [Chen, Howard H.; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. [Seitz, Oliver] Humboldt Univ, Dept Chem, D-10099 Berlin, Germany. RP Schellenberger, E (reprint author), Charite, D-13353 Berlin, Germany. EM eyk.schellenberger@charite.de FU German Research Foundation [SCH 1416/2] FX This work was supported by a grant of the German Research Foundation (SCH 1416/2). We thank Gesche Genter for assisting and performing various experiments and Bettina Herwig for language editing. NR 24 TC 2 Z9 2 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 EI 1555-4317 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JUL PY 2014 VL 9 IS 4 BP 291 EP 299 DI 10.1002/cmmi.1575 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AE2TG UT WOS:000333825300005 PM 24706613 ER PT J AU Isayama, T Chen, Y Kono, M Fabre, E Slavsky, M DeGrip, WJ Ma, JX Crouch, RK Makino, CL AF Isayama, Tomoki Chen, Ying Kono, Masahiro Fabre, Eduard Slavsky, Michael DeGrip, Willem J. Ma, Jian-Xing Crouch, Rosalie K. Makino, Clint L. TI Coexpression of Three Opsins in Cone Photoreceptors of the Salamander Ambystoma tigrinum SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE electrophysiology; immunocytochemistry; phototransduction; retina; visual pigment ID VERTEBRATE VISUAL PIGMENTS; LOCUS-CONTROL REGION; THYROID-HORMONE; COLOR-VISION; HUMAN RED; MONOCLONAL-ANTIBODIES; POECILIA-RETICULATA; SPECTRAL PROPERTIES; MOLECULAR-CLONING; SEXUAL SELECTION AB Although more than one type of visual opsin is present in the retina of most vertebrates, it was thought that each type of photoreceptor expresses only one opsin. However, evidence has accumulated that some photoreceptors contain more than one opsin, in many cases as a result of a developmental transition from the expression of one opsin to another. The salamander UV-sensitive (UV) cone is particularly notable because it contains three opsins (Makino and Dodd [1996] J Gen Physiol 108:27-34). Two opsin types are expressed at levels more than 100 times lower than the level of the primary opsin. Here, immunohistochemical experiments identified the primary component as a UV cone opsin and the two minor components as the short wavelength-sensitive (S) and long wavelength-sensitive (L) cone opsins. Based on single-cell recordings of 156 photoreceptors, the presence of three components in UV cones of hatchlings and terrestrial adults ruled out a developmental transition. There was no evidence for multiple opsin types within rods or S cones, but immunohistochemistry and partial bleaching in conjunction with single-cell recording revealed that both single and double L cones contained low levels of short wavelength-sensitive pigments in addition to the main L visual pigment. These results raise the possibility that coexpression of multiple opsins in other vertebrates was overlooked because a minor component absorbing at short wavelengths was masked by the main visual pigment or because the expression level of a component absorbing at long wavelengths was exceedingly low. J. Comp. Neurol. 522:2249-2265, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Isayama, Tomoki; Fabre, Eduard; Slavsky, Michael; Makino, Clint L.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Isayama, Tomoki; Fabre, Eduard; Slavsky, Michael; Makino, Clint L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chen, Ying; Ma, Jian-Xing] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Oklahoma City, OK 73104 USA. [Kono, Masahiro; Crouch, Rosalie K.] Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. [DeGrip, Willem J.] Radboud Univ Nijmegen, Med Ctr, NCMLS, Dept Biochem, NL-6525 HP Nijmegen, Netherlands. RP Isayama, T (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM tomoki_isayama@meei.harvard.edu RI Grip, W.J./L-4335-2015; OI Makino, Clint/0000-0002-6005-9069 FU National Eye Institute [EY011358, EY012231, EY014104, EY019515]; Howe Laboratory Endowment of the Massachusetts Eye and Ear Infirmary; Research to Prevent Blindness, Inc. FX Grant sponsor: National Eye Institute; Grant numbers: EY011358; EY012231; Grant number: EY014104; EY019515; Grant sponsor: Howe Laboratory Endowment of the Massachusetts Eye and Ear Infirmary; Grant sponsor: Research to Prevent Blindness, Inc. NR 94 TC 6 Z9 6 U1 1 U2 42 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2014 VL 522 IS 10 BP 2249 EP 2265 DI 10.1002/cne.23531 PG 17 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA AF1QR UT WOS:000334488900002 PM 24374736 ER PT J AU Steele, JW Brautigam, H Short, JA Sowa, A Shi, MX Yadav, A Weaver, CM Westaway, D Fraser, PE St George-Hyslop, PH Gandy, S Hof, PR Dickstein, DL AF Steele, John W. Brautigam, Hannah Short, Jennifer A. Sowa, Allison Shi, Mengxi Yadav, Aniruddha Weaver, Christina M. Westaway, David Fraser, Paul E. St George-Hyslop, Peter H. Gandy, Sam Hof, Patrick R. Dickstein, Dara L. TI Early Fear Memory Defects Are Associated With Altered Synaptic Plasticity and Molecular Architecture in the TgCRND8 Alzheimer's Disease Mouse Model SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE amyloid beta; mouse model of dementia; neuronal morphology; dendritic pathology; spine pathology ID AMYLOID PRECURSOR PROTEIN; DENDRITIC SPINE MORPHOLOGY; MEDIAL PREFRONTAL CORTEX; TRANSGENIC MICE; ISOTROPIC FRACTIONATOR; MICROSCOPY IMAGES; PYRAMIDAL NEURONS; BETA OLIGOMERS; VISUAL-CORTEX; A-BETA AB Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to the early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wildtype littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid- protein, may underlie the observed neuronal loss. J. Comp. Neurol. 522:2319-2335, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Steele, John W.] Rockefeller Univ, Lab Mol & Cellular Neurosci, New York, NY 10065 USA. [Steele, John W.; Brautigam, Hannah; Short, Jennifer A.; Sowa, Allison; Shi, Mengxi; Yadav, Aniruddha; Hof, Patrick R.; Dickstein, Dara L.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Steele, John W.; Brautigam, Hannah; Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Brautigam, Hannah; Short, Jennifer A.; Sowa, Allison; Shi, Mengxi; Yadav, Aniruddha; Hof, Patrick R.; Dickstein, Dara L.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Weaver, Christina M.] Franklin & Marshall Coll, Dept Math & Comp Sci, Lancaster, PA 17604 USA. [Westaway, David] Univ Alberta, Ctr Prions & Prot Folding Dis, Edmonton, AB T6G 2M8, Canada. [Fraser, Paul E.; St George-Hyslop, Peter H.] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. [Fraser, Paul E.; St George-Hyslop, Peter H.] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 3H2, Canada. [St George-Hyslop, Peter H.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0XY, England. [Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Gandy, Sam] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Dickstein, DL (reprint author), Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, One Gustave L Levy Pl,Box 1639, New York, NY 10029 USA. EM jsteele@amicusrx.com; dara.dickstein@mssm.edu FU National Institutes of Health [T32 GM062754, F31 AG039890, P50 AG005138, P01 AG010491, R01 AG035071]; Canadian Institutes of Health Research [MOP-115056]; Canada Research Chairs; Alberta Innovatives-Health Solutions; Alberta Prion Research Institute; Wellcome Trust; Medical Research Council; Howard Hughes Medical Institute; Alzheimer Society of Ontario FX Grant sponsor: National Institutes of Health; Grant numbers: T32 GM062754 (to J.W.S.); F31 AG039890 (to H. B.); P50 AG005138 (to D. L. D., S. G., P. R. H.); P01 AG010491 (to S. G.); and R01 AG035071 (to P. R. H., C. M. W.); Grant sponsor: Canadian Institutes of Health Research; Grant number: MOP-115056 (to P. E. F.); Grant sponsors: the Canada Research Chairs, Alberta Innovatives-Health Solutionsand the Alberta Prion Research Institute (to D. W.); Grant sponsors: Wellcome Trust, Medical Research Council, the Howard Hughes Medical Institute, and the Alzheimer Society of Ontario (to P.E.F., P.H.H.). NR 77 TC 7 Z9 7 U1 0 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2014 VL 522 IS 10 BP 2319 EP 2335 DI 10.1002/cne.23536 PG 17 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA AF1QR UT WOS:000334488900006 PM 24415002 ER PT J AU Siddesha, JM Valente, AJ Sakamuri, SSVP Gardner, JD Delafontaine, P Noda, M Chandrasekar, B AF Siddesha, Jalahalli M. Valente, Anthony J. Sakamuri, Siva S. V. P. Gardner, Jason D. Delafontaine, Patrice Noda, Makoto Chandrasekar, Bysani TI Acetylsalicylic Acid Inhibits IL-18-Induced Cardiac Fibroblast Migration Through the Induction of RECK SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID NF-KAPPA-B; ALPHA-CONVERTING ENZYME; MUSCLE-CELL MIGRATION; OXIDATIVE STRESS; DOWN-REGULATION; CANCER CELLS; CIKS ACT1; IN-VITRO; EXPRESSION; ASPIRIN AB The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-B- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H2O2 generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H2O2 generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms. J. Cell. Physiol. 229: 845-855, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Siddesha, Jalahalli M.; Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, Res Serv, New Orleans, LA USA. [Siddesha, Jalahalli M.; Sakamuri, Siva S. V. P.; Delafontaine, Patrice; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Valente, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Valente, Anthony J.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Gardner, Jason D.] Louisiana State Univ, Dept Physiol, Hlth Sci Ctr, New Orleans, LA USA. [Noda, Makoto] Kyoto Univ, Dept Mol Oncol, Grad Sch Med, Sakyo Ku, Kyoto, Japan. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave,SL 48, New Orleans, LA 70112 USA. EM bchandra@tulane.edu OI Delafontaine, Patrice/0000-0003-3744-3617 FU Veterans Affairs Office of Research and Development-Biomedical Laboratory Research and Development Service Award [1IO1BX000246]; NHLBI [HL-86787, HL-70241, HL-80682] FX Contract grant sponsor: Veterans Affairs Office of Research and Development-Biomedical Laboratory Research and Development Service Award;; Contract grant number: 1IO1BX000246.; Contract grant sponsor: NHLBI;; Contract grant numbers: HL-86787, HL-70241, HL-80682. NR 47 TC 15 Z9 16 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUL PY 2014 VL 229 IS 7 BP 845 EP 855 DI 10.1002/jcp.24511 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AD4DW UT WOS:000333198200003 PM 24265116 ER PT J AU McMahon, PM Meza, R Plevritis, SK Black, WC Tammemagi, CM Erdogan, A ten Haaf, K Hazelton, W Holford, TR Jeon, J Clarke, L Kong, CY Choi, SE Munshi, VN Han, SS van Rosmalen, J Pinsky, PF Moolgavkar, S de Koning, HJ Feuer, EJ AF McMahon, Pamela M. Meza, Rafael Plevritis, Sylvia K. Black, William C. Tammemagi, C. Martin Erdogan, Ayca ten Haaf, Kevin Hazelton, William Holford, Theodore R. Jeon, Jihyoun Clarke, Lauren Kong, Chung Yin Choi, Sung Eun Munshi, Vidit N. Han, Summer S. van Rosmalen, Joost Pinsky, Paul F. Moolgavkar, Suresh de Koning, Harry J. Feuer, Eric J. TI Comparing Benefits from Many Possible Computed Tomography Lung Cancer Screening Programs: Extrapolating from the National Lung Screening Trial Using Comparative Modeling SO PLOS ONE LA English DT Article ID THORACIC-SURGERY GUIDELINES; DECISION-MAKING; AMERICAN ASSOCIATION; POTENTIAL BENEFITS; ELDERLY-PATIENTS; TASK-FORCE; RISK MODEL; SMOKING; MORTALITY; PROSTATE AB Background. The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking. Methods and Findings: We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. 'Efficient' (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 'consensus efficient (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient. Conclusions:Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics. C1 [McMahon, Pamela M.; Kong, Chung Yin; Choi, Sung Eun; Munshi, Vidit N.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [McMahon, Pamela M.; Kong, Chung Yin] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Meza, Rafael] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Plevritis, Sylvia K.; Erdogan, Ayca; Han, Summer S.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Black, William C.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Radiol, Hanover, NH 03756 USA. [Tammemagi, C. Martin] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [ten Haaf, Kevin; van Rosmalen, Joost; de Koning, Harry J.] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Hazelton, William] Fred Hutchinson Canc Res Ctr, Program Computat Biol, Seattle, WA 98104 USA. [Holford, Theodore R.] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Jeon, Jihyoun; Moolgavkar, Suresh] Fred Hutchinson Canc Res Ctr, Dept Biostat & Biomath, Seattle, WA 98104 USA. [Clarke, Lauren] Cornerstone Syst Northwest Inc, Lynden, WA USA. [Pinsky, Paul F.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Moolgavkar, Suresh] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP McMahon, PM (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. EM pamela@mgh-ita.org OI van Rosmalen, Joost/0000-0002-9187-244X FU Agency for Healthcare Research and Quality FX This report is based on research conducted by the Cancer Intervention and Surveillance Modeling Network under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Administrative Supplement to U01 CA152956). The National Cancer Institute supported the infrastructure for the CISNET models. The Agency for Healthcare Research and Quality funded this work and provided review. The authors worked witah USPSTF members to specify the overall questions. The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 11 Z9 11 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2014 VL 9 IS 6 AR e99978 DI 10.1371/journal.pone.0099978 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5ZO UT WOS:000338506400012 PM 24979231 ER PT J AU Gazit, R Mandal, PK Ebina, W Ben-Zvi, A Nombela-Arrieta, C Silberstein, LE Rossi, DJ AF Gazit, Roi Mandal, Pankaj K. Ebina, Wataru Ben-Zvi, Ayal Nombela-Arrieta, Cesar Silberstein, Leslie E. Rossi, Derrick J. TI Fgd5 identifies hematopoietic stem cells in the murine bone marrow SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ENDOTHELIAL-CELLS; IN-VIVO; PHENOL SULFOTRANSFERASE; PROGENITOR CELLS; SPLEEN COLONIES; MOUSE MARROW; SELF-RENEWAL; AGM REGION; EXPRESSION; MICE AB Hematopoietic stem cells (HSCs) are the best-characterized tissue-specific stem cells, yet experimental study of HSCs remains challenging, as they are exceedingly rare and methods to purify them are cumbersome. Moreover, genetic tools for specifically investigating HSC biology are lacking. To address this we sought to identify genes uniquely expressed in HSCs within the hematopoietic system and to develop a reporter strain that specifically labels them. Using microarray profiling we identified several genes with HSC-restricted expression. Generation of mice with targeted reporter knock-in/knock-out alleles of one such gene, Fgd5, revealed that though Fgd5 was required for embryonic development, it was not required for definitive hematopoiesis or HSC function. Fgd5 reporter expression near exclusively labeled cells that expressed markers consistent with HSCs. Bone marrow cells isolated based solely on Fgd5 reporter signal showed potent HSC activity that was comparable to stringently purified HSCs. The labeled fraction of the Fgd5 reporter mice contained all HSC activity, and HSC-specific labeling was retained after transplantation. Derivation of next generation mice bearing an Fgd5-CreERT2 allele allowed tamoxifen-inducible deletion of a conditional allele specifically in HSCs. In summary, reporter expression from the Fgd5 locus permits identification and purification of HSCs based on single-color fluorescence. C1 [Gazit, Roi; Mandal, Pankaj K.; Ebina, Wataru; Rossi, Derrick J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Gazit, Roi; Mandal, Pankaj K.; Ebina, Wataru; Silberstein, Leslie E.; Rossi, Derrick J.] Boston Childrens Hosp, Div Hematol Oncol, Program Cellular & Mol Med, Boston, MA 02116 USA. [Nombela-Arrieta, Cesar; Silberstein, Leslie E.] Boston Childrens Hosp, Dept Lab Med, Div Transfus Med, Boston, MA 02116 USA. [Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Ben-Zvi, Ayal] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Silberstein, Leslie E.; Rossi, Derrick J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Rossi, DJ (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM derrick.rossi@childrens.harvard.edu RI mandal, pankaj/B-4885-2016; OI Nombela-Arrieta, Cesar/0000-0003-0415-259X; Gazit, Roi/0000-0002-0548-2147 FU JCF Machiah post-doctoral fellowship; National Institutes of Health [RO1HL107630, UO1DK072473-01]; GlaxoSmithKline; Leona M. and Harry B. Helmsley Charitable Trust; New York Stem Cell Foundation; Harvard Stem Cell Institute FX R. Gazit was supported by a JCF Machiah post-doctoral fellowship. This work was supported by the National Institutes of Health grants RO1HL107630 (D.J. Rossi) and UO1DK072473-01 (D.J. Rossi), grants from GlaxoSmithKline (D.J. Rossi), The Leona M. and Harry B. Helmsley Charitable Trust (D.J. Rossi), the New York Stem Cell Foundation (D.J. Rossi), and the Harvard Stem Cell Institute (D.J. Rossi). D.J. Rossi is a New York Stem Cell Foundation Robertson Investigator. NR 68 TC 22 Z9 22 U1 0 U2 12 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUN 30 PY 2014 VL 211 IS 7 BP 1314 EP 1330 DI 10.1084/jem.20130428 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AL2AD UT WOS:000338927200006 PM 24958848 ER PT J AU Su, R Kirillin, M Chang, EW Sergeeva, E Yun, SH Mattsson, L AF Su, Rong Kirillin, Mikhail Chang, Ernest W. Sergeeva, Ekaterina Yun, Seok H. Mattsson, Lars TI Perspectives of mid-infrared optical coherence tomography for inspection and micrometrology of industrial ceramics SO OPTICS EXPRESS LA English DT Article ID LIGHT-SCATTERING; ALUMINA; WAVELENGTH; DISPERSION; DEPTH AB Optical coherence tomography (OCT) is a promising tool for detecting micro channels, metal prints, defects and delaminations embedded in alumina and zirconia ceramic layers at hundreds of micrometers beneath surfaces. The effect of surface roughness and scattering of probing radiation within sample on OCT inspection is analyzed from the experimental and simulated OCT images of the ceramic samples with varying surface roughnesses and operating wavelengths. By Monte Carlo simulations of the OCT images in the mid-IR the optimal operating wavelength is found to be 4 mu m for the alumina samples and 2 mu m for the zirconia samples for achieving sufficient probing depth of about 1 mm. The effects of rough surfaces and dispersion on the detection of the embedded boundaries are discussed. Two types of image artefacts are found in OCT images due to multiple reflections between neighboring boundaries and inhomogeneity of refractive index. (C)2014 Optical Society of America C1 [Su, Rong; Mattsson, Lars] KTH Royal Inst Technol, Dept Prod Engn, S-10044 Stockholm, Sweden. [Kirillin, Mikhail; Sergeeva, Ekaterina] RAS, Inst Appl Phys, Lab Biophoton, Nizhnii Novgorod 603950, Russia. [Chang, Ernest W.; Yun, Seok H.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Sergeeva, Ekaterina] NI Lobachevskii State Univ, Nizhnii Novgorod 603950, Russia. RP Su, R (reprint author), KTH Royal Inst Technol, Dept Prod Engn, 68 Brinellvagen, S-10044 Stockholm, Sweden. EM rongs@kth.se OI Su, Rong/0000-0003-0776-3716 FU joint European project Multilayer [FP7-NMP4-2007-214122]; National Institute of Health [P41EB015903] FX This work was partly supported by the joint European project Multilayer (FP7-NMP4-2007-214122) and National Institute of Health (P41EB015903). The authors would like to acknowledge Dr. Johanna Stiernstedt at Swerea IVF and Dr. Petko Petkov at Cardiff University for preparing the samples, Prof. Arne Roos at Uppsala University for supporting the spectrophotometry measurement, and Dr. Michael Leitner, Christian Luhrs and Laura Hinkel supporting the Telesto OCT test at Thorlabs GmbH (Lubeck). NR 24 TC 9 Z9 9 U1 4 U2 14 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUN 30 PY 2014 VL 22 IS 13 BP 15804 EP 15819 DI 10.1364/OE.22.015804 PG 16 WC Optics SC Optics GA AJ9TN UT WOS:000338055900065 PM 24977838 ER PT J AU Waters, AM Nazarian, M Mineka, S Zinbarg, RE Griffith, JW Naliboff, B Ornitz, EM Craske, MG AF Waters, Allison M. Nazarian, Maria Mineka, Susan Zinbarg, Richard E. Griffith, James W. Naliboff, Bruce Ornitz, Edward M. Craske, Michelle G. TI Context and explicit threat cue modulation of the startle reflex: Preliminary evidence of distinctions between adolescents with principal fear disorders versus distress disorders SO PSYCHIATRY RESEARCH LA English DT Article DE Fear disorders; Distress disorders; Startle reflexes; Adolescents ID POSTTRAUMATIC-STRESS-DISORDER; GENERALIZED ANXIETY DISORDER; MAJOR DEPRESSIVE DISORDER; PANIC DISORDER; POTENTIATED STARTLE; INTERNALIZING PSYCHOPATHOLOGY; HIERARCHICAL MODEL; TRIPARTITE MODEL; SOCIAL PHOBIA; COMORBIDITY AB Anxiety and depression are prevalent, impairing disorders. High comorbidity has raised questions about how to define and classify them. Structural models emphasise distinctions between "fear" and "distress" disorders while other initiatives propose they be defined by neurobiological indicators that cut across disorders. This study examined startle reflex (SR) modulation in adolescents with principal fear disorders (specific phobia; social phobia) (n=20), distress disorders (unipolar depressive disorders, dysthymia, generalised anxiety disorder; post-traumatic stress disorder) (n=9), and controls (n=29) during (a) baseline conditions, (b) threat context conditions (presence of contraction pads over the biceps muscle), and (c) an explicit threat cue paradigm involving phases that signalled safety from aversive stimuli (early and late stages of safe phases; early stages of danger phases) and phases that signalled immediate danger of an aversive stimulus (late stages of danger phases). Adolescents with principal fear disorders showed larger SRs than other groups throughout safe phases and early stages of danger phases. SRs did not differ between groups during late danger phases. Adolescents with principal distress disorders showed attenuated SRs during baseline and context conditions compared to other groups. Preliminary findings support initiatives to redefine emotional disorders based on neurobiological functioning. (C) 2014 Elsevier Ireland Ltd. All rights resented. C1 [Nazarian, Maria; Craske, Michelle G.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Waters, Allison M.] Griffith Univ, Sch Appl Psychol, Brisbane, Qld 4111, Australia. [Mineka, Susan; Zinbarg, Richard E.; Griffith, James W.] Northwestern Univ, Dept Psychol, Evanston, IL USA. [Naliboff, Bruce; Ornitz, Edward M.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Zinbarg, Richard E.] Northwestern Univ, Family Inst, Evanston, IL USA. [Naliboff, Bruce] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Ornitz, Edward M.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA USA. RP Craske, MG (reprint author), Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. EM craske@psych.ucla.edu RI Griffith, James/O-2551-2016; OI Griffith, James/0000-0002-4840-8692; Waters, Allison/0000-0003-2453-793X FU National Institutes of Health [MH065651]; Virginia Friedhofer Charitable Trust [MH065652] FX This work was supported by Grants from the National Institutes of Health to Dr. Craske (MH065651) and Drs. Zinbarg and Mineka (MH065652) and from the Virginia Friedhofer Charitable Trust to Dr. Ornitz. NR 65 TC 5 Z9 5 U1 5 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUN 30 PY 2014 VL 217 IS 1-2 BP 93 EP 99 DI 10.1016/j.psychres.2014.01.047 PG 7 WC Psychiatry SC Psychiatry GA AI2SR UT WOS:000336708900015 PM 24679992 ER PT J AU Machiels, JPH Licitra, LF Haddad, RI Tahara, M Cohen, EEW AF Machiels, Jean-Pascal H. Licitra, Lisa F. Haddad, Robert I. Tahara, Makoto Cohen, Ezra E. W. TI Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy SO BMC CANCER LA English DT Article DE Afatinib; Methotrexate; Head and neck; Phase III; Recurrent; Metastatic ID GROWTH-FACTOR RECEPTOR; CISPLATIN PLUS FLUOROURACIL; COOPERATIVE-ONCOLOGY-GROUP; ADVANCED SOLID TUMORS; LUNG-CANCER; ANTIBODY CETUXIMAB; DOSE-ESCALATION; TYROSINE KINASE; OPEN-LABEL; BIBW 2992 AB Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of similar to 7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting. Methods/Design: Patients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m(2) once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed. Discussion: If the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population. C1 [Machiels, Jean-Pascal H.] Catholic Univ Louvain, Clin Univ St Luc, Ctr Canc, Med Oncol Serv, B-1200 Brussels, Belgium. [Machiels, Jean-Pascal H.] Catholic Univ Louvain, Inst Rech Clin & Expt Pole MIRO, B-1200 Brussels, Belgium. [Licitra, Lisa F.] Ist Nazl Tumori, I-20133 Milan, Italy. [Haddad, Robert I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Tahara, Makoto] Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. [Cohen, Ezra E. W.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Machiels, JPH (reprint author), Catholic Univ Louvain, Clin Univ St Luc, Ctr Canc, Med Oncol Serv, B-1200 Brussels, Belgium. EM jean-pascal.machiels@uclouvain.be RI Licitra, Lisa/C-6271-2017 OI Licitra, Lisa/0000-0003-0623-4118 FU Boehringer Ingelheim FX The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Medical writing assistance provided by Sophie Albon of Ogilvy Healthworld and editorial support provided by Katie McClendon of GeoMed, part of KnowledgePoint360, an Ashfield Company, was supported financially by Boehringer Ingelheim during the preparation of this manuscript. NR 45 TC 8 Z9 8 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUN 28 PY 2014 VL 14 AR 473 DI 10.1186/1471-2407-14-473 PG 9 WC Oncology SC Oncology GA AL2PH UT WOS:000338967000002 PM 24973959 ER PT J AU Lopez-Fraga, M Dominguez-Gil, B Capron, AM Van Assche, K Martin, D Cozzi, E Delmonico, FL AF Lopez-Fraga, Marta Dominguez-Gil, Beatriz Capron, Alexander M. Van Assche, Kristof Martin, Dominique Cozzi, Emanuele Delmonico, Francis L. TI A needed Convention against trafficking in human organs Comment SO LANCET LA English DT Editorial Material C1 [Lopez-Fraga, Marta] European Comm Organ Transplantat, European Directorate Qual Med & HealthCare, Council Europe, F-67081 Strasbourg, France. [Dominguez-Gil, Beatriz] Org Nacl Trasplantes, Dept Med, Madrid, Spain. [Capron, Alexander M.] Univ So Calif, Pacific Ctr Hlth Policy & Eth, Los Angeles, CA USA. [Van Assche, Kristof] Vrije Univ Brussel, Res Grp Law Sci Technol & Soc, Brussels, Belgium. [Martin, Dominique] Univ Melbourne, Sch Populat & Global Hlth, Ctr Hlth & Soc, Melbourne, VA, Australia. [Cozzi, Emanuele] Ist Super Sanita, Ctr Nazl Trapianti, I-00161 Rome, Italy. [Cozzi, Emanuele] Padua Univ Hosp, Transplant Immunol Unit, Padua, Italy. [Delmonico, Francis L.] Transplantat Soc, Montreal, PQ, Canada. [Delmonico, Francis L.] World Hlth Org, Geneva, Switzerland. [Delmonico, Francis L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Delmonico, Francis L.] New England Organ Bank Inc, Waltham, MA USA. RP Lopez-Fraga, M (reprint author), European Comm Organ Transplantat, European Directorate Qual Med & HealthCare, Council Europe, F-67081 Strasbourg, France. EM marta.fraga@edqm.eu FU World Health Organization [001] NR 10 TC 9 Z9 9 U1 0 U2 7 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 28 PY 2014 VL 383 IS 9936 BP 2187 EP 2189 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AK8DO UT WOS:000338657600004 PM 24976316 ER PT J AU Zhang, XL Gierman, HJ Levy, D Plump, A Dobrin, R Goring, HHH Curran, JE Johnson, MP Blangero, J Kim, SK O'Donnell, CJ Emilsson, V Johnson, AD AF Zhang, Xiaoling Gierman, Hinco J. Levy, Daniel Plump, Andrew Dobrin, Radu Goring, Harald H. H. Curran, Joanne E. Johnson, Matthew P. Blangero, John Kim, Stuart K. O'Donnell, Christopher J. Emilsson, Valur Johnson, Andrew D. TI Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs SO BMC GENOMICS LA English DT Article DE eQTL; RNA; Gene expression; Genomics; Transcriptome; GWAS; Genome-wide; Tissue; Cis; Trans ID CORONARY-ARTERY-DISEASE; HUMAN GENE-EXPRESSION; REGULATORY VARIATION; MONOALLELIC EXPRESSION; POPULATION GENOMICS; SUSCEPTIBILITY LOCI; DNA METHYLATION; ASSOCIATION; EVOLUTION; ANNOTATION AB Background: Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs. Results: We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5' or 3' positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/]. Conclusions: Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation. C1 [Zhang, Xiaoling; Levy, Daniel; O'Donnell, Christopher J.; Johnson, Andrew D.] NHLBI, Div Intramural Res, Cardiovasc Epidemiol & Human Genom Branch, Framingham, MA 01702 USA. [Gierman, Hinco J.; Kim, Stuart K.] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. [Plump, Andrew] Sanofi Aventis Pharmaceut, Bridgewater, NJ 08807 USA. [Dobrin, Radu] Johnson & Johnson Pharmaceut Res & Dev, Radnor, PA 19477 USA. [Goring, Harald H. H.; Curran, Joanne E.; Johnson, Matthew P.; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Emilsson, Valur] Iceland Heart Assoc, Kopavogur, Iceland. RP Johnson, AD (reprint author), NHLBI, Div Intramural Res, Cardiovasc Epidemiol & Human Genom Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013; OI Dobrin, Radu/0000-0002-3336-0091 FU Glenn Center for Aging; National Institutes of Health; GTEx Portal [08/06/2013]; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS; NCI \SAIC-Frederick, Inc. (SAIC-F) [10XS170]; Roswell Park Cancer Institute [10XS171]; Science Care, Inc. [X10S172]; Laboratory, Data Analysis, and Coordinating Center (LDACC) through Broad Institute, Inc. [HHSN268201000029C]; SAIC-F subcontract to Van Andel Institute [10ST1035]; SAIC-F [HHSN261200800001E]; University of Miami [DA006227]; University of Geneva [MH090941]; University of Chicago [MH090951, MH090937]; University of North Carolina - Chapel Hill [MH090936]; Harvard University [MH090948] FX XZ and ADJ were supported by NIH Intramural Funds. The authors acknowledge Heather E. Wheeler for contribution to the kidney eQTL data. The kidney eQTL work was supported by the Glenn Center for Aging. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). The GTEx datasets used for the analyses described in this manuscript were obtained from: GTEx Portal on 08/06/2013. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI \SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941), the University of Chicago (MH090951 & MH090937), the University of North Carolina - Chapel Hill (MH090936) and to Harvard University (MH090948). NR 94 TC 19 Z9 19 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 27 PY 2014 VL 15 AR 532 DI 10.1186/1471-2164-15-532 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AL2JM UT WOS:000338951900001 PM 24973796 ER PT J AU Shi, Y Ivannikov, MV Walsh, ME Liu, YH Zhang, YQ Jaramillo, CA Macleod, GT Van Remmen, H AF Shi, Yun Ivannikov, Maxim V. Walsh, Michael E. Liu, Yuhong Zhang, Yiqiang Jaramillo, Carlos A. Macleod, Gregory T. Van Remmen, Holly TI The Lack of CuZnSOD Leads to Impaired Neurotransmitter Release, Neuromuscular Junction Destabilization and Reduced Muscle Strength in Mice SO PLOS ONE LA English DT Article ID SPINAL MUSCULAR-ATROPHY; SKELETAL-MUSCLE; SUPEROXIDE-DISMUTASE; MOUSE MODEL; OXIDATIVE STRESS; KNOCKOUT MICE; MOTOR-NEURONS; ION CHANNELS; SYNAPSE; TRANSMISSION AB Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to -a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1(-/-)), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1(-/-) mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1(-/-) mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1(-/-) mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1(-/-) and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1(-/-) mice. C1 [Shi, Yun; Ivannikov, Maxim V.; Walsh, Michael E.; Liu, Yuhong; Zhang, Yiqiang; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Shi, Yun; Walsh, Michael E.; Liu, Yuhong; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Shi, Yun; Liu, Yuhong; Jaramillo, Carlos A.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Ivannikov, Maxim V.; Zhang, Yiqiang; Macleod, Gregory T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Jaramillo, Carlos A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Rehabil Med, San Antonio, TX 78229 USA. [Van Remmen, Holly] Oklahoma City VA Med Ctr, Oklahoma City, OK USA. RP Van Remmen, H (reprint author), Florida Atlantic Univ, Dept Biol Sci, Jupiter, FL 33458 USA. EM holly-vanremmen@omrf.org FU NIH [AG020591, NS061914, T32-AG021890] FX This study was supported by NIH grants AG020591 to HVR, NS061914 to GTM and T32-AG021890 to MVI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 12 Z9 12 U1 3 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2014 VL 9 IS 6 AR e100834 DI 10.1371/journal.pone.0100834 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6BK UT WOS:000338512200066 PM 24971750 ER PT J AU Patorno, E Neuman, MD Schneeweiss, S Mogun, H Bateman, BT AF Patorno, Elisabetta Neuman, Mark D. Schneeweiss, Sebastian Mogun, Helen Bateman, Brian T. TI Comparative safety of anesthetic type for hip fracture surgery in adults: retrospective cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID MAJOR NONCARDIAC SURGERY; GENERAL-ANESTHESIA; REGIONAL ANESTHESIA; RANDOMIZED-TRIALS; MORTALITY; OUTCOMES; METAANALYSIS; RISK; COMPLICATIONS; THERAPY AB Objective To evaluate the effect of anesthesia type on the risk of in-hospital mortality among adults undergoing hip fracture surgery in the United States. Design Retrospective cohort study. Setting Premier research database, United States. Participants 73 284 adults undergoing hip fracture surgery on hospital day 2 or greater between 2007 and 2011. Of those, 61 554 (84.0%) received general anesthesia, 6939 (9.5%) regional anesthesia, and 4791 (6.5%) combined general and regional anesthesia. Main outcome measure In-hospital all cause mortality. Results In-hospital deaths occurred in 1362 (2.2%) patients receiving general anesthesia, 144 (2.1%) receiving regional anesthesia, and 115 (2.4%) receiving combined anesthesia. In the multivariable adjusted analysis, when compared with general anesthesia the mortality risk did not differ significantly between regional anesthesia (risk ratio 0.93, 95% confidence interval 0.78 to 1.11) or combined anesthesia (1.00, 0.82 to 1.22). A mixed effects analysis accounting for differences between hospitals produced similar results: compared with general anesthesia the risk from regional anesthesia was 0.91 (0.75 to 1.10) and from combined anesthesia was 0.98 (0.79 to 1.21). Findings were also consistent in subgroup analyses. Conclusions In this large nationwide sample of hospital admissions, mortality risk did not differ significantly by anesthesia type among patients undergoing hip fracture surgery. Our results suggest that if the previously posited beneficial effect of regional anesthesia on short term mortality exists, it is likely to be more modest than previously reported. C1 [Patorno, Elisabetta; Schneeweiss, Sebastian; Mogun, Helen; Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02120 USA. [Neuman, Mark D.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Patorno, E (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02120 USA. EM epatorno@partners.org RI Schneeweiss, Sebastian/C-2125-2013 FU Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School; Foundation for Anesthesia Education and Research (Rochester, MN); National Institute on Aging [K08AG043548]; Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health [K08HD075831] FX This study was supported by the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School and by grants to MDN from the Foundation for Anesthesia Education and Research (Rochester, MN) and the National Institute on Aging (K08AG043548) and to BTB from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award No K08HD075831. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 33 TC 19 Z9 20 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUN 27 PY 2014 VL 348 AR g4022 DI 10.1136/bmj.g4022 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AK1UP UT WOS:000338202700001 PM 24972901 ER PT J AU Albritton, A Leonard, DA Barone, AL Keegan, J Mallard, C Sachs, DH Kurtz, JM Cetrulo, CL AF Albritton, Alexander Leonard, David A. Barone, Angelo Leto Keegan, Josh Mallard, Christopher Sachs, David H. Kurtz, Josef M. Cetrulo, Curtis L., Jr. TI Lack of Cross-Sensitization Between alpha-1, 3-Galactosyltransferase Knockout Porcine and Allogeneic Skin Grafts Permits Serial Grafting SO TRANSPLANTATION LA English DT Article DE Xenotransplantation; Burns; Skin grafting ID RED DUROC PIG; WOUND EXCISION; ANIMAL-MODEL; XENOGRAFTS; SIMILARITIES; ANTIGENS; SURVIVAL; BABOONS; FEMALE; BURNS AB Background The current standard of care for burns requiring operative treatment consists of early burn excision and autologous split-thickness skin grafting. However, in large burns, sufficient donor sites may not be available to achieve total coverage, necessitating temporary coverage with allogeneic human cadaver skin grafts or synthetic skin substitutes. A previous study from this laboratory demonstrated that skin grafts from alpha-1,3 galactosyltransferase knockout (GalT-KO) miniature swine enjoyed survival comparable to that of allogeneic skin grafts in baboons. Methods In the present study, we have evaluated the immune response against sequential GalT-KO and allogeneic skin grafts to determine whether such serial grafts could extend the period of temporary wound coverage before definitive grafting with autologous skin. Results We report that rejection of primary GalT-KO skin grafts led to an anti-xenogeneic humoral response with no evidence for sensitization to alloantigens nor acceleration of rejection of allogeneic skin grafts. Similarly, presensitization with allogeneic skin did not lead to accelerated rejection of xenogeneic skin. Conclusions These data suggest that GalT-KO skin grafts could provide an early first-line treatment in the management of severe burns that would not preclude subsequent use of allografts, and that serial grafting of GalT-KO skin and allogeneic skin could potentially be used to provide an extended period of temporary burn wound coverage. C1 [Albritton, Alexander; Leonard, David A.; Barone, Angelo Leto; Keegan, Josh; Mallard, Christopher; Sachs, David H.; Kurtz, Josef M.; Cetrulo, Curtis L., Jr.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Leonard, David A.; Barone, Angelo Leto; Cetrulo, Curtis L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg, Boston, MA USA. [Keegan, Josh; Kurtz, Josef M.] Emmanuel Coll, Dept Biol, Boston, MA USA. RP Cetrulo, CL (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH East Bldg,149-9019,13th St, Boston, MA 02114 USA. EM ccetrulo@partners.org FU Department of Defense [W81XWH-09-1-0419/DoDDR080729]; [CO6RR020135-01] FX Support from CO6RR020135-01 was provided for construction of the facility utilized for production and maintenance of miniature swine. Experimental funding was provided by Department of Defense, W81XWH-09-1-0419/DoDDR080729. NR 23 TC 5 Z9 5 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2014 VL 97 IS 12 BP 1209 EP 1215 DI 10.1097/TP.0000000000000093 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AJ5MC UT WOS:000337726300008 PM 24798308 ER PT J AU Gallant, JR Traeger, LL Volkening, JD Moffett, H Chen, PH Novina, CD Phillips, GN Anand, R Wells, GB Pinch, M Guth, R Unguez, GA Albert, JS Zakon, HH Samanta, MP Sussman, MR AF Gallant, Jason R. Traeger, Lindsay L. Volkening, Jeremy D. Moffett, Howell Chen, Po-Hao Novina, Carl D. Phillips, George N., Jr. Anand, Rene Wells, Gregg B. Pinch, Matthew Gueth, Robert Unguez, Graciela A. Albert, James S. Zakon, Harold H. Samanta, Manoj P. Sussman, Michael R. TI NONHUMAN GENETICS Genomic basis for the convergent evolution of electric organs SO SCIENCE LA English DT Article ID GROWTH; PROTEINS; SUBUNIT; MUSCLE; SIZE; EXPRESSION; MEMBRANES; DOGS AB Little is known about the genetic basis of convergent traits that originate repeatedly over broad taxonomic scales. The myogenic electric organ has evolved six times in fishes to produce electric fields used in communication, navigation, predation, or defense. We have examined the genomic basis of the convergent anatomical and physiological origins of these organs by assembling the genome of the electric eel (Electrophorus electricus) and sequencing electric organ and skeletal muscle transcriptomes from three lineages that have independently evolved electric organs. Our results indicate that, despite millions of years of evolution and large differences in the morphology of electric organ cells, independent lineages have leveraged similar transcription factors and developmental and cellular pathways in the evolution of electric organs. C1 [Gallant, Jason R.] Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. [Gallant, Jason R.; Zakon, Harold H.] Michigan State Univ, BEACON Ctr Study Evolut Act, E Lansing, MI 48824 USA. [Traeger, Lindsay L.] Univ Wisconsin, Dept Genet, Madison, WI 53706 USA. [Traeger, Lindsay L.; Volkening, Jeremy D.; Sussman, Michael R.] Univ Wisconsin, Biotechnol Ctr, Madison, WI 53706 USA. [Volkening, Jeremy D.; Sussman, Michael R.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Moffett, Howell; Chen, Po-Hao; Novina, Carl D.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Moffett, Howell; Chen, Po-Hao; Novina, Carl D.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Chen, Po-Hao; Novina, Carl D.] Broad Inst Harvard & MIT, Cambridge, MA 02141 USA. [Phillips, George N., Jr.] Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77005 USA. [Phillips, George N., Jr.] Rice Univ, Dept Chem, Houston, TX 77005 USA. [Anand, Rene] Ohio State Univ, Coll Med, Dept Pharmacol, Wexner Med Ctr, Columbus, OH 43210 USA. [Anand, Rene] Ohio State Univ, Coll Med, Dept Neurosci, Wexner Med Ctr, Columbus, OH 43210 USA. [Wells, Gregg B.] Texas A&M Univ, Dept Mol & Cellular Med, College Stn, TX 77483 USA. [Pinch, Matthew; Gueth, Robert; Unguez, Graciela A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Albert, James S.] Univ Louisiana, Dept Biol, Lafayette, LA 70503 USA. [Zakon, Harold H.] Univ Texas Austin, Austin, TX 78712 USA. [Zakon, Harold H.] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA. [Samanta, Manoj P.] Systemix Inst, Redmond, WA 98053 USA. RP Zakon, HH (reprint author), Michigan State Univ, BEACON Ctr Study Evolut Act, E Lansing, MI 48824 USA. EM h.zakon@austin.utexas.edu; manoj.samanta@systemix.org; msussman@wisc.edu RI Gallant, Jason/A-9629-2015 OI Gallant, Jason/0000-0002-6528-090X FU NSF grant MCB [1144012]; NSF grant CNS [1248109]; NSF grant DEB [0741450]; W.M. Keck Foundation; NIH [R01 GM084879, R01 GM088670, 1SC1GM092297-01A1]; Texas A&M University Health Science Center College of Medicine; Cornell University Center for Vertebrate Genomics; University of Wisconsin Genetics NIH Graduate Training Grant; Morgridge Graduate Fellowship FX This project has been funded in part by NSF grants MCB no. 1144012 (M.R.S.), CNS no. 1248109 (G.A.U.), and DEB no. 0741450 (J.S.A.); the W.M. Keck Foundation Distinguished Young Scholars in Medical Research (C.D.N.); NIH grants R01 GM084879 (H.H.Z.), R01 GM088670 (R.A.), and 1SC1GM092297-01A1 (G.A.U.); the Texas A&M University Health Science Center College of Medicine (G.B.W.); the Cornell University Center for Vertebrate Genomics (J.R.G.); the University of Wisconsin Genetics NIH Graduate Training Grant (L.L.T.); and the Morgridge Graduate Fellowship (J.D.V.). E. V. Armbrust provided computing assistance, and S. B. McKay assisted with data analysis. M. P. S. acknowledges useful discussions with R. Chikhi, R. Luo, and J. Simpson. We thank J. Bayliss for dissection of E. electricus and R. Amasino for help in preparing this manuscript. M. R. S. and L. L. T. acknowledge the guidance of J. Hyman, M. Adams, and J. Speers from the University of Wisconsin Biotechnology Center for their excellent assistance in E. electricus sequencing. The raw sequencing reads have been deposited in the National Center for Biotechnology Information short-read archive for the E. electricus genome (BioProject ID: PRJNA249073) and transcriptome sequences of E. electricus, S. macrurus, E. virescens, M. electricus, and B. brachyistius (BioProject ID: PRJNA248545). The whole-genome assemblies and annotation, together with the transcriptome assemblies, are available at http://efishgenomics.zoology.msu.edu, along with BLAST and genome-browsing services. NR 24 TC 38 Z9 38 U1 16 U2 110 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 27 PY 2014 VL 344 IS 6191 BP 1522 EP 1525 DI 10.1126/science.1254432 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ7PZ UT WOS:000337889900052 PM 24970089 ER PT J AU Riches, JC O'Donovan, CJ Kingdon, SJ McClanahan, F Clear, AJ Neuberg, DS Werner, L Croce, CM Ramsay, AG Rassenti, LZ Kipps, TJ Gribben, JG AF Riches, John C. O'Donovan, Conor J. Kingdon, Sarah J. McClanahan, Fabienne Clear, Andrew J. Neuberg, Donna S. Werner, Lillian Croce, Carlo M. Ramsay, Alan G. Rassenti, Laura Z. Kipps, Thomas J. Gribben, John G. TI Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations SO BLOOD LA English DT Article ID LEUKOCYTE ADHESION; CD38 EXPRESSION; LYMPH-NODES; BONE-MARROW; CHEMOKINE; DISEASE; CD49D; SURVIVAL; CLL; TRANSFORMATION AB The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with beta 2-integrin expression being modulated by NOTCH1 mutation status. C1 [Riches, John C.; O'Donovan, Conor J.; Kingdon, Sarah J.; McClanahan, Fabienne; Clear, Andrew J.; Ramsay, Alan G.; Gribben, John G.] Queen Mary Univ London, Barts Canc Inst, Dept Haematooncol, London EC1M 6BQ, England. [Neuberg, Donna S.; Werner, Lillian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Croce, Carlo M.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Wexner Med Ctr, Columbus, OH 43210 USA. [Rassenti, Laura Z.; Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Riches, JC (reprint author), Queen Mary Univ London, Barts Canc Inst, John Vane Sci Ctr, 3rd Floor,Charterhouse Sq, London EC1M 6BQ, England. EM johnriches@doctors.org.uk RI Ramsay, Alan/A-8374-2015 OI Ramsay, Alan/0000-0002-0452-0420 FU Cancer Research UK; European Hematology Association; National Cancer Institute [P01 CA95426]; Goldman Sachs FX This work was supported by grants from Cancer Research UK (J.C.R. and J.G.G.), the European Hematology Association (A. G. R.), and by funding from the National Cancer Institute (P01 CA95426; J.G.G., C. M. C., L.Z.R., L. W., D.S.N., and T.J.K.) for the CLL Research Consortium and from Goldman Sachs (J.C.R. and J.G.G.). NR 32 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 26 PY 2014 VL 123 IS 26 BP 4101 EP 4110 DI 10.1182/blood-2014-01-552307 PG 10 WC Hematology SC Hematology GA AQ2LR UT WOS:000342618100014 PM 24829201 ER PT J AU Roccaro, AM Sacco, A Jimenez, C Maiso, P Moschetta, M Mishima, Y Aljawai, Y Sahin, I Kuhne, M Cardarelli, P Cohen, L San Miguel, JF Garcia-Sanz, R Ghobrial, IM AF Roccaro, Aldo M. Sacco, Antonio Jimenez, Cristina Maiso, Patricia Moschetta, Michele Mishima, Yuji Aljawai, Yosra Sahin, Ilyas Kuhne, Michelle Cardarelli, Pina Cohen, Lewis San Miguel, Jesus F. Garcia-Sanz, Ramon Ghobrial, Irene M. TI C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; WALDENSTROM MACROGLOBULINEMIA; WHIM-SYNDROME; MULTIPLE-MYELOMA; TARGETING RAS; CXCR4; EXPRESSION; CANCER; MYD88; CELLS AB The C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in modulating cell trafficking in hematopoietic stem cells and clonal B cells. We screened 418 patients with B-cell lymphoproliferative disorders and described the presence of the C1013G/CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis-associated mutation in 28.2% (37/131) of patients with lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM]), being either absent or present in only 7% of other B-cell lymphomas. In vivo functional characterization demonstrates its activating role in WM cells, as demonstrated by significant tumor proliferation and dissemination to extramedullary organs, leading to disease progression and decreased survival. The use of a monoclonal antibody anti-CXCR4 led to significant tumor reduction in a C1013G/CXCR4 WM model, whereas drug resistance was observed in mutated WM cells exposed to Bruton's tyrosine kinase, mammalian target of rapamycin, and phosphatidylinositol 3-kinase inhibitors, but not proteasome inhibitors. These findings demonstrate that C1013G/CXCR4 is an activating mutation in WM and support its role as a critical regulator of WM molecular pathogenesis and as an important therapeutic target. C1 [Roccaro, Aldo M.; Sacco, Antonio; Maiso, Patricia; Moschetta, Michele; Mishima, Yuji; Aljawai, Yosra; Sahin, Ilyas; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jimenez, Cristina; Garcia-Sanz, Ramon] Univ Salamanca, E-37008 Salamanca, Spain. [Kuhne, Michelle; Cardarelli, Pina] Bristol Myers Squibb Co, Redwood City, CA USA. [Cohen, Lewis] Bristol Myers Squibb Co, Lawrenceville, NJ USA. [San Miguel, Jesus F.] Univ Navarra, E-31080 Pamplona, Spain. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Garcia-Sanz, Ramon/B-7986-2017; OI Sacco, Antonio/0000-0003-2945-9416; Garcia-Sanz, Ramon/0000-0003-4120-2787; Maiso, Patricia/0000-0003-3745-1924; Roccaro, Aldo/0000-0002-1872-5128; SAN MIGUEL, JESUS/0000-0002-9183-4857 FU International Waldenstrom's Macroglobulinemia Foundation; Leukemia & Lymphoma Society; Kirsch Laboratory for Waldenstrom; Heje Fellowship FX This work was supported in part by research grants from the International Waldenstrom's Macroglobulinemia Foundation, the Leukemia & Lymphoma Society, The Kirsch Laboratory for Waldenstrom, and the Heje Fellowship. NR 32 TC 47 Z9 47 U1 4 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 26 PY 2014 VL 123 IS 26 BP 4120 EP 4131 DI 10.1182/blood-2014-03-564583 PG 12 WC Hematology SC Hematology GA AQ2LR UT WOS:000342618100016 PM 24711662 ER PT J AU San-Miguel, J Blade, J Shpilberg, O Grosicki, S Maloisel, F Min, CK Zarzuela, MP Robak, T Prasad, SVSS Goh, YT Laubach, J Spencer, A Mateos, MV Palumbo, A Puchalski, T Reddy, M Uhlar, C Qin, X van de Velde, H Xie, H Orlowski, RZ AF San-Miguel, Jesus Blade, Joan Shpilberg, Ofer Grosicki, Sebastian Maloisel, Frederic Min, Chang-Ki Polo Zarzuela, Marta Robak, Tadeusz Prasad, Sripada V. S. S. Goh, Yeow Tee Laubach, Jacob Spencer, Andrew Mateos, Maria-Victoria Palumbo, Antonio Puchalski, Tom Reddy, Manjula Uhlar, Clarissa Qin, Xiang van de Velde, Helgi Xie, Hong Orlowski, Robert Z. TI Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma SO BLOOD LA English DT Article ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; PRECLINICAL MODELS; INTERLEUKIN-6; DISEASE; CELLS; INHIBITION; EXPRESSION; INDUCTION; TRIALS AB Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S+VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P =.0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade >= 3 adverse-event incidence was 92% on S+VMP and 81% on VMP (P =.09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.govas # NCT00911859. C1 [San-Miguel, Jesus] Univ Navarra Clin, Ctr Invest Med Aplicada, Navarra, Spain. [Blade, Joan] Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Shpilberg, Ofer] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Grosicki, Sebastian] SPZOZ Zespol Szpitali Miejskich Chorzowie, Oddzial Hematol, Chorzow, Poland. [Maloisel, Frederic] Clin St Anne, Strasbourg, France. [Min, Chang-Ki] Seoul St Marys Hosp, Seoul, South Korea. [Polo Zarzuela, Marta] Hosp Clin San Carlos, Madrid, Spain. [Robak, Tadeusz] Med Univ Lodz, Lodz, Poland. [Prasad, Sripada V. S. S.] Apollo Hosp & Res Fdn, Hyderabad, Andhra Pradesh, India. [Goh, Yeow Tee] Singapore Gen Hosp, Singapore, Singapore. [Laubach, Jacob] Dana Farber Canc Inst, Boston, MA 02115 USA. [Spencer, Andrew] Monash Univ, Alfred Hlth, Melbourne, Vic 3004, Australia. [Mateos, Maria-Victoria] Hosp Univ Salamanca, Salamanca, Spain. [Palumbo, Antonio] Osped Molinette, Turin, Italy. [Puchalski, Tom; Reddy, Manjula; Uhlar, Clarissa; Qin, Xiang; Xie, Hong] Janssen Res & Dev, Spring House, PA USA. [van de Velde, Helgi] Janssen Res & Dev, Beerse, Belgium. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP San-Miguel, J (reprint author), Univ Navarra, Univ Navarra Clin, Navarra 31009, Spain. EM sanmiguel@unav.es FU Janssen Pharmaceutical Research Development; Janssen Research Development FX Research support was provided by Janssen Pharmaceutical Research & Development.; The authors thank the patients and staff members at the study sites and acknowledge An Van Eyken from Janssen Research & Development for excellent editorial assistance. This study was funded by Janssen Research & Development. NR 30 TC 39 Z9 39 U1 0 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 26 PY 2014 VL 123 IS 26 BP 4136 EP 4142 DI 10.1182/blood-2013-12-546374 PG 7 WC Hematology SC Hematology GA AQ2LR UT WOS:000342618100018 PM 24833354 ER PT J AU Huang, F Dong, JX Kong, J Wang, HC Meng, H Spaeth, RB Camhi, S Liao, X Li, X Zhai, X Li, SY Zhu, B Rong, P AF Huang, Feng Dong, Jianxun Kong, Jian Wang, Hongcai Meng, Hong Spaeth, Rosa B. Camhi, Stephanie Liao, Xing Li, Xia Zhai, Xu Li, Shaoyuan Zhu, Bing Rong, Peijing TI Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Article ID FOLLOW-UP; TRIAL; TREAT AB Background: Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure. Methods: In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). Results: 100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period. Conclusions: Our study suggests that taVNS is a promising, simple, and cost-effective treatment for IGT/pre-diabetes with only slight risk of mild side-effects. C1 [Huang, Feng; Wang, Hongcai; Meng, Hong; Li, Shaoyuan; Zhu, Bing; Rong, Peijing] China Acad Chinese Med Sci, Inst Acu Mox, Beijing 100700, Peoples R China. Beijing Univ Chinese Med, Beijing 100029, Peoples R China. Capital Univ Med Sci, Beijing Hosp T C M, Beijing 100010, Peoples R China. Massachusetts Gen Hosp, Harvard Med Sch, Dept Psychiat, Boston, MA USA. Endicott Coll, Dept Phys, Beverly, MA USA. China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing 100700, Peoples R China. RP Huang, F (reprint author), China Acad Chinese Med Sci, Inst Acu Mox, 16 Nanxiao St, Beijing 100700, Peoples R China. EM drrongpj@163.com FU Chinese Medicine of the National Basic Research Program of China (973 Program) [2012CB518503]; National Science and Technology Support Program of China [2012BAF14B10] FX We are most grateful to the Special Program of Chinese Medicine of the National Basic Research Program of China (973 Program 2012CB518503), the "Twelfth Five-year Plan" National Science and Technology Support Program of China (2012BAF14B10), the Acupuncture Hospital affiliated to China Academy of Chinese Medical Sciences, and the Institutional Ethics Committee of the China Academy of Chinese Medical Sciences for their invaluable contribution to the study. We would also like to thank the participants for volunteering their time to be involved in the study. We also thank Limei Bai for providing the consent for her ear on the publication. NR 18 TC 11 Z9 11 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6882 J9 BMC COMPLEM ALTERN M JI BMC Complement. Altern. Med. PD JUN 26 PY 2014 VL 14 AR 203 DI 10.1186/1472-6882-14-203 PG 8 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA AM0GP UT WOS:000339522700002 PM 24968966 ER PT J AU Raina, D Uchida, Y Kharbanda, A Rajabi, H Panchamoorthy, G Jin, C Kharbanda, S Scaltriti, M Baselga, J Kufe, D AF Raina, D. Uchida, Y. Kharbanda, A. Rajabi, H. Panchamoorthy, G. Jin, C. Kharbanda, S. Scaltriti, M. Baselga, J. Kufe, D. TI Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells SO ONCOGENE LA English DT Article DE MUC1; HER2; HER3; trastuzumab; resistance; breast cancer ID GROWTH-FACTOR RECEPTOR; KINASE INHIBITOR P27(KIP1); FACTOR-I RECEPTOR; CYCLIN-E; PHOSPHORYLATION; CONTRIBUTES; LAPATINIB; ERBB3; CHEMOTHERAPY; MECHANISM AB Patients with HER2-positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1 C-terminal subunit (MUC1-C) in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in the downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine-phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (B20-fold) as compared with that in sensitive cells. In addition, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with the downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance. C1 [Raina, D.; Panchamoorthy, G.; Kharbanda, S.] Genus Oncol, Boston, MA USA. [Uchida, Y.; Kharbanda, A.; Rajabi, H.; Jin, C.; Kufe, D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Scaltriti, M.; Baselga, J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA166480]; Susan G Komen for the Cure Grant [SAC110046] FX This work was supported by Grants CA97098 and CA166480 awarded by the National Cancer Institute, and by the Susan G Komen for the Cure Grant SAC110046 (MS and JB). NR 47 TC 20 Z9 22 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 26 PY 2014 VL 33 IS 26 BP 3422 EP 3431 DI 10.1038/onc.2013.308 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AK9WM UT WOS:000338779300009 PM 23912457 ER PT J AU Kawabata, S Mercado-Matos, JR Hollander, MC Donahue, D Wilson, W Regales, L Butaney, M Pao, W Wong, KK Jaenne, PA Dennis, PA AF Kawabata, Shigeru Mercado-Matos, Jose R. Hollander, M. Christine Donahue, Danielle Wilson, Willie, III Regales, Lucia Butaney, Mohit Pao, William Wong, Kwok-Kin Jaenne, Pasi A. Dennis, Phillip A. TI Rapamycin Prevents the Development and Progression of Mutant Epidermal Growth Factor Receptor Lung Tumors with the Acquired Resistance Mutation T790M SO CELL REPORTS LA English DT Article ID TYROSINE KINASE INHIBITOR; EGFR T790M; CANCER; DISEASE; GEFITINIB; ADENOCARCINOMAS; DIFFERENTIATION; ERLOTINIB; MURINE; MICE AB Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers. C1 [Kawabata, Shigeru; Dennis, Phillip A.] Johns Hopkins Bayview Med Ctr, Dept Oncol, Baltimore, MD 21224 USA. [Mercado-Matos, Jose R.; Hollander, M. Christine; Wilson, Willie, III] NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Donahue, Danielle] Natl Inst Neurol Disorders & Stroke, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Regales, Lucia] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Butaney, Mohit; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Pao, William] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Med, Div Hematol Oncol, Nashville, TN 37232 USA. RP Dennis, PA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Oncol, Baltimore, MD 21224 USA. EM pdennis@jhmi.edu FU NIH [R01CA135257]; NCI; CCR; Open Access Promotion Fund of the Johns Hopkins University Libraries FX The authors would like to thank Maiga Emmanuel (Office of the Director, NCI) for assistance with genotyping; Morales-Contreras Juan, Dumas Tarra, and Dr. John U. Dennis (Laboratory Animal Medicine, NCI) for veterinary services; Dr. Jeffrey A. Whitsett (University of Cincinnati College of Medicine) for providing CCSP-rtTA transgenic mice; Dr. Nathanael S. Gray (Harvard Medical School) for providing WZ4002 compound; and the NIH Fellows Editorial Board for editorial assistance. This research was supported by the Intramural Research Program of the NIH, NCI, and CCR (P.A.D.) and NIH R01CA135257 (P.A.J.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Publication of this article was funded in part by the Open Access Promotion Fund of the Johns Hopkins University Libraries. NR 21 TC 6 Z9 6 U1 0 U2 1 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 26 PY 2014 VL 7 IS 6 BP 1824 EP 1832 DI 10.1016/j.celrep.2014.05.039 PG 9 WC Cell Biology SC Cell Biology GA AK3LL UT WOS:000338325400009 PM 24931608 ER PT J AU Jambhekar, A Emerman, AB Schweidenback, CTH Blower, MD AF Jambhekar, Ashwini Emerman, Amy B. Schweidenback, Caterina T. H. Blower, Michael D. TI RNA Stimulates Aurora B Kinase Activity during Mitosis SO PLOS ONE LA English DT Article ID CHROMOSOMAL PASSENGER COMPLEX; MAJOR DEVELOPMENTAL TRANSITION; EARLY XENOPUS-EMBRYOS; MITOTIC SPINDLE; MESSENGER-RNA; BINDING-PROTEIN; IMPORTIN-BETA; EGG EXTRACTS; CAENORHABDITIS-ELEGANS; MICROTUBULE DYNAMICS AB Accurate chromosome segregation is essential for cell viability. The mitotic spindle is crucial for chromosome segregation, but much remains unknown about factors that regulate spindle assembly. Recent work implicates RNA in promoting proper spindle assembly independently of mRNA translation; however, the mechanism by which RNA performs this function is currently unknown. Here, we show that RNA regulates both the localization and catalytic activity of the mitotic kinase, Aurora-B (AurB), which is present in a ribonucleoprotein (RNP) complex with many mRNAs. Interestingly, AurB kinase activity is reduced in Xenopus egg extracts treated with RNase, and its activity is stimulated in vitro by RNA binding. Spindle assembly defects following RNase-treatment are partially rescued by inhibiting MCAK, a microtubule depolymerase that is inactivated by AurB-dependent phosphorylation. These findings implicate AurB as an important RNA-dependent spindle assembly factor, and demonstrate a translation-independent role for RNA in stimulating AurB. C1 [Jambhekar, Ashwini; Emerman, Amy B.; Schweidenback, Caterina T. H.; Blower, Michael D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Jambhekar, Ashwini; Emerman, Amy B.; Schweidenback, Caterina T. H.; Blower, Michael D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Blower, MD (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM blower@molbio.mgh.harvard.edu FU National Institutes of Health (NIH) [RO1GM086434]; Burroughs Wellcome Fund Career Award in the Biomedical Sciences; National Science Foundation (NSF) GRFP; NIH [F32 GM090533] FX This work was funded the following grants: National Institutes of Health (NIH) RO1 (RO1GM086434) (M. D. B.), Burroughs Wellcome Fund Career Award in the Biomedical Sciences (M. D. B.), National Science Foundation (NSF) GRFP (A. E.), and NIH F32 GM090533 (C. T. H. S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 9 Z9 9 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2014 VL 9 IS 6 AR e100748 DI 10.1371/journal.pone.0100748 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2WP UT WOS:000338280800063 PM 24968351 ER PT J AU Lin, FH Ahveninen, J Raij, T Witzel, T Chu, YH Jaaskelainen, IP Tsai, KWK Kuo, WJ Belliveau, JW AF Lin, Fa-Hsuan Ahveninen, Jyrki Raij, Tommi Witzel, Thomas Chu, Ying-Hua Jaaskelainen, Iiro P. Tsai, Kevin Wen-Kai Kuo, Wen-Jui Belliveau, John W. TI Increasing fMRI Sampling Rate Improves Granger Causality Estimates SO PLOS ONE LA English DT Article ID MULTIVARIATE AUTOREGRESSIVE MODELS/; DIRECTED TRANSFER-FUNCTION; SURFACE-BASED ANALYSIS; MAGNETIC-RESONANCE; EFFECTIVE CONNECTIVITY; CORTICAL SURFACE; STATISTICAL ASSESSMENT; NONLINEAR CAUSALITY; SENSORY STIMULATION; COORDINATE SYSTEM AB Estimation of causal interactions between brain areas is necessary for elucidating large-scale functional brain networks underlying behavior and cognition. Granger causality analysis of time series data can quantitatively estimate directional information flow between brain regions. Here, we show that such estimates are significantly improved when the temporal sampling rate of functional magnetic resonance imaging (fMRI) is increased 20-fold. Specifically, healthy volunteers performed a simple visuomotor task during blood oxygenation level dependent (BOLD) contrast based whole-head inverse imaging (InI). Granger causality analysis based on raw InI BOLD data sampled at 100-ms resolution detected the expected causal relations, whereas when the data were downsampled to the temporal resolution of 2 s typically used in echo-planar fMRI, the causality could not be detected. An additional control analysis, in which we SINC interpolated additional data points to the downsampled time series at 0.1-s intervals, confirmed that the improvements achieved with the real InI data were not explainable by the increased time-series length alone. We therefore conclude that the high-temporal resolution of InI improves the Granger causality connectivity analysis of the human brain. C1 [Lin, Fa-Hsuan; Chu, Ying-Hua; Tsai, Kevin Wen-Kai] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. [Lin, Fa-Hsuan; Jaaskelainen, Iiro P.; Tsai, Kevin Wen-Kai] Aalto Univ, Dept Biomed Engn & Computat Sci, Espoo, Finland. [Ahveninen, Jyrki; Raij, Tommi; Witzel, Thomas; Belliveau, John W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Kuo, Wen-Jui] Natl Yang Ming Univ, Inst Neurosci, Taipei 112, Taiwan. RP Lin, FH (reprint author), Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. EM fhlin@ntu.edu.tw RI Jaaskelainen, Iiro/C-7392-2012; Witzel, Thomas/P-1402-2014; Lin, Fa-Hsuan/G-6988-2012 OI Jaaskelainen, Iiro/0000-0001-6001-6950; Lin, Fa-Hsuan/0000-0002-9539-1731 FU National Institutes of Health [R01MH083744, R01HD040712, R01NS037462, R01NS048279]; National Science Council, Taiwan [NSC 101-2628-B-002-005-MY3, NSC 100-2325-B-002-046]; Ministry of Economic Affairs, Taiwan [100-EC-17-A-19-S1-175]; National Health Research Institute, Taiwan [NHRI-EX102-10247EI]; Academy of Finland (the FiDiPro program) FX This work was supported by R01MH083744, R01HD040712, R01NS037462, R01NS048279 (National Institutes of Health), NSC 101-2628-B-002-005-MY3, NSC 100-2325-B-002-046 (National Science Council, Taiwan), 100-EC-17-A-19-S1-175 (Ministry of Economic Affairs, Taiwan), NHRI-EX102-10247EI (National Health Research Institute, Taiwan), and Academy of Finland (the FiDiPro program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 5 Z9 5 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2014 VL 9 IS 6 AR e100319 DI 10.1371/journal.pone.0100319 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2WP UT WOS:000338280800033 PM 24968356 ER PT J AU Lee, YJ Dominy, JE Choi, YJ Jurczak, M Tolliday, N Camporez, JP Chim, H Lim, JH Ruan, HB Yang, XY Vazquez, F Sicinski, P Shulman, GI Puigserver, P AF Lee, Yoonjin Dominy, John E. Choi, Yoon Jong Jurczak, Michael Tolliday, Nicola Camporez, Joao Paulo Chim, Helen Lim, Ji-Hong Ruan, Hai-Bin Yang, Xiaoyong Vazquez, Francisca Sicinski, Piotr Shulman, Gerald I. Puigserver, Pere TI Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression SO NATURE LA English DT Article ID HEPATIC GLUCONEOGENESIS; INSULIN-RESISTANCE; MICE LACKING; PHOSPHORYLATION; INHIBITION; EXPRESSION; CDK4; PGC-1-ALPHA; ACTIVATION; RECEPTOR AB Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis(1-3); dysregulation of this axis causes diabetes(2,4). PGC-1 alpha(peroxisome-proliferator-activated receptor-gamma coactivator-1 alpha) links insulin signalling to the expression of glucose and lipid metabolic genes(5-7). The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1 alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1 alpha(8,9). Although insulin is a mitogenic signal in proliferative cells(10,11), whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1 alpha acetylation. Insulin/GSK-3 beta (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1 alpha activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division. C1 [Lee, Yoonjin; Dominy, John E.; Choi, Yoon Jong; Chim, Helen; Lim, Ji-Hong; Vazquez, Francisca; Sicinski, Piotr; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Lee, Yoonjin; Dominy, John E.; Chim, Helen; Lim, Ji-Hong; Vazquez, Francisca; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Lee, Yoonjin] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Choi, Yoon Jong; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Jurczak, Michael; Camporez, Joao Paulo; Ruan, Hai-Bin; Yang, Xiaoyong; Shulman, Gerald I.] Yale Univ, Sch Med, Yales Mouse Metab Phenotyping Ctr, New Haven, CT 06510 USA. [Jurczak, Michael; Camporez, Joao Paulo; Ruan, Hai-Bin; Yang, Xiaoyong; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Jurczak, Michael; Camporez, Joao Paulo; Ruan, Hai-Bin; Yang, Xiaoyong; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Tolliday, Nicola] Broad Inst Harvard & MIT, Chem Biol Platform, Cambridge Ctr 7, Cambridge, MA 02141 USA. RP Puigserver, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu RI Ruan, Hai-Bin/G-9907-2012; Camporez, Joao Paulo/B-9122-2015; OI Ruan, Hai-Bin/0000-0002-3858-1272; Jurczak, Michael/0000-0002-6335-6915 FU Ewha Womans University; National Research Service Award Kirschstein Fellowship from the National Institutes of Health (NIH); Dana-Farber Cancer Institute; American Diabetes Association; Department of Defense; NIH/National Institute of Diabetes and Digestive and Kidney Diseases [R01069966, R24DK080261-06]; NIH [R03 MH092174, R01 CA108420, DK059635] FX We thank all the members of the Puigserver laboratory for discussions and suggestions about this project. We also appreciate the consultations with and efforts by M. Jedrychowski and S. Gygi for proteomic analysis. Y.L. was supported in part by a 21st Century Leaders scholarship from Ewha Womans University. J.E.D. was supported in part by a National Research Service Award Kirschstein Fellowship from the National Institutes of Health (NIH). The participating researchers were supported with funds from the Dana-Farber Cancer Institute and with grants from the American Diabetes Association, Department of Defense, NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01069966 and R24DK080261-06), NIH (R03 MH092174) awarded to P.P., NIH (R01 CA108420) awarded to P.S. and NIH (DK059635) awarded to Yale's Mouse Metabolic Phenotyping Center/G.I.S. NR 35 TC 44 Z9 45 U1 2 U2 31 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 26 PY 2014 VL 510 IS 7506 BP 547 EP + DI 10.1038/nature13267 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ6LK UT WOS:000337806300049 PM 24870244 ER PT J AU Boulware, DR Meya, DB Muzoora, C Rolfes, MA Hullsiek, KH Musubire, A Taseera, K Nabeta, HW Schutz, C Williams, DA Rajasingham, R Rhein, J Thienemann, F Lo, MW Nielsen, K Bergemann, TL Kambugu, A Manabe, YC Janoff, EN Bohjanen, PR Meintjes, G AF Boulware, David R. Meya, David B. Muzoora, Conrad Rolfes, Melissa A. Hullsiek, Katherine Huppler Musubire, Abdu Taseera, Kabanda Nabeta, Henry W. Schutz, Charlotte Williams, Darlisha A. Rajasingham, Radha Rhein, Joshua Thienemann, Friedrich Lo, Melanie W. Nielsen, Kirsten Bergemann, Tracy L. Kambugu, Andrew Manabe, Yukari C. Janoff, Edward N. Bohjanen, Paul R. Meintjes, Graeme CA COAT Trial Team TI Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RECONSTITUTION INFLAMMATORY SYNDROME; HIGH-DOSE FLUCONAZOLE; EARLY MORTALITY; TUBERCULOUS MENINGITIS; AMPHOTERICIN-B; HIV; INFECTION; ADULTS; DISEASE; COHORT AB BACKGROUND Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered. METHODS We assessed survival at 26 weeks among 177 human immunodeficiency virus-infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole. RESULTS The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P = 0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P = 0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P = 0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P = 0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups. CONCLUSIONS Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. C1 [Boulware, David R.; Meya, David B.; Rolfes, Melissa A.; Hullsiek, Katherine Huppler; Williams, Darlisha A.; Rajasingham, Radha; Rhein, Joshua; Lo, Melanie W.; Nielsen, Kirsten; Bergemann, Tracy L.; Bohjanen, Paul R.] Univ Minnesota, Minneapolis, MN USA. [Meya, David B.; Musubire, Abdu; Nabeta, Henry W.; Williams, Darlisha A.; Rajasingham, Radha; Rhein, Joshua; Lo, Melanie W.; Kambugu, Andrew; Manabe, Yukari C.] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Meya, David B.] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Muzoora, Conrad; Taseera, Kabanda] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Schutz, Charlotte; Thienemann, Friedrich; Meintjes, Graeme] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Manabe, Yukari C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Janoff, Edward N.] Univ Colorado Denver, Mucosal & Vaccine Res Program Colorado MAVRC, Aurora, CO USA. [Janoff, Edward N.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Meintjes, Graeme] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. RP Boulware, DR (reprint author), MTRF 3-222,2001 6th St SE, Minneapolis, MN 55455 USA. EM boulw001@umn.edu RI Bohjanen, Paul/B-2329-2015; Schutz, Charlotte/G-6864-2016; OI Bohjanen, Paul/0000-0002-2772-3597; Bahr, Nathan/0000-0002-9431-8938; Boulware, David/0000-0002-4715-0060; Schutz, Charlotte/0000-0001-8329-6158; Bergemann, Tracy/0000-0003-3902-2605 FU National Institute of Allergy and Infectious Diseases FX Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152. NR 40 TC 83 Z9 85 U1 1 U2 19 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 26 PY 2014 VL 370 IS 26 BP 2487 EP 2498 DI 10.1056/NEJMoa1312884 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AJ6KY UT WOS:000337804400006 PM 24963568 ER PT J AU Connors, JM AF Connors, Jean M. TI Prophylaxis against Venous Thromboembolism in Ambulatory Patients with Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID CLINICAL-PRACTICE GUIDELINES; RECEIVING CHEMOTHERAPY; PULMONARY-EMBOLISM; RISK-FACTORS; THROMBOSIS; THROMBOPROPHYLAXIS; ONCOLOGY C1 [Connors, Jean M.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Connors, Jean M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Connors, JM (reprint author), Brigham & Womens Hosp, Div Hematol, 75 Francis St, Boston, MA 02115 USA. EM jconnors@partners.org NR 22 TC 11 Z9 13 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 26 PY 2014 VL 370 IS 26 BP 2515 EP 2519 DI 10.1056/NEJMra1401468 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AJ6KY UT WOS:000337804400009 PM 24963570 ER PT J AU Finn, KM Ginns, LC Robbins, GK Wu, CC Branda, JA AF Finn, Kathleen M. Ginns, Leo C. Robbins, Gregory K. Wu, Carol C. Branda, John A. TI Case 20-2014: A 65-Year-Old Man with Dyspnea and Progressively Worsening Lung Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; PNEUMOCYSTIS-CARINII-PNEUMONIA; NONSPECIFIC INTERSTITIAL PNEUMONIA; OBSTRUCTIVE PULMONARY-DISEASE; GROUND-GLASS OPACITY; HIV-INFECTION; ANTIRETROVIRAL THERAPY; OPPORTUNISTIC INFECTIONS; JIROVECII PNEUMONIA; DIAGNOSIS C1 [Finn, Kathleen M.; Ginns, Leo C.; Robbins, Gregory K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Wu, Carol C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Finn, Kathleen M.; Ginns, Leo C.; Robbins, Gregory K.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wu, Carol C.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Finn, KM (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 38 TC 4 Z9 4 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 26 PY 2014 VL 370 IS 26 BP 2521 EP 2530 DI 10.1056/NEJMcpc1400841 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AJ6KY UT WOS:000337804400012 PM 24963572 ER PT J AU Phillippe, M AF Phillippe, Mark TI Cell-free Fetal DNA - A Trigger for Parturition SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID MATERNAL PLASMA; PRENATAL-DIAGNOSIS C1 Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Phillippe, M (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. NR 7 TC 17 Z9 17 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 26 PY 2014 VL 370 IS 26 BP 2534 EP 2536 DI 10.1056/NEJMcibr1404324 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AJ6KY UT WOS:000337804400014 PM 24963574 ER PT J AU Shaw, AT Engelman, JA AF Shaw, Alice T. Engelman, Jeffrey A. TI Ceritinib in ALK-Rearranged Non-Small-Cell Lung Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Shaw, Alice T.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ashaw1@partners.org NR 4 TC 42 Z9 46 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 26 PY 2014 VL 370 IS 26 BP 2537 EP 2539 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AJ6KY UT WOS:000337804400016 PM 24963575 ER PT J AU Cho, TA Chi, AS Schaefer, PW AF Cho, Tracey A. Chi, Andrew S. Schaefer, Pamela W. TI Case 8-2014: A Man with Headache, Vomiting, and Diplopia REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Cho, Tracey A.; Chi, Andrew S.; Schaefer, Pamela W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cho, TA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM tcho@partners.org NR 2 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 26 PY 2014 VL 370 IS 26 BP 2545 EP 2545 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AJ6KY UT WOS:000337804400027 PM 24963586 ER PT J AU Canning, P Tan, L Chu, K Lee, SW Gray, NS Bullock, AN AF Canning, Peter Tan, Li Chu, Kiki Lee, Sam W. Gray, Nathanael S. Bullock, Alex N. TI Structural Mechanisms Determining Inhibition of the Collagen Receptor DDR1 by Selective and Multi-Targeted Type II Kinase Inhibitors SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE phosphorylation; crystallography; drug design; oncology; gleevec ID DISCOIDIN DOMAIN RECEPTOR-1; CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE; STI-571 INHIBITION; CRYSTAL-STRUCTURES; CELL-SURVIVAL; LUNG FIBROSIS; CANCER; IMATINIB AB The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9 nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and alpha D helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a beta-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer. (C) 2014 The Authors. Published by Elsevier Ltd. C1 [Canning, Peter; Bullock, Alex N.] Univ Oxford, Struct Genom Consortium, Old Rd Campus,Roosevelt Dr, Oxford OX3 7DQ, England. [Tan, Li; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Tan, Li; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Chu, Kiki; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Chu, Kiki; Lee, Sam W.] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu; alex.bullock@sgc.ox.ac.uk OI Canning, Peter/0000-0001-9678-4169 FU National Institutes of Health [P01 CA154303-01A1]; AbbVie, Bayer PHARMA AG, Boehringer Ingelheim [1097737]; Canada Foundation for Innovation; Canadian Institutes for Health Research; Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda; Wellcome Trust [092809/Z/1 0/Z] FX The authors would like to thank Diamond Light Source for beamtime (proposal mx8421) and the staff of beamlines 102, 103 and 104-1 for assistance with crystal testing and data collection. N.S.G. acknowledges funding from the National Institutes of Health Grant P01 CA154303-01A1. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer PHARMA AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/1 0/Z). NR 62 TC 18 Z9 19 U1 1 U2 30 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 26 PY 2014 VL 426 IS 13 BP 2457 EP 2470 DI 10.1016/j.jmb.2014.04.014 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ6DP UT WOS:000337780200004 PM 24768818 ER PT J AU Gallun, FJ McMillan, GP Molis, MR Kampel, SD Dann, SM Konrad-Martin, DL AF Gallun, Frederick J. McMillan, Garnett P. Molis, Michelle R. Kampel, Sean D. Dann, Serena M. Konrad-Martin, Dawn L. TI Relating age and hearing loss to monaural, bilateral, and binaural temporal sensitivity SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE aging; hearing loss; gap discrimination; monaural; binaural ID FINE-STRUCTURE; FREQUENCY-SELECTIVITY; IMPAIRED HEARING; INTERAURAL PHASE; GAP DETECTION; SPEECH RECEPTION; BAND STIMULI; LISTENERS; NOISE; MODULATION AB Older listeners are more likely than younger listeners to have difficulties in making temporal discriminations among auditory stimuli presented to one or both ears. In addition, the performance of older listeners is often observed to be more variable than that of younger listeners. The aim of this work was to relate age and hearing loss to temporal processing ability in a group of younger and older listeners with a range of hearing thresholds. Seventy-eight listeners were tested on a set of three temporal discrimination tasks (monaural gap discrimination, bilateral gap discrimination, and binaural discrimination of interaural differences in time). To examine the role of temporal fine structure in these tasks, four types of brief stimuli were used: tone bursts, broad-frequency chirps with rising or falling frequency contours, and random-phase noise bursts. Between-subject group analyses conducted separately for each task revealed substantial increases in temporal thresholds for the older listeners across all three tasks, regardless of stimulus type, as well as significant correlations among the performance of individual listeners across most combinations of tasks and stimuli. Differences in performance were associated with the stimuli in the monaural and binaural tasks, but not the bilateral task. Temporal fine structure differences among the stimuli had the greatest impact on monaural thresholds. Threshold estimate values across all tasks and stimuli did not show any greater variability for the older listeners as compared to the younger listeners. A linear mixed model applied to the data suggested that age and hearing loss are independent factors responsible for temporal processing ability, thus supporting the increasingly accepted hypothesis that temporal processing can be impaired for older compared to younger listeners with similar hearing and/or amounts of hearing loss. C1 [Gallun, Frederick J.; McMillan, Garnett P.; Molis, Michelle R.; Kampel, Sean D.; Dann, Serena M.; Konrad-Martin, Dawn L.] Portland VA Med Ctr, Natl Ctr Rehabi Auditory Res, Dept Vet Afffairs, Portland, OR 97207 USA. [Gallun, Frederick J.; Molis, Michelle R.; Konrad-Martin, Dawn L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [McMillan, Garnett P.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. RP Gallun, FJ (reprint author), Portland VA Med Ctr, VA RR&D Natl Ctr Rehabi Auditory Res, 3710 SW US Vet Hosp Rd NCRAR, Portland, OR 97207 USA. EM frederick.gallun@va.gov FU Department of Veterans Affairs Rehabilitation Research and Development (VA RRD) Service [C7450R, C4963W, C6116W, C7113N] FX This research was supported by the Department of Veterans Affairs Rehabilitation Research and Development (VA RR&D) Service [Merit Award C7450R, Career Development Awards C4963W (Gallun) and C6116W (Molis), and Career Development Transition Award C7113N (Konrad-Martin)]. The work was supported with resources and the use of facilities at VA RR&D National Center for Rehabilitative Auditory Research, which is located at the Portland VA Medical Center. We are extremely grateful to the many participants who volunteered their time and ears to make this work possible. The code used to create the chirp stimuli was modified from original Matlab functions generously provided by Dr. Torsten Dau. The contents of this article are the private views of the authors and should not be assumed to represent the views of the Department of Veterans Affairs or the United States Government. NR 43 TC 6 Z9 8 U1 2 U2 9 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 25 PY 2014 VL 8 AR 172 DI 10.3389/fnins.2014.00172 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AW8EN UT WOS:000346493600001 PM 25009458 ER PT J AU Chu, JH Hersh, CP Castaldi, PJ Cho, MH Raby, BA Laird, N Bowler, R Rennard, S Loscalzo, J Quackenbush, J Silverman, EK AF Chu, Jen-hwa Hersh, Craig P. Castaldi, Peter J. Cho, Michael H. Raby, Benjamin A. Laird, Nan Bowler, Russell Rennard, Stephen Loscalzo, Joseph Quackenbush, John Silverman, Edwin K. TI Analyzing networks of phenotypes in complex diseases: methodology and applications in COPD SO BMC SYSTEMS BIOLOGY LA English DT Article DE Network medicine; Phenotypic networks; COPD; Genetic association analysis ID OBSTRUCTIVE PULMONARY-DISEASE; ASSOCIATION AB Background: The investigation of complex disease heterogeneity has been challenging. Here, we introduce a network-based approach, using partial correlations, that analyzes the relationships among multiple disease-related phenotypes. Results: We applied this method to two large, well-characterized studies of chronic obstructive pulmonary disease (COPD). We also examined the associations between these COPD phenotypic networks and other factors, including case-control status, disease severity, and genetic variants. Using these phenotypic networks, we have detected novel relationships between phenotypes that would not have been observed using traditional epidemiological approaches. Conclusion: Phenotypic network analysis of complex diseases could provide novel insights into disease susceptibility, disease severity, and genetic mechanisms. C1 [Chu, Jen-hwa; Hersh, Craig P.; Castaldi, Peter J.; Cho, Michael H.; Raby, Benjamin A.; Loscalzo, Joseph; Silverman, Edwin K.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chu, Jen-hwa; Hersh, Craig P.; Castaldi, Peter J.; Cho, Michael H.; Raby, Benjamin A.; Loscalzo, Joseph; Silverman, Edwin K.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hersh, Craig P.; Cho, Michael H.; Raby, Benjamin A.; Silverman, Edwin K.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Laird, Nan; Quackenbush, John] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bowler, Russell] Natl Jewish Hlth, Dept Med, Denver, CO USA. [Rennard, Stephen] Univ Nebraska Med Ctr, Omaha, NE USA. [Loscalzo, Joseph] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chu, JH (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM stjhc@channing.harvard.edu OI Chu, Jen-hwa/0000-0001-7179-9428 FU U.S. National Institutes of Health (NIH) [K99HL114651 (Chu), P01HL105339 (Silverman), R01HL075478 (Silverman), R01HL111759 (Quackenbush/Silverman/Yuan), R01HL089897 (Crapo), R01HL089856 (Silverman), R37HL061795 (Loscalzo), P50HL107192 (Loscalzo)]; National Heart, Lung, and Blood Institute [U01HL108630 (MAPGen Consortium) (Loscalzo)]; COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca; Boehringer Ingelheim, Novartis, Pfizer, Siemens and Sunovion; ECLIPSE [NCT00292552, GSK code SCO104960, SC0104960] FX This work was supported by U.S. National Institutes of Health (NIH) grants K99HL114651 (Chu), P01HL105339 (Silverman), R01HL075478 (Silverman), R01HL111759 (Quackenbush/Silverman/Yuan), R01HL089897 (Crapo), R01HL089856 (Silverman), R37HL061795 (Loscalzo), P50HL107192 (Loscalzo), and U01HL108630 (MAPGen Consortium) (Loscalzo) from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens and Sunovion. The ECLIPSE study (NCT00292552; GSK code SCO104960) was sponsored by GlaxoSmithKline. NR 29 TC 9 Z9 9 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD JUN 25 PY 2014 VL 8 AR 78 DI 10.1186/1752-0509-8-78 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AL7BJ UT WOS:000339287600001 PM 24964944 ER PT J AU Elmariah, SB Reddy, VB Lerner, EA AF Elmariah, Sarina B. Reddy, Vemuri B. Lerner, Ethan A. TI Cathepsin S Signals via PAR2 and Generates a Novel Tethered Ligand Receptor Agonist SO PLOS ONE LA English DT Article ID PROTEINASE-ACTIVATED RECEPTOR-2; MHC CLASS-II; THROMBIN-RECEPTOR; CYSTEINE CATHEPSINS; HUMAN KERATINOCYTES; NETHERTON SYNDROME; INVARIANT CHAIN; EXPRESSION; IDENTIFICATION; SPECIFICITY AB Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation. C1 [Lerner, Ethan A.] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lerner, EA (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. EM elerner@partners.org FU NIAMS/NIH [1R01AR057744]; Dermatology Foundation; Women's Dermatologic Society; LaRoche-Posay; NIH training [5T32AR007098] FX This work was supported by grant number 1R01AR057744 from NIAMS/NIH to EAL and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAMS or NIH. In addition, SBE was supported by the Dermatology Foundation, the Women's Dermatologic Society, an award from LaRoche-Posay and by NIH training grant 5T32AR007098. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 15 Z9 15 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 25 PY 2014 VL 9 IS 6 AR e99702 DI 10.1371/journal.pone.0099702 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8WO UT WOS:000338709500014 PM 24964046 ER PT J AU Friedewald, SM Rafferty, EA Rose, SL Durand, MA Plecha, DM Greenberg, JS Hayes, MK Copit, DS Carlson, KL Cink, TM Barke, LD Greer, LN Miller, DP Conant, EF AF Friedewald, Sarah M. Rafferty, Elizabeth A. Rose, Stephen L. Durand, Melissa A. Plecha, Donna M. Greenberg, Julianne S. Hayes, Mary K. Copit, Debra S. Carlson, Kara L. Cink, Thomas M. Barke, Lora D. Greer, Linda N. Miller, Dave P. Conant, Emily F. TI Breast Cancer Screening Using Tomosynthesis in Combination With Digital Mammography SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PERFORMANCE; POPULATION; TRIAL AB IMPORTANCE Mammography plays a key role in early breast cancer detection. Single-institution studies have shown that adding tomosynthesis to mammography increases cancer detection and reduces false-positive results. OBJECTIVE To determine if mammography combined with tomosynthesis is associated with better performance of breast screening programs in the United States. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of screening performance metrics from 13 academic and nonacademic breast centers using mixed models adjusting for site as a random effect. EXPOSURES Period 1: digital mammography screening examinations 1 year before tomosynthesis implementation (start dates ranged from March 2010 to October 2011 through the date of tomosynthesis implementation); period 2: digital mammography plus tomosynthesis examinations from initiation of tomosynthesis screening (March 2011 to October 2012) through December 31, 2012. MAIN OUTCOMES AND MEASURES Recall rate for additional imaging, cancer detection rate, and positive predictive values for recall and for biopsy. RESULTS A total of 454 850 examinations (n = 281 187 digital mammography; n = 173 663 digital mammography + tomosynthesis) were evaluated. With digital mammography, 29 726 patients were recalled and 5056 biopsies resulted in cancer diagnosis in 1207 patients (n = 815 invasive; n = 392 in situ). With digital mammography + tomosynthesis, 15 541 patients were recalled and 3285 biopsies resulted in cancer diagnosis in 950 patients (n = 707 invasive; n = 243 in situ). Model-adjusted rates per 1000 screens were as follows: for recall rate, 107 (95% CI, 89-124) with digital mammography vs 91 (95% CI, 73-108) with digital mammography + tomosynthesis; difference, -16 (95% CI, -18 to -14; P < .001); for biopsies, 18.1 (95% CI, 15.4-20.8) with digital mammography vs 19.3 (95% CI, 16.6-22.1) with digital mammography + tomosynthesis; difference, 1.3 (95% CI, 0.4-2.1; P = .004); for cancer detection, 4.2 (95% CI, 3.8-4.7) with digital mammography vs 5.4 (95% CI, 4.9-6.0) with digital mammography + tomosynthesis; difference, 1.2 (95% CI, 0.8-1.6; P < .001); and for invasive cancer detection, 2.9 (95% CI, 2.5-3.2) with digital mammography vs 4.1 (95% CI, 3.7-4.5) with digital mammography + tomosynthesis; difference, 1.2 (95% CI, 0.8-1.6; P < .001). The in situ cancer detection rate was 1.4 (95% CI, 1.2-1.6) per 1000 screens with both methods. Adding tomosynthesis was associated with an increase in the positive predictive value for recall from 4.3% to 6.4%(difference, 2.1%; 95% CI, 1.7%-2.5%; P < .001) and for biopsy from 24.2% to 29.2%(difference, 5.0%; 95% CI, 3.0%-7.0%; P < .001). CONCLUSIONS AND RELEVANCE Addition of tomosynthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate. Further studies are needed to assess the relationship to clinical outcomes. C1 [Friedewald, Sarah M.] Advocate Lutheran Gen Hosp, Ctr Adv Care, Caldwell Breast Ctr, Park Ridge, IL 60068 USA. [Rafferty, Elizabeth A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rose, Stephen L.] TOPS Comprehens Breast Ctr, Houston, TX USA. [Rose, Stephen L.] Solis Womens Hlth, Dallas, TX USA. [Durand, Melissa A.] Yale Univ, Sch Med, Dept Diagnost Radiol, Breast Imaging Sect, New Haven, CT 06510 USA. [Plecha, Donna M.] Univ Hosp Case Med Ctr, Dept Radiol, Cleveland, OH USA. [Greenberg, Julianne S.] Washington Radiol Associates, Fairfax, VA USA. [Hayes, Mary K.] Radiol Associates Hollywood, Hollywood, FL USA. [Hayes, Mary K.] Mem Healthcare Syst, Hollywood, FL USA. [Copit, Debra S.] Albert Einstein Healthcare Network, Dept Diagnost Radiol, Philadelphia, PA USA. [Carlson, Kara L.] Evergreen Hlth Breast Ctr, Kirkland, WA USA. [Carlson, Kara L.] Radia Inc, Kirkland, WA USA. [Cink, Thomas M.] Edith Sanford Breast Hlth Inst, Sioux Falls, SD USA. [Barke, Lora D.] Invis Sally Jobe Breast Ctr, Denver, CO USA. [Barke, Lora D.] Radiol Imaging Associates, Denver, CO USA. [Greer, Linda N.] John C Lincoln Breast Hlth & Res Ctr, Phoenix, AZ USA. [Miller, Dave P.] ICON Clin Res, San Francisco, CA USA. [Conant, Emily F.] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Friedewald, SM (reprint author), Advocate Lutheran Gen Hosp, Ctr Adv Care, Caldwell Breast Ctr, Third Floor,1700 Luther Ln, Park Ridge, IL 60068 USA. EM sarah.friedewald@advocatehealth.com FU Hologic; National Cancer Institute [5U54CA163316-03] FX Drs Friedewald, Rafferty, Rose, Durand, Plecha, Greenberg, Hayes, Copit, Carlson, Cink, Barke, and Greer received a research grant from Hologic. Dr Conant received research grant 5U54CA163316-03 from the National Cancer Institute. NR 18 TC 149 Z9 150 U1 2 U2 28 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 25 PY 2014 VL 311 IS 24 BP 2499 EP 2507 DI 10.1001/jama.2014.6095 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AJ5VE UT WOS:000337757000023 PM 25058084 ER PT J AU Vaduganathan, M Greene, SJ AF Vaduganathan, Muthiah Greene, Stephen J. TI Influence of Chronic Kidney Disease on Warfarin Therapy for Atrial Fibrillation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ACUTE MYOCARDIAL-INFARCTION; REGISTRY; RISK C1 [Vaduganathan, Muthiah] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Greene, Stephen J.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. RP Vaduganathan, M (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM muthu@md.northwestern.edu NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 25 PY 2014 VL 311 IS 24 BP 2541 EP 2542 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AJ5VE UT WOS:000337757000030 PM 25058089 ER PT J AU Kwon, M Lu, ZL Miller, A Kazlas, M Hunter, DG Bex, PJ AF Kwon, MiYoung Lu, Zhong-Lin Miller, Alexandra Kazlas, Melanie Hunter, David G. Bex, Peter J. TI Assessing Binocular Interaction in Amblyopia and Its Clinical Feasibility SO PLOS ONE LA English DT Article ID STRABISMIC AMBLYOPIA; ANISOMETROPIC AMBLYOPIA; INTEROCULAR SUPPRESSION; CONTRAST SENSITIVITY; GLOBAL MOTION; QUANTITATIVE MEASUREMENT; VISUOMOTOR BEHAVIOR; VISUAL DEFICITS; VISION; SUMMATION AB Purpose: To measure binocular interaction in amblyopes using a rapid and patient-friendly computer-based method, and to test the feasibility of the assessment in the clinic. Methods: Binocular interaction was assessed in subjects with strabismic amblyopia (n = 7), anisometropic amblyopia (n = 6), strabismus without amblyopia (n = 15) and normal vision (n = 40). Binocular interaction was measured with a dichoptic phase matching task in which subjects matched the position of a binocular probe to the cyclopean perceived phase of a dichoptic pair of gratings whose contrast ratios were systematically varied. The resulting effective contrast ratio of the weak eye was taken as an indicator of interocular imbalance. Testing was performed in an ophthalmology clinic under 8 mins. We examined the relationships between our binocular interaction measure and standard clinical measures indicating abnormal binocularity such as interocular acuity difference and stereoacuity. The test-retest reliability of the testing method was also evaluated. Results: Compared to normally-sighted controls, amblyopes exhibited significantly reduced effective contrast (similar to 20%) of the weak eye, suggesting a higher contrast requirement for the amblyopic eye compared to the fellow eye. We found that the effective contrast ratio of the weak eye covaried with standard clincal measures of binocular vision. Our results showed that there was a high correlation between the 1(st) and 2(nd) measurements (r = 0.94, p<0.001) but without any significant bias between the two. Conclusions: Our findings demonstrate that abnormal binocular interaction can be reliably captured by measuring the effective contrast ratio of the weak eye and quantitative assessment of binocular interaction is a quick and simple test that can be performed in the clinic. We believe that reliable and timely assessment of deficits in a binocular interaction may improve detection and treatment of amblyopia. C1 [Kwon, MiYoung; Miller, Alexandra; Bex, Peter J.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Kwon, MiYoung; Miller, Alexandra; Kazlas, Melanie; Hunter, David G.; Bex, Peter J.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Lu, Zhong-Lin] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Kazlas, Melanie; Hunter, David G.] Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA. RP Kwon, M (reprint author), Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. EM miyoungkwon02@gmail.com FU NIH [R01 EY021553] FX This work was supported by NIH grant R01 EY021553. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 8 Z9 8 U1 0 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 24 PY 2014 VL 9 IS 6 AR e100156 DI 10.1371/journal.pone.0100156 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7UT UT WOS:000338633900023 PM 24959842 ER PT J AU Michelena, HI Prakash, SK Della Corte, A Bissell, MM Anavekar, N Mathieu, P Bosse, Y Limongelli, G Bossone, E Benson, DW Lancellotti, P Isselbacher, EM Enriquez-Sarano, M Sundt, TM Pibarot, P Evangelista, A Milewicz, DM Body, SC AF Michelena, Hector I. Prakash, Siddharth K. Della Corte, Alessandro Bissell, Malenka M. Anavekar, Nandan Mathieu, Patrick Bosse, Yohan Limongelli, Giuseppe Bossone, Eduardo Benson, D. Woodrow Lancellotti, Patrizio Isselbacher, Eric M. Enriquez-Sarano, Maurice Sundt, Thoralf M., III Pibarot, Philippe Evangelista, Artur Milewicz, Dianna M. Body, Simon C. CA BAVCon Investigators TI Bicuspid Aortic Valve Identifying Knowledge Gaps and Rising to the Challenge From the International Bicuspid Aortic Valve Consortium (BAVCon) SO CIRCULATION LA English DT Review DE aortic aneurysm, thoracic; aortic valve, bicuspid; aortic valve stenosis; heart defects, congenital ID WALL SHEAR-STRESS; ASCENDING AORTA; TRANSTHORACIC ECHOCARDIOGRAPHY; MARFAN-SYNDROME; COMPUTED-TOMOGRAPHY; MAGNETIC-RESONANCE; NATURAL-HISTORY; 2-DIMENSIONAL ECHOCARDIOGRAPHY; PRACTICE GUIDELINES; AMERICAN-COLLEGE C1 [Michelena, Hector I.; Anavekar, Nandan; Enriquez-Sarano, Maurice] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Prakash, Siddharth K.; Milewicz, Dianna M.] Univ Texas Hlth Sci Ctr Houston, Div Med Genet, Dept Internal Med, Houston, TX 77030 USA. [Della Corte, Alessandro] Univ Naples 2, Dept Cardiothorac Sci, Naples, Italy. [Bissell, Malenka M.] Univ Oxford, Radcliffe Dept Med, Dept Cardiovasc Med, Oxford OX1 2JD, England. [Mathieu, Patrick; Bosse, Yohan; Pibarot, Philippe] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Limongelli, Giuseppe] Monaldi Hosp, Cardiol SUN, Naples, Italy. [Bossone, Eduardo] Univ Salerno, Heart Dept, Cava de Tirreni & Amalfi Coast Hosp, Div Cardiol, Salerno, Italy. [Benson, D. Woodrow] Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. [Lancellotti, Patrizio] CHU Sart Tilman, Univ Hosp Liege, GIGA Cardiovasc Sci, B-4000 Liege, Belgium. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 USA. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Corrigan Minehan Heart Ctr, Boston, MA 02114 USA. [Evangelista, Artur] Univ Autonoma Barcelona, Serv Cardiol, Hosp Vall dHebron, E-08193 Barcelona, Spain. [Body, Simon C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. RP Michelena, HI (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM michelena.hector@mayo.edu RI Della Corte, Alessandro/K-9383-2016; OI Della Corte, Alessandro/0000-0002-4636-3339; LImongelli, Giuseppe/0000-0002-8291-9517 FU British Heart Foundation [FS/10/43/28415]; NCATS NIH HHS [UL1 TR000371]; NHLBI NIH HHS [R01 HL114823] NR 107 TC 38 Z9 38 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 24 PY 2014 VL 129 IS 25 BP 2691 EP 2704 DI 10.1161/CIRCULATIONAHA.113.007851 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK0TZ UT WOS:000338129800015 PM 24958752 ER PT J AU Unitt, C Montazeri, K Tolaney, S Moslehi, J AF Unitt, Christine Montazeri, Kamaneh Tolaney, Sara Moslehi, Javid TI Breast Cancer Chemotherapy and Your Heart SO CIRCULATION LA English DT Editorial Material C1 [Unitt, Christine; Montazeri, Kamaneh; Moslehi, Javid] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiooncol Program,Dana Farber Canc Inst, Boston, MA 02115 USA. [Tolaney, Sara; Moslehi, Javid] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Moslehi, Javid] Vanderbilt Univ Sch Med, Cardiooncol Program, Nashville, TN USA. RP Moslehi, J (reprint author), Vanderbilt Univ, Med Ctr, Cardiooncol Program, 2220 Pierce Ave, Nashville, TN 37232 USA. EM javid.moslehi@vanderbilt.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 24 PY 2014 VL 129 IS 25 BP E680 EP E682 DI 10.1161/CIRCULATIONAHA.113.007181 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK0TZ UT WOS:000338129800003 PM 24958758 ER PT J AU Ayrapetov, MK Gursoy-Yuzugullu, O Xu, C Xu, Y Price, BD AF Ayrapetov, Marina K. Gursoy-Yuzugullu, Ozge Xu, Chang Xu, Ye Price, Brendan D. TI DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE histone methylation; homologous recombination ID DAMAGE RESPONSE; HETEROCHROMATIN PROTEIN-1; HOMOLOGOUS RECOMBINATION; KAP-1 PHOSPHORYLATION; REPAIR; ATM; ACETYLATION; ACTIVATION; GENOME; TIP60 AB Dynamic changes in histone modification are critical for regulating DNA double-strand break (DSB) repair. Activation of the Tip60 acetyltransferase by DSBs requires interaction of Tip60 with histone H3 methylated on lysine 9 (H3K9me3). However, how H3K9 methylation is regulated during DSB repair is not known. Here, we demonstrate that a complex containing kap-1, HP1, and the H3K9 methyltransferase suv39h1 is rapidly loaded onto the chromatin at DSBs. Suv39h1 methylates H3K9, facilitating loading of additional kap-1/HP1/suv39h1 through binding of HP1's chromodomain to the nascent H3K9me3. This process initiates cycles of kap-1/HP1/suv39h1 loading and H3K9 methylation that facilitate spreading of H3K9me3 and kap-1/HP1/suv39h1 complexes for tens of kilobases away from the DSB. These domains of H3K9me3 function to activate the Tip60 acetyltransferase, allowing Tip60 to acetylate both ataxia telangiectasia-mutated (ATM) kinase and histone H4. Consequently, cells lacking suv39h1 display defective activation of Tip60 and ATM, decreased DSB repair, and increased radiosensitivity. Importantly, activated ATM rapidly phosphorylates kap-1, leading to release of the repressive kap-1/HP1/suv39h1 complex from the chromatin. ATM activation therefore functions as a negative feedback loop to remove repressive suv39h1 complexes at DSBs, which may limit DSB repair. Recruitment of kap-1/HP1/suv39h1 to DSBs therefore provides a mechanism for transiently increasing the levels of H3K9me3 in open chromatin domains that lack H3K9me3 and thereby promoting efficient activation of Tip60 and ATM in these regions. Further, transient formation of repressive chromatin may be critical for stabilizing the damaged chromatin and for remodeling the chromatin to create an efficient template for the DNA repair machinery. C1 [Ayrapetov, Marina K.; Gursoy-Yuzugullu, Ozge; Xu, Chang; Xu, Ye; Price, Brendan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Xu, Chang] Chinese Acad Med Sci, Inst Radiat Med, Tianjin Key Lab Mol Nucl Med, Tianjin 300192, Peoples R China. [Xu, Chang] Peking Union Med Coll, Tianjin 300192, Peoples R China. RP Price, BD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM brendan_price@dfci.harvard.edu FU National Institutes of Health [CA64585, CA93602, CA177884] FX We thank Sangamo Biosciences for p84-ZFN and Dipanjan Chowdhury for the kap1 constructs. This work was supported by National Institutes of Health Grants CA64585, CA93602, and CA177884 (to B.D.P.). NR 47 TC 69 Z9 72 U1 4 U2 16 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 24 PY 2014 VL 111 IS 25 BP 9169 EP 9174 DI 10.1073/pnas.1403565111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ5WJ UT WOS:000337760600046 PM 24927542 ER PT J AU Whitton, JP Hancock, KE Polley, DB AF Whitton, Jonathon P. Hancock, Kenneth E. Polley, Daniel B. TI Immersive audiomotor game play enhances neural and perceptual salience of weak signals in noise SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE foraging; hearing; cortical; gradient search; noise suppression ID PRIMARY AUDITORY-CORTEX; ACTION VIDEO GAMES; IMPROVED PROBABILISTIC INFERENCE; HEARING-IMPAIRED LISTENERS; RECEPTIVE-FIELD PLASTICITY; SPEECH-IN-NOISE; TASK-DIFFICULTY; DEPENDENT PLASTICITY; LEARNING INCREASES; PREFRONTAL CORTEX AB All sensory systems face the fundamental challenge of encoding weak signals in noisy backgrounds. Although discrimination abilities can improve with practice, these benefits rarely generalize to untrained stimulus dimensions. Inspired by recent findings that action video game training can impart a broader spectrum of benefits than traditional perceptual learning paradigms, we trained adult humans and mice in an immersive audio game that challenged them to forage for hidden auditory targets in a 2D soundscape. Both species learned to modulate their angular search vectors and target approach velocities based on real-time changes in the level of a weak tone embedded in broadband noise. In humans, mastery of this tone in noise task generalized to an improved ability to comprehend spoken sentences in speech babble noise. Neural plasticity in the auditory cortex of trained mice supported improved decoding of low-intensity sounds at the training frequency and an enhanced resistance to interference from background masking noise. These findings highlight the potential to improve the neural and perceptual salience of degraded sensory stimuli through immersive computerized games. C1 [Whitton, Jonathon P.; Hancock, Kenneth E.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Whitton, Jonathon P.] MIT, Harvard Mit Div Hlth Sci & Technol, Program Speech Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Hancock, Kenneth E.; Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Whitton, JP (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. EM jpwhit05@mit.edu; daniel_polley@meei.harvard.edu FU National Institutes of Health [R01 DC009836, P30 DC5029]; Mass Eye and Ear Curing Kids Award FX We thank R. Williamson for computational assistance, D. Barbour for discussion, and R. Froemke for comments. Animal research was supported by National Institutes of Health Grants R01 DC009836 (to D.B.P.) and P30 DC5029. Human research was supported by a Mass Eye and Ear Curing Kids Award (to D.B.P.). NR 85 TC 8 Z9 9 U1 1 U2 16 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 24 PY 2014 VL 111 IS 25 BP E2606 EP E2615 DI 10.1073/pnas.1322184111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ5WJ UT WOS:000337760600014 PM 24927596 ER PT J AU Balseanu, AT Buga, AM Catalin, B Wagner, DC Boltze, J Zagrean, AM Reymann, K Schaebitz, W Popa-Wagner, A AF Balseanu, Adrian Tudor Buga, Ana-Maria Catalin, Bogdan Wagner, Daniel-Christoph Boltze, Johannes Zagrean, Ana-Maria Reymann, Klaus Schaebitz, Wolf Popa-Wagner, Aurel TI Multimodal approaches for regenerative stroke therapies: combination of granulocyte colony-stimulating factor with bone marrow mesenchymal stem cells is not superior to G-CSF alone SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE aging; stroke; cell therapy; G-CSF; translational medicine; BM MSC; angiogenesis ID BLOOD-BRAIN-BARRIER; ENDOTHELIAL GROWTH-FACTOR; FOCAL CEREBRAL-ISCHEMIA; SPINAL-CORD-INJURY; STROMAL CELLS; AGED RATS; POSTISCHEMIC NEUROPROTECTION; MEMORY IMPAIRMENTS; ADULT RATS; TRANSPLANTATION AB Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 mu g/kg) or in combination with a single dose (106 cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time. C1 [Balseanu, Adrian Tudor; Buga, Ana-Maria; Catalin, Bogdan; Popa-Wagner, Aurel] Univ Med & Pharm Craiova, Ctr Clin & Expt Med, Craiova, Romania. [Buga, Ana-Maria; Popa-Wagner, Aurel] Univ Med Rostock, Dept Psychiat, D-18147 Rostock, Germany. [Wagner, Daniel-Christoph; Boltze, Johannes] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Boltze, Johannes] Univ Leipzig, Translat Ctr Regenerat Med, D-04109 Leipzig, Germany. [Boltze, Johannes] Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. [Boltze, Johannes] Harvard Univ, Sch Med, Charlestown, MA USA. [Zagrean, Ana-Maria] Carol Davila Univ Med & Pharm, Bucharest, Romania. [Reymann, Klaus] German Ctr Neurodegenerat Dis DZNE Magdeburg, Collobarat Leibniz Inst Neurobiol, Magdeburg, Germany. [Schaebitz, Wolf] Univ Munster, Evangel Krankenhaus Bielefeld gGmbH Akad Lehrkran, D-48149 Munster, Germany. RP Popa-Wagner, A (reprint author), Univ Med Rostock, Dept Psychiat, Gehlsheimerstr 20, D-18147 Rostock, Germany. EM aurel.popa-wagner@med.uni-rostock.de RI Popa-Wagner, Aurel/E-2541-2013; Catalin, Bogdan/G-2565-2013; Zagrean, Ana-Maria/M-5628-2015; Popa-Wagner, Aurel/D-8193-2017 OI Catalin, Bogdan/0000-0002-5706-8722; Zagrean, Ana-Maria/0000-0002-4302-629X; FU Ministry of Research and Education of Germany [FKZ 01GN0982]; Romanian National Authority for Scientific Research, CNCS - UEFISCDI [PN-II-PT-PCCA-2011-3, 80/2012] FX This study was partially supported by a grant from the Ministry of Research and Education of Germany (FKZ 01GN0982) to Aurel Popa-Wagner and Johannes Boltze. Dr. Adrian Tudor Balseanu was supported by a grant of the Romanian National Authority for Scientific Research, CNCS - UEFISCDI, project number PN-II-PT-PCCA-2011-3, No 80/2012. NR 75 TC 27 Z9 27 U1 1 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUN 23 PY 2014 VL 6 AR 130 DI 10.3389/fnagi.2014.00130 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CT8BC UT WOS:000363038900001 PM 25002846 ER PT J AU Dyer, MA Arvold, ND Chen, YH Pinnell, NE Mitin, T Lee, EQ Hodi, FS Ibrahim, N Weiss, SE Kelly, PJ Floyd, SR Mahadevan, A Alexander, BM AF Dyer, Michael A. Arvold, Nils D. Chen, Yu-Hui Pinnell, Nancy E. Mitin, Timur Lee, Eudocia Q. Hodi, F. Stephen Ibrahim, Nageatte Weiss, Stephanie E. Kelly, Paul J. Floyd, Scott R. Mahadevan, Anand Alexander, Brian M. TI The role of whole brain radiation therapy in the management of melanoma brain metastases SO RADIATION ONCOLOGY LA English DT Article DE Melanoma; Brain metastases; Radiosurgery; Whole brain radiation therapy ID RENAL-CELL CARCINOMA; STEREOTACTIC RADIOSURGERY; MALIGNANT-MELANOMA; PROGNOSTIC-FACTORS; ONCOLOGY-GROUP; SURVIVAL; TRIAL; RADIOTHERAPY; INDEX AB Background: Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as "radioresistant," the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). Methods: We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years ( hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases ( HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) <= 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). Conclusions: Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials. C1 [Dyer, Michael A.] Harvard Radiat Oncol Program, Boston, MA USA. [Arvold, Nils D.; Pinnell, Nancy E.; Alexander, Brian M.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA 02115 USA. [Arvold, Nils D.; Mitin, Timur; Lee, Eudocia Q.; Hodi, F. Stephen; Ibrahim, Nageatte; Floyd, Scott R.; Mahadevan, Anand; Alexander, Brian M.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Yu-Hui] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mitin, Timur] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Lee, Eudocia Q.] Dana Farber Brigham Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Hodi, F. Stephen; Ibrahim, Nageatte] Dana Farber Canc Inst, Melanoma Dis Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Weiss, Stephanie E.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Weiss, Stephanie E.] Temple Univ, Sch Med, Philadelphia, PA USA. [Kelly, Paul J.] Cork Univ Hosp, Dept Radiotherapy, Cork, Ireland. [Kelly, Paul J.] Univ Coll Cork, Cork, Ireland. [Floyd, Scott R.; Mahadevan, Anand] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. RP Alexander, BM (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA 02115 USA. EM bmalexander@lroc.harvard.edu NR 30 TC 6 Z9 6 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD JUN 22 PY 2014 VL 9 AR 143 DI 10.1186/1748-717X-9-143 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AN7QK UT WOS:000340795200001 PM 24954062 ER PT J AU Corey, KE Misdraji, J Gelrud, L Zheng, H Chung, RT Krauss, RM AF Corey, Kathleen E. Misdraji, Joseph Gelrud, Lou Zheng, Hui Chung, Raymond T. Krauss, Ronald M. TI Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile SO LIPIDS IN HEALTH AND DISEASE LA English DT Article DE Ion mobility analysis; Lipid subfractions; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis ID FATTY LIVER-DISEASE; CORONARY-HEART-DISEASE; LDL PARTICLES; FOLLOW-UP; CHOLESTEROL; RISK AB Background: Nonalcoholic steatohepatitis (NASH) carries an increased risk of cardiovascular disease (CVD) relative to the general population. We sought to evaluate whether differences in lipoprotein subfractions in obese patients with and without NASH contributes to this difference in CVD risk. Findings: Ion mobility analysis was performed on 78 individuals with obesity undergoing weight loss surgery. All individuals had standard of care liver biopsies performed during surgery. Patients with NASH had significantly smaller peak LDL diameter (P = 0.02, 219.0 angstrom vs. 222.6 angstrom), and levels of IDL2 (P = 0.01, 104. nmol/L vs. 133.4 nmol/L) and HDL2b (P = 0.05, 676.7 nmol/L vs. 880.1 nmol/L) compared to those without NASH. NASH patients had significantly higher LDL-IVb levels than those without NASH (P = 0.02, 49.0 nmol/L vs. 37.1 nmol/L). The inverse association of LDL peak diameter with NASH remained significant after adjustment for diabetes (P = 0.02). HDL2b levels were inversely correlated with hepatocyte ballooning and NASH and these remained significant after adjustment for diabetes (P = 0.0017 and P = 0.007, respectively). IDL2 levels were inversely correlated with NASH, hepatocyte ballooning and fibrosis stage but these were not significant after adjustment for diabetes. Conclusions: The lipoprotein subfraction profile in subjects with NASH is characterized by small peak LDL diameter, reduced HDL2b levels and elevated LDL-IVb levels. These changes may contribute to the increased CVD seen in patients with NASH. C1 [Corey, Kathleen E.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Corey, Kathleen E.] Bon Secours Richmond Hlth Syst, Dept Internal Med, Richmond, VA USA. [Zheng, Hui] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Corey, Kathleen E.; Misdraji, Joseph; Gelrud, Lou; Zheng, Hui; Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA USA. [Krauss, Ronald M.] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. RP Corey, KE (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM kcorey@partners.org FU NIH [K23 DK099422, K24 DK078772] FX NIH K23 DK099422 (KEC); K24 DK078772 (RTC). NR 15 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD JUN 21 PY 2014 VL 13 AR 100 DI 10.1186/1476-511X-13-100 PG 4 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA AK5KT UT WOS:000338464200001 PM 24952382 ER PT J AU Dunlop, BW Rothbaum, BO Binder, EB Duncan, E Harvey, PD Jovanovic, T Kelley, ME Kinkead, B Kutner, M Iosifescu, DV Mathew, SJ Neylan, TC Kilts, CD Nemeroff, CB Mayberg, HS AF Dunlop, Boadie W. Rothbaum, Barbara O. Binder, Elisabeth B. Duncan, Erica Harvey, Philip D. Jovanovic, Tanja Kelley, Mary E. Kinkead, Becky Kutner, Michael Iosifescu, Dan V. Mathew, Sanjay J. Neylan, Thomas C. Kilts, Clinton D. Nemeroff, Charles B. Mayberg, Helen S. TI Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Clinical Research Protocol; Drugs; Investigational; HPA Axis; Anxiety disorders; Fear-potentiated startle; Fear conditioning; Neuropsychological tests; Placebo; Psychophysiology; CRH ID POTENTIATED STARTLE PARADIGM; CLINICAL-APPLICATIONS; FEAR INHIBITION; DEPRESSION; SCALE; PTSD; ANTIDEPRESSANTS; QUESTIONNAIRE; VALIDATION; ANXIETY AB Background: Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. Methods/design: Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects. Discussion: Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD. C1 [Dunlop, Boadie W.; Rothbaum, Barbara O.; Binder, Elisabeth B.; Duncan, Erica; Jovanovic, Tanja; Kinkead, Becky; Mayberg, Helen S.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Binder, Elisabeth B.] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Duncan, Erica] Atlanta Vet Affairs Med Ctr, Decatur, GA USA. [Harvey, Philip D.; Nemeroff, Charles B.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Kelley, Mary E.; Kutner, Michael] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Mathew, Sanjay J.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Michael Debakey VA Med Ctr, Houston, TX 77030 USA. [Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Neylan, Thomas C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Kilts, Clinton D.] Univ Arkansas Med Sci, Inst Psychiat Res, Little Rock, AR 72205 USA. RP Dunlop, BW (reprint author), Emory Univ, Sch Med, Dept Psychiat & Behav Sci, 12 Execut Pk Dr NE,3rd Floor, Atlanta, GA 30322 USA. EM bdunlop@emory.edu RI Binder, Elisabeth/K-8905-2014; Duncan, Erica/B-1671-2016 FU National Institute of Mental Health [U19 MH069056]; CSRD [09S-NIMH-002]; [K23 MH086690] FX Funding for the study is provided from a grant from the National Institute of Mental Health, U19 MH069056 (BWD, HM). Additional support was received from K23 MH086690 (BWD) and VA CSRD Project ID 09S-NIMH-002 (TCN). GlaxoSmithKline contributed the study medication and matching placebo, as well as funds to support subject recruitment and laboratory testing. GSK is uninvolved in the data collection, data analysis (excepting some pharmacokinetic analysis), or interpretation of findings. The GSK561679 compound is currently licensed by Neurocrine Biosciences, which will also perform pharmacokinetic analyses.; This work was supported with resources and the use of facilities at the Michael E DeBakey VA Medical Center, Houston, TX. Disclaimer: the views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 49 TC 8 Z9 8 U1 4 U2 10 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 21 PY 2014 VL 15 AR 240 DI 10.1186/1745-6215-15-240 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK5KG UT WOS:000338462800001 PM 24950747 ER PT J AU Moteabbed, M Yock, TI Paganetti, H AF Moteabbed, Maryam Yock, Torunn I. Paganetti, Harald TI The risk of radiation-induced second cancers in the high to medium dose region: a comparison between passive and scanned proton therapy, IMRT and VMAT for pediatric patients with brain tumors SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE second cancer risk; pediatric; head and neck; brain; radiation therapy ID INTENSITY-MODULATED PHOTON; OUT-OF-FIELD; SECONDARY MALIGNANT NEOPLASMS; CENTRAL-NERVOUS-SYSTEM; CHILDHOOD-CANCER; CRANIOSPINAL IRRADIATION; RESPONSE RELATIONSHIPS; HODGKINS-DISEASE; PROSTATE-CANCER; GRADE GLIOMAS AB The incidence of second malignant tumors is a clinically observed adverse late effect of radiation therapy, especially in organs close to the treatment site, receiving medium to high doses (>2.5 Gy). For pediatric patients, choosing the least toxic radiation modality is of utmost importance, due to their high radiosensitivity and small size. This study aims to evaluate the risk of second cancer incidence in the vicinity of the primary radiation field, for pediatric patients with brain/head and neck tumors and compare four treatment modalities: passive scattering and pencil beam scanning proton therapy (PPT and PBS), intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). For a cohort of six pediatric patients originally treated with PPT, additional PBS, IMRT and VMAT plans were created. Dose distributions from these plans were used to calculate the excess absolute risk (EAR) and lifetime attributable risk (LAR) for developing a second tumor in soft tissue and skull. A widely used risk assessment formalism was employed and compared with a linear model based on recent clinical findings. In general, LAR was found to range between 0.01%-2.8% for PPT/PBS and 0.04%-4.9% for IMRT/VMAT. PBS was associated with the lowest risk for most patients using carcinoma and sarcoma models, whereas IMRT and VMAT risks were comparable and the highest among all modalities. The LAR for IMRT/VMAT relative to PPT ranged from 1.3-4.6 for soft tissue and from 3.5-9.5 for skull. Larger absolute LAR was observed for younger patients and using linear risk models. The number of fields used in proton therapy and IMRT had minimal effect on the risk. When planning treatments and deciding on the treatment modality, the probability of second cancer incidence should be carefully examined and weighed against the possibility of developing acute side effects for each patient individually. C1 [Moteabbed, Maryam; Yock, Torunn I.; Paganetti, Harald] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moteabbed, Maryam; Yock, Torunn I.; Paganetti, Harald] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Moteabbed, M (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mmoteabbed@partners.org FU Federal Share of Project Income Program at Massachusetts General Hospital [C06 CA059267] FX The authors would like to thank J Adams, D Craft and N Depauw (MGH) for their support and assistance with the treatment planning systems and evaluating the generated plans. This project was supported by the Federal Share of Project Income Program at Massachusetts General Hospital on C06 CA059267. NR 55 TC 25 Z9 27 U1 2 U2 19 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 2014 VL 59 IS 12 BP 2883 EP 2899 DI 10.1088/0031-9155/59/12/2883 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AI8NV UT WOS:000337176600003 PM 24828559 ER PT J AU Unkelbach, J Craft, D Hong, T Papp, D Ramakrishnan, J Salari, E Wolfgang, J Bortfeld, T AF Unkelbach, Jan Craft, David Hong, Theodore Papp, David Ramakrishnan, Jagdish Salari, Ehsan Wolfgang, John Bortfeld, Thomas TI Exploiting tumor shrinkage through temporal optimization of radiotherapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE temporal optimization; split-course radiotherapy; tumor shrinkage; liver tumors ID SPLIT-COURSE RADIOTHERAPY; RADIATION-THERAPY; HEPATOCELLULAR-CARCINOMA; LIVER METASTASES; CERVICAL-CANCER; TIME; RADIOSENSITIVITY; REGRESSION; SURVIVAL; MODEL AB In multi-stage radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated mostly by radiobiological considerations, but also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. The paper considers the optimal design of multi-stage treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of multi-stage radiotherapy is formulated as a mathematical optimization problem in which the total dose to the normal tissue is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one-third of the dose should be delivered in the first stage. The projected benefit of multi-stage treatments in terms of normal tissue sparing depends on model assumptions. However, the model predicts large dose reductions by more than a factor of 2 for plausible model parameters. The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at multi-stage radiotherapy for selected disease sites where substantial tumor regression translates into reduced target volumes. C1 [Unkelbach, Jan; Craft, David; Hong, Theodore; Papp, David; Wolfgang, John; Bortfeld, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Unkelbach, Jan; Craft, David; Hong, Theodore; Papp, David; Wolfgang, John; Bortfeld, Thomas] Harvard Univ, Sch Med, Boston, MA USA. [Ramakrishnan, Jagdish] Univ Wisconsin, Wisconsin Inst Discovery, Madison, WI USA. [Salari, Ehsan] Wichita State Univ, Dept Ind & Mfg Engn, Wichita, KS USA. RP Unkelbach, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM tbortfeld@partners.org NR 24 TC 2 Z9 2 U1 0 U2 5 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 2014 VL 59 IS 12 BP 3059 EP 3079 DI 10.1088/0031-9155/59/12/3059 PG 21 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AI8NV UT WOS:000337176600012 PM 24839901 ER PT J AU Ning, JF Wakimoto, H AF Ning, Jianfang Wakimoto, Hiroaki TI Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE glioblastoma; oncolytic virus; hemes simplex virus type 1; gene therapy; glioblastoma stem cells; combination therapy; synergy; molecular targeted therapy ID RECURRENT MALIGNANT GLIOMAS; HIGH-GRADE GLIOMA; NEWLY-DIAGNOSED GLIOBLASTOMA; ENHANCES ANTITUMOR EFFICACY; CANCER STEM-CELLS; PHASE-I TRIAL; BRAIN-TUMORS; DNA-REPAIR; RIBONUCLEOTIDE REDUCTASE; IONIZING-RADIATION AB Oncolytic viruses (OV) are a class of antitumor agents that selectively kill tumor cells while sparing normal cells. Oncolytic herpes simplex virus (oHSV) has been investigated in clinical trials for patients with the malignant brain tumor glioblastoma for more than a decade. These clinical studies have shown the safety of oHSV administration to the human brain, however, therapeutic efficacy of oHSV as a single treatment remains unsatisfactory. Factors that could hamper the anti-glioblastoma efficacy of oHSV include: attenuated potency of oHSV due to deletion or mutation of viral genes involved in virulence, restricting viral replication and spread within the tumor; suboptimal oHSV delivery associated with intratumoral injection; virus infection-induced inflammatory and cellular immune responses which could inhibit oHSV replication and promote its clearance; lack of effective incorporation of oHSV into standard-of-care, and poor knowledge about the ability of oHSV to target glioblastoma stem cells (GSCs). In an attempt to address these issues, recent research efforts have been directed at: (1) design of new engineered viruses to enhance potency, (2) better understanding of the role of the cellular immunity elicited by oHSV infection of tumors, (3) combinatorial strategies with different antitumor agents with a mechanistic rationale, (4) "armed" viruses expressing therapeutic transgenes, (5) use of GSC-derived models in oHSV evaluation, and (6) combinations of these. In this review, we will describe the current status of oHSV clinical trials for glioblastoma, and discuss recent research advances and future directions toward successful oHSV-based therapy of glioblastoma. C1 [Ning, Jianfang; Wakimoto, Hiroaki] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg,Brain Tumor Res Ctr, Boston, MA 02114 USA. RP Wakimoto, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Brain Tumor Stem Cell Lab,Dept Neurosurg,Brain Tu, 185 Cambridge St,CPZN 3800, Boston, MA 02114 USA. EM hwakimoto@mgh.harvard.edu FU NIH [R01NS032677, R01CA160762] FX The authors appreciate Dr. Samuel Rabkin for helpful suggestions on the article. This work was supported by grants from the NIH (R01NS032677 and R01CA160762). NR 115 TC 11 Z9 12 U1 2 U2 18 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JUN 20 PY 2014 VL 5 AR 303 DI 10.3389/fmicb.2014.00303 PG 13 WC Microbiology SC Microbiology GA AK9EE UT WOS:000338729600001 PM 24999342 ER PT J AU Hamilton, AB Mittman, BS Williams, JK Liu, HHH Eccles, AM Hutchinson, CS Wyatt, GE AF Hamilton, Alison B. Mittman, Brian S. Williams, John K. Liu, Honghu H. Eccles, Alicia M. Hutchinson, Craig S. Wyatt, Gail E. TI Community-based implementation and effectiveness in a randomized trial of a risk reduction intervention for HIV-serodiscordant couples: study protocol SO IMPLEMENTATION SCIENCE LA English DT Article DE Implementation science; Hybrid design; HIV prevention; Serodiscordance; Couples; African Americans; Behavioral intervention; Sustainability ID SEXUALLY-TRANSMITTED DISEASES; MENTAL-HEALTH-SERVICES; CONDOM-USE; ORGANIZATIONAL READINESS; PREVENTION INTERVENTION; FUTURE-RESEARCH; UNITED-STATES; QUERI SERIES; WOMEN; AIDS AB Background: The HIV/AIDS epidemic continues to disproportionately affect African American communities in the US, particularly those located in urban areas. Despite the fact that HIV is often transmitted from one sexual partner to another, most HIV prevention interventions have focused only on individuals, rather than couples. This five-year study investigates community-based implementation, effectiveness, and sustainability of 'Eban II,' an evidence-based risk reduction intervention for African-American heterosexual, serodiscordant couples. Methods/design: This hybrid implementation/effectiveness implementation study is guided by organizational change theory as conceptualized in the Texas Christian University Program Change Model (PCM), a model of phased organizational change from exposure to adoption, implementation, and sustainability. The primary implementation aims are to assist 10 community-based organizations (CBOs) to implement and sustain Eban II; specifically, to partner with CBOs to expose providers to the intervention; facilitate its adoption, implementation and sustainment; and to evaluate processes and determinants of implementation, effectiveness, fidelity, and sustainment. The primary effectiveness aim is to evaluate the effect of Eban II on participant (n = 200 couples) outcomes, specifically incidents of protected sex and proportion of condom use. We will also determine the cost-effectiveness of implementation, as measured by implementation costs and potential cost savings. A mixed methods evaluation will examine implementation at the agency level; staff members from the CBOs will complete baseline measures of organizational context and climate, while key stakeholders will be interviewed periodically throughout implementation. Effectiveness of Eban II will be assessed using a randomized delayed enrollment (waitlist) control design to evaluate the impact of treatment on outcomes at posttest and three month follow up. Multi level hierarchical modeling with a multi-level nested structure will be used to evaluate the effects of agency- and couples-level characteristics on couples-level outcomes (e.g., condom use). Discussion: This study will produce important information regarding the value of the Eban II program and a theory-guided implementation process and tools designed for use in Eban II and other evidence-based programs in demographically diverse, resource-constrained treatment settings. C1 [Hamilton, Alison B.; Williams, John K.; Eccles, Alicia M.; Hutchinson, Craig S.; Wyatt, Gail E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Hamilton, Alison B.; Mittman, Brian S.] VA Greater Angeles Healthcare Syst, Sepulveda, CA 91343 USA. [Liu, Honghu H.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Hamilton, AB (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza,38-240 NPI,Box 175919, Los Angeles, CA 90024 USA. EM alisonh@ucla.edu FU National Institutes of Mental Health [NIMH R01 MH093230] FX Funding provided by National Institutes of Mental Health (NIMH R01 MH093230). We wish to acknowledge the generous participation of the community-based organizations. We also wish to thank Ms. Louise Datu and Ms. Elizabeth Aguilar for their administrative support. NR 76 TC 1 Z9 1 U1 4 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUN 20 PY 2014 VL 9 AR 79 DI 10.1186/1748-5908-9-79 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AK8MJ UT WOS:000338681600001 PM 24950708 ER PT J AU Altintas, MM Moriwaki, K Wei, CL Moller, CC Flesche, J Li, J Yaddanapudi, S Faridi, MH Godel, M Huber, TB Preston, RA Jiang, JX Kerjaschki, D Sever, S Reiser, J AF Altintas, Mehmet M. Moriwaki, Kumiko Wei, Changli Moeller, Clemens C. Flesche, Jan Li, Jing Yaddanapudi, Suma Faridi, Mohd Hafeez Goedel, Markus Huber, Tobias B. Preston, Richard A. Jiang, Jean X. Kerjaschki, Dontscho Sever, Sanja Reiser, Jochen TI Reduction of Proteinuria through Podocyte Alkalinization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METABOLIC FLUX ANALYSIS; HUMAN CARBOHYDRATE-METABOLISM; AMINO-ACID-TRANSPORT; NEPHROTIC-SYNDROME; INTRACELLULAR PH; CELL-METABOLISM; KIDNEY-DISEASE; SLIT DIAPHRAGM; GENE FAMILY; CATHEPSIN-L AB Podocytes are highly differentiated cells and critical elements for the filtration barrier of the kidney. Loss of their foot process (FP) architecture (FP effacement) results in urinary protein loss. Here we show a novel role for the neutral amino acid glutamine in structural and functional regulation of the kidney filtration barrier. Metabolic flux analysis of cultured podocytes using genetic, toxic, and immunologic injury models identified increased glutamine utilization pathways. We show that glutamine uptake is increased in diseased podocytes to couple nutrient support to increased demand during the disease state of FP effacement. This feature can be utilized to transport increased amounts of glutamine into damaged podocytes. The availability of glutamine determines the regulation of podocyte intracellular pH (pH(i)). Podocyte alkalinization reduces cytosolic cathepsin L protease activity and protects the podocyte cytoskeleton. Podocyte glutamine supplementation reduces proteinuria in LPS-treated mice, whereas acidification increases glomerular injury. In summary, our data provide a metabolic opportunity to combat urinary protein loss through modulation of podocyte amino acid utilization and pH(i). C1 [Faridi, Mohd Hafeez] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60035 USA. [Moriwaki, Kumiko] Univ Miami, Miller Sch Med, Div Nephrol & Hypertens, Dept Med, Miami, FL 33136 USA. [Moeller, Clemens C.; Flesche, Jan; Yaddanapudi, Suma; Sever, Sanja] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02129 USA. [Moeller, Clemens C.; Flesche, Jan; Yaddanapudi, Suma; Sever, Sanja] Massachusetts Gen Hosp, Program Glomerular Dis, Boston, MA 02129 USA. [Moeller, Clemens C.; Flesche, Jan; Yaddanapudi, Suma; Sever, Sanja] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Goedel, Markus; Huber, Tobias B.] Univ Hosp Freiburg, Div Renal, D-79106 Freiburg, Germany. [Huber, Tobias B.] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79106 Freiburg, Germany. [Preston, Richard A.] Univ Miami, Miller Sch Med, Dept Med, Div Clin Pharmacol, Miami, FL 33136 USA. [Jiang, Jean X.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Kerjaschki, Dontscho] Med Univ Vienna, Clin Inst Pathol, A-1090 Vienna, Austria. RP Reiser, J (reprint author), Rush Univ, Med Ctr, Dept Med, 1735 W Harrison St,Cohn Res Bldg,Ste 724, Chicago, IL 60612 USA. EM jochen_reiser@rush.edu OI Altintas, Mehmet/0000-0002-1871-6985 FU National Institutes of Health [DK073495]; Ajinomoto Amino Acid Research Program; Welch Foundation [AQ-1507] FX This work was supported, in whole or in part, by National Institutes of Health Grant DK073495 (to J. R.). This work was also supported by funds from the Ajinomoto Amino Acid Research Program (to J. R.) and Welch Foundation Grant AQ-1507 (to J. X. J.). D. Reiser is an inventor of issued and pending patents related to proteinuric kidney disease diagnostic and treatment, and he stands to gain royalties from future commercializations. NR 64 TC 3 Z9 3 U1 0 U2 1 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 20 PY 2014 VL 289 IS 25 BP 17454 EP 17467 DI 10.1074/jbc.M114.568998 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9HE UT WOS:000338018100014 PM 24817115 ER PT J AU Weathington, NM Snavely, CA Chen, BB Zhao, J Zhao, YT Mallampalli, RK AF Weathington, Nathaniel M. Snavely, Courtney A. Chen, Bill B. Zhao, Jing Zhao, Yutong Mallampalli, Rama K. TI Glycogen Synthase Kinase-3 beta Stabilizes the Interleukin (IL)-22 Receptor from Proteasomal Degradation in Murine Lung Epithelia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INNATE LYMPHOID-CELLS; MUCOSAL HOST-DEFENSE; ACTIN POLYMERIZATION; TH17 CELLS; PROTEIN; IL-22; UBIQUITINATION; INFLAMMATION; CORTACTIN; PHOSPHORYLATES AB Signaling through the interleukin (IL)-22 cytokine axis provides essential immune protection in the setting of extracellular infection as part of type 17 immunity. Molecular regulation of IL-22 receptor (IL-22R) protein levels is unknown. In murine lung epithelia, IL-22R is a relatively short-lived protein (t(1/2) similar to 1.5 h) degraded by the ubiquitin proteasome under normal unstimulated conditions, but its degradation is accelerated by IL-22 treatment. Lys(449) within the intracellular C-terminal domain of the IL-22R serves as a ubiquitin acceptor site as disruption of this site by deletion or site-directed mutagenesis creates an IL-22R variant that, when expressed in cells, is degradation-resistant and not ubiquitinated. Glycogen synthase kinase (GSK)-3 beta phosphorylates the IL-22R within a consensus phosphorylation signature at Ser(410) and Ser(414), and IL-22 treatment of cells triggers GSK-3 beta inactivation. GSK-3 beta overexpression results in accumulation of IL-22R protein, whereas GSK-3 beta depletion in cells reduces levels of the receptor. Mutagenesis of IL-22R at Ser(410) and Ser(414) results in receptor variants that display reduced phosphorylation levels and are more labile as compared with wild-type IL-22R when expressed in cells. Further, the cytoskeletal protein cortactin, which is important for epithelial spreading and barrier formation, is phosphorylated and activated at the epithelial cell leading edge after treatment with IL-22, but this effect is reduced after GSK-3 beta knockdown. These findings reveal the ability of GSK-3 beta to modulate IL-22R protein stability that might have significant implications for cyto-protective functions and therapeutic targeting of the IL-22 signaling axis. C1 [Weathington, Nathaniel M.; Snavely, Courtney A.; Chen, Bill B.; Zhao, Jing; Zhao, Yutong; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Zhao, Yutong; Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, UPMC Montefiore, Dept Med, Div Pulm Allergy & Crit Care Med, NW 628, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; United States Department of Veterans Affairs; National Institutes of Health R01 [HL096376, HL097376, HL098174, HL081784, UH2 HL123502, P01 HL114453, HL116472, HL01916]; American Heart Association [12SDG9050005] FX This work was supported in part by the United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, and a Merit Review Award from the United States Department of Veterans Affairs (to R. K. M. and N.M.W.). This work was also supported, in part, by National Institutes of Health R01 Grants HL096376, HL097376, HL098174, HL081784, UH2 HL123502, and P01 HL114453 (to R. K. M.), HL116472 (to B. B. C.), and HL01916 (to Y.Z.), and an American Heart Association Award 12SDG9050005 (to J.Z.). NR 31 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 20 PY 2014 VL 289 IS 25 BP 17610 EP 17619 DI 10.1074/jbc.M114.551747 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9HE UT WOS:000338018100026 PM 24742671 ER PT J AU Zou, MR Cao, J Liu, ZZ Huh, SJ Polyak, K Yan, Q AF Zou, Mike Ran Cao, Jian Liu, Zongzhi Huh, Sung Jin Polyak, Kornelia Yan, Qin TI Histone Demethylase Jumonji AT-rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; REPRESSOR PLU-1/JARID1B; DUCTAL MORPHOGENESIS; H3K4 METHYLATION; SELF-RENEWAL; BINDING; FOXA1; TRANSCRIPTION; DIFFERENTIATION; PROLIFERATION AB The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b(-/-) mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b(-/-) strains, the majority of these Jarid1b(-/-) mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b(-/-) mice exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor alpha. Mechanistically, JARID1B was required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms. C1 [Zou, Mike Ran; Cao, Jian; Liu, Zongzhi; Yan, Qin] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Huh, Sung Jin; Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Huh, Sung Jin; Polyak, Kornelia] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Yan, Q (reprint author), Yale Univ, Sch Med, Dept Pathol, 310 Cedar St,BML 348C,POB 208023, New Haven, CT 06520 USA. EM qin.yan@yale.edu RI Cao, Jian/K-2440-2014; Yan, Qin/E-8893-2012 OI Yan, Qin/0000-0003-4077-453X FU Alexander and Margaret Stewart Trust fellowship; Breast Cancer Alliance young investigator grant; Melanoma Research Foundation career development award; United States Department of Defense Peer-reviewed Cancer Research Program Career Development Award [W81XWH-13-1-0235]; American Cancer Society Research Scholar Grant [RSG-13-384-01-DMC]; National Institutes of Health from the NCI [R01 CA076120, P01 CA080111]; NCI fellowship [F32 CA156991] FX This work was supported by an Alexander and Margaret Stewart Trust fellowship (to Q. Y.), a Breast Cancer Alliance young investigator grant (to Q. Y.), a Melanoma Research Foundation career development award (to Q. Y.), United States Department of Defense Peer-reviewed Cancer Research Program Career Development Award W81XWH-13-1-0235 (to Q. Y.), and American Cancer Society Research Scholar Grant RSG-13-384-01-DMC (to Q. Y.). This work was also supported in part by National Institutes of Health Grants R01 CA076120 (to W. G. K.) and P01 CA080111 (to K. P.) from the NCI and F32 CA156991, an NCI fellowship (to S. J. H.). NR 49 TC 10 Z9 10 U1 0 U2 5 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 20 PY 2014 VL 289 IS 25 BP 17620 EP 17633 DI 10.1074/jbc.M114.570853 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9HE UT WOS:000338018100027 PM 24802759 ER PT J AU Choueiri, TK Jacobus, S Bellmunt, J Qu, A Appleman, LJ Tretter, C Bubley, GJ Stack, EC Signoretti, S Walsh, M Steele, G Hirsch, M Sweeney, CJ Taplin, ME Kibel, AS Krajewski, KM Kantoff, PW Ross, RW Rosenberg, JE AF Choueiri, Toni K. Jacobus, Susanna Bellmunt, Joaquim Qu, Angela Appleman, Leonard J. Tretter, Christopher Bubley, Glenn J. Stack, Edward C. Signoretti, Sabina Walsh, Meghara Steele, Graeme Hirsch, Michelle Sweeney, Christopher J. Taplin, Mary-Ellen Kibel, Adam S. Krajewski, Katherine M. Kantoff, Philip W. Ross, Robert W. Rosenberg, Jonathan E. TI Neoadjuvant Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With Pegfilgrastim Support in Muscle-Invasive Urothelial Cancer: Pathologic, Radiologic, and Biomarker Correlates SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADVANCED BLADDER-CANCER; CELL LUNG-CANCER; PHASE-III TRIAL; DNA-REPAIR; CHEMOTHERAPY; CARCINOMA; ERCC1; EXPRESSION; MARKERS AB Purpose In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC). Patients and Methods Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to <= pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Results Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of <= pT1N0M0, and we concluded this regimen was effective. High-grade (grade >= 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival. Conclusion In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging. (C) 2014 by American Society of Clinical Oncology. C1 [Choueiri, Toni K.; Jacobus, Susanna; Bellmunt, Joaquim; Qu, Angela; Stack, Edward C.; Signoretti, Sabina; Walsh, Meghara; Steele, Graeme; Hirsch, Michelle; Sweeney, Christopher J.; Taplin, Mary-Ellen; Kibel, Adam S.; Krajewski, Katherine M.; Kantoff, Philip W.; Ross, Robert W.; Rosenberg, Jonathan E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, Toni K.; Jacobus, Susanna; Bellmunt, Joaquim; Qu, Angela; Stack, Edward C.; Signoretti, Sabina; Walsh, Meghara; Steele, Graeme; Hirsch, Michelle; Sweeney, Christopher J.; Taplin, Mary-Ellen; Kibel, Adam S.; Krajewski, Katherine M.; Kantoff, Philip W.; Ross, Robert W.; Rosenberg, Jonathan E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Tretter, Christopher] Lahey Clin Fdn, Burlington, MA USA. [Bubley, Glenn J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Appleman, Leonard J.] Univ Pittsburgh, Pittsburgh, PA USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM toni_choueiri@dfci.harvard.edu RI Mendez, Pedro /J-8955-2016; OI Mendez, Pedro /0000-0001-6713-7907; Appleman, Leonard/0000-0003-4951-7388; Rosenberg, Jonathan/0000-0003-2637-4249 FU Dana-Farber Cancer Institute as an investigator-initiated study FX Supported by the Dana-Farber Cancer Institute as an investigator-initiated study (principal investigator, T. K. C.) and in part by Amgen. NR 21 TC 47 Z9 47 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 BP 1889 EP 1894 DI 10.1200/JCO.2013.52.4785 PG 6 WC Oncology SC Oncology GA AJ7TT UT WOS:000337901200007 PM 24821883 ER PT J AU O'Connell, MJ Colangelo, LH Beart, RW Petrelli, NJ Allegra, CJ Sharif, S Pitot, HC Shields, AF Landry, JC Ryan, DP Parda, DS Mohiuddin, M Arora, A Evans, LS Bahary, N Soori, GS Eakle, J Robertson, JM Moore, DF Mullane, MR Marchello, BT Ward, PJ Wozniak, TF Roh, MS Yothers, G Wolmark, N AF O'Connell, Michael J. Colangelo, Linda H. Beart, Robert W. Petrelli, Nicholas J. Allegra, Carmen J. Sharif, Saima Pitot, Henry C. Shields, Anthony F. Landry, Jerome C. Ryan, David P. Parda, David S. Mohiuddin, Mohammed Arora, Amit Evans, Lisa S. Bahary, Nathan Soori, Gamini S. Eakle, Janice Robertson, John M. Moore, Dennis F., Jr. Mullane, Michael R. Marchello, Benjamin T. Ward, Patrick J. Wozniak, Timothy F. Roh, Mark S. Yothers, Greg Wolmark, Norman TI Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Rectal Cancer: Surgical End Points From National Surgical Adjuvant Breast and Bowel Project Trial R-04 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; METASTATIC COLORECTAL-CANCER; RANDOMIZED-TRIAL; ORAL CAPECITABINE; POOLED ANALYSIS; COLON-CANCER; FLUOROURACIL; LEUCOVORIN; CHEMORADIOTHERAPY; 5-FLUOROURACIL AB The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT. Patients and Methods Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery). Results From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001). Conclusion Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred. (C) 2014 by American Society of Clinical Oncology C1 [O'Connell, Michael J.; Colangelo, Linda H.; Beart, Robert W.; Petrelli, Nicholas J.; Allegra, Carmen J.; Sharif, Saima; Pitot, Henry C.; Shields, Anthony F.; Ryan, David P.; Mohiuddin, Mohammed; Arora, Amit; Evans, Lisa S.; Bahary, Nathan; Soori, Gamini S.; Eakle, Janice; Robertson, John M.; Moore, Dennis F., Jr.; Mullane, Michael R.; Marchello, Benjamin T.; Ward, Patrick J.; Wozniak, Timothy F.; Roh, Mark S.; Yothers, Greg; Wolmark, Norman] Natl Surg Adjuvant Breast & Bowel Project Operat, Pittsburgh, PA 15212 USA. [Parda, David S.; Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Bahary, Nathan] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Bahary, Nathan] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Beart, Robert W.] Glendale Mem Hosp, Colorectal Surg Inst, Glendale, CA USA. [Arora, Amit] Kaiser Permanente Hayward, Hayward, CA USA. [Petrelli, Nicholas J.; Wozniak, Timothy F.] Christiana Care Hlth Syst, Helen F Graham Canc Ctr, Newark, DE USA. [Allegra, Carmen J.] Univ Florida, Gainesville, FL USA. [Eakle, Janice] Florida Canc Specialists, Sarasota, FL USA. [Roh, Mark S.] Orlando Hlth, MD Anderson Canc Ctr, Orlando, FL USA. [Pitot, Henry C.] Mayo Clin, Rochester, MN USA. [Shields, Anthony F.] Karmanos Canc Inst, SW Oncol Grp, Detroit, MI USA. [Robertson, John M.] Beaumont Hosp Syst, Royal Oak, MI USA. [Landry, Jerome C.] Emory Univ, Winship Canc Inst, Eastern Cooperat Oncol Grp, Atlanta, GA 30322 USA. [Ryan, David P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Evans, Lisa S.] Southeast CCC Novant Hlth Derrick L Davis Forsyth, Community Clin Oncol Program, Winston Salem, NC USA. [Soori, Gamini S.] Missouri Valley Canc Consortium, Community Clin Oncol Program, Omaha, NE USA. [Moore, Dennis F., Jr.] Via Christi Reg Med Ctr, Wichita St Francis Reg Med Ctr, Community Clin Oncol Program, Wichita, KS USA. [Mullane, Michael R.] John H Stroger Jr Hosp Cook Cty, Minor Based Community Clin Oncol Program, Chicago, IL USA. [Marchello, Benjamin T.] Montana Canc Consortium, Billings, MT USA. [Ward, Patrick J.] Oncol Hematol Care, Cincinnati, OH USA. [Mohiuddin, Mohammed] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. RP O'Connell, MJ (reprint author), Natl Surg Adjuvant Breast & Bowel Project NSABP, 2 Allegheny Ctr,12th Floor, Pittsburgh, PA 15212 USA. EM michael.oconnell@nsabp.org OI Yothers, Greg/0000-0002-7965-7333 FU Public Health Service from the National Cancer Institute, US Department of Health and Human Services [U10-CA-12027, U10-CA-37377, U10-CA-69651, U-10-CA-69974]; National Institutes of Health [CA22453]; Southwest Oncology Group Treatment from the National Institutes of Health [CA032102]; Sanofi-Synthelabo and Roche Laboratories FX Supported by Public Health Service Grants No. U10-CA-12027, U10-CA-37377, U10-CA-69651, and U-10-CA-69974 from the National Cancer Institute, US Department of Health and Human Services; Cancer Support Grant No. CA22453 from the National Institutes of Health (A.F.S.); Southwest Oncology Group Treatment Grant No. CA032102 from the National Institutes of Health (A.F.S.); and Sanofi-Synthelabo and Roche Laboratories. NR 28 TC 84 Z9 86 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 BP 1927 EP 1934 DI 10.1200/JCO.2013.53.7753 PG 8 WC Oncology SC Oncology GA AJ7TT UT WOS:000337901200012 PM 24799484 ER PT J AU Kuppusamy, H Ogmundsdottir, HM Baigorri, E Warkentin, A Steingrimsdottir, H Haraldsdottir, V Mant, MJ Mackey, J Johnston, JB Adamia, S Belch, AR Pilarski, LM AF Kuppusamy, Hemalatha Ogmundsdottir, Helga M. Baigorri, Eva Warkentin, Amanda Steingrimsdottir, Hlif Haraldsdottir, Vilhelmina Mant, Michael J. Mackey, John Johnston, James B. Adamia, Sophia Belch, Andrew R. Pilarski, Linda M. TI Inherited Polymorphisms in Hyaluronan Synthase 1 Predict Risk of Systemic B-Cell Malignancies but Not of Breast Cancer SO PLOS ONE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENOME-WIDE ASSOCIATION; MULTIPLE-MYELOMA; WALDENSTROMS MACROGLOBULINEMIA; GENE; DISEASE; RECEPTOR; HAS1; EXPRESSION; VARIANTS AB Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10(-5)), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78), but not for sporadic MGUS or for breast cancer (OR, 1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors. C1 [Kuppusamy, Hemalatha; Baigorri, Eva; Warkentin, Amanda; Mant, Michael J.; Mackey, John; Belch, Andrew R.; Pilarski, Linda M.] Univ Alberta, Edmonton, AB, Canada. [Kuppusamy, Hemalatha; Baigorri, Eva; Warkentin, Amanda; Mant, Michael J.; Mackey, John; Belch, Andrew R.; Pilarski, Linda M.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Ogmundsdottir, Helga M.] Univ Iceland, Reykjavik, Iceland. [Steingrimsdottir, Hlif; Haraldsdottir, Vilhelmina] Landspitali Univ Hosp, Reykjavik, Iceland. [Johnston, James B.] Canc Care Manitoba, Dept Hematol, Winnipeg, MB, Canada. [Johnston, James B.] Univ Manitoba, Winnipeg, MB, Canada. [Adamia, Sophia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Pilarski, LM (reprint author), Univ Alberta, Edmonton, AB, Canada. EM lpilarsk@ualberta.ca RI Ogmundsdottir, Helga /L-6970-2015 FU Myeloma Alberta; Alberta Cancer Foundation; Canadian Institutes of Health Research FX This work was funded by grants to LMP and ARB from Myeloma Alberta, the Alberta Cancer Foundation and the Canadian Institutes of Health Research (www.cihr-irsc.gc.ca). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 1 Z9 1 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 20 PY 2014 VL 9 IS 6 AR e100691 DI 10.1371/journal.pone.0100691 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2UZ UT WOS:000338276300109 PM 24950197 ER PT J AU Thorndike, AN Mills, S Sonnenberg, L Palakshappa, D Gao, T Pau, CT Regan, S AF Thorndike, Anne N. Mills, Sarah Sonnenberg, Lillian Palakshappa, Deepak Gao, Tian Pau, Cindy T. Regan, Susan TI Activity Monitor Intervention to Promote Physical Activity of Physicians-In-Training: Randomized Controlled Trial SO PLOS ONE LA English DT Article ID INTERNAL-MEDICINE RESIDENTS; COUNSELING PRACTICES; PATIENT-CARE; HEALTH BEHAVIORS; BURNOUT; WELLNESS; PROGRAM; QUALITY; RISK; LIFE AB Background: Physicians are expected to serve as role models for healthy lifestyles, but long work hours reduce time for healthy behaviors. A hospital-based physical activity intervention could improve physician health and increase counseling about exercise. Methods: We conducted a two-phase intervention among 104 medical residents at a large hospital in Boston, Massachusetts. Phase 1 was a 6-week randomized controlled trial comparing daily steps of residents assigned to an activity monitor displaying feedback about steps and energy consumed (intervention) or to a blinded monitor (control). Phase 2 immediately followed and was a 6-week non-randomized team steps competition in which all participants wore monitors with feedback. Phase 1 outcomes were: 1) median steps/day and 2) proportion of days activity monitor worn. The Phase 2 outcome was mean steps/day on days monitor worn ($500 steps/day). Physiologic measurements were collected at baseline and study end. Median steps/day were compared using Wilcoxon rank-sum tests. Mean steps were compared using repeated measures regression analyses. Results: In Phase 1, intervention and control groups had similar activity (6369 vs. 6063 steps/day, p = 0.16) and compliance with wearing the monitor (77% vs. 77% of days, p = 0.73). In Phase 2 (team competition), residents recorded more steps/day than during Phase 1 (Control: 7,971 vs. 7,567, p = 0.002; Intervention: 7,832 vs. 7,739, p = 0.13). Mean compliance with wearing the activity monitor decreased for both groups during Phase 2 compared to Phase 1 (60% vs. 77%, p<0.001). Mean systolic blood pressure decreased (p = 0.004) and HDL cholesterol increased (p<0.001) among all participants at end of study compared to baseline. Conclusions: Although the activity monitor intervention did not have a major impact on activity or health, the high participation rates of busy residents and modest changes in steps, blood pressure, and HDL suggest that more intensive hospital-based wellness programs have potential for promoting healthier lifestyles among physicians. C1 [Thorndike, Anne N.; Mills, Sarah; Palakshappa, Deepak; Gao, Tian; Pau, Cindy T.; Regan, Susan] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sonnenberg, Lillian] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Thorndike, AN (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM athorndike@partners.org OI Regan, Susan/0000-0003-0940-2017 FU National Institutes of Health/National Heart Lung and Blood Institute [K23 HL93221] FX Dr. Thorndike is supported by the grant K23 HL93221 from the National Institutes of Health/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. NR 46 TC 7 Z9 7 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 20 PY 2014 VL 9 IS 6 AR e100251 DI 10.1371/journal.pone.0100251 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2UZ UT WOS:000338276300054 PM 24950218 ER PT J AU Nahrendorf, M Swirski, FK AF Nahrendorf, Matthias Swirski, Filip K. TI Regulating Repair Regulatory T Cells in Myocardial Infarction SO CIRCULATION RESEARCH LA English DT Editorial Material DE Editorials; lymphocytes; macrophages; monocytes; myocardial infarction; wound healing ID INFLAMMATION; MONOCYTES; HEART; DIFFERENTIATION; ATHEROSCLEROSIS; SURVIVAL; NR4A1; MICE C1 [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02163 USA. RP Nahrendorf, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02163 USA. EM mnahrendorf@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL114477, R01HL114477, R01 HL095629, R01 HL095612, R01HL095612, R01HL095629]; NIAID NIH HHS [R56 AI104695, R56AI104695] NR 19 TC 3 Z9 3 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 20 PY 2014 VL 115 IS 1 BP 7 EP 9 DI 10.1161/CIRCRESAHA.114.304295 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AJ5PY UT WOS:000337738900005 PM 24951758 ER PT J AU Patel, AP Tirosh, I Trombetta, JJ Shalek, AK Gillespie, SM Wakimoto, H Cahill, DP Nahed, BV Curry, WT Martuza, RL Louis, DN Rozenblatt-Rosen, O Suva, ML Regev, A Bernstein, BE AF Patel, Anoop P. Tirosh, Itay Trombetta, John J. Shalek, Alex K. Gillespie, Shawn M. Wakimoto, Hiroaki Cahill, Daniel P. Nahed, Brian V. Curry, William T. Martuza, Robert L. Louis, David N. Rozenblatt-Rosen, Orit Suva, Mario L. Regev, Aviv Bernstein, Bradley E. TI Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma SO SCIENCE LA English DT Article ID STEM-LIKE CELLS; INTEGRATED GENOMIC ANALYSIS; TUMOR HETEROGENEITY; GROWTH; EXPRESSION; EVOLUTION; RECEPTOR; GENOTYPE; REVEALS; CANCER AB Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy. C1 [Patel, Anoop P.; Wakimoto, Hiroaki; Cahill, Daniel P.; Nahed, Brian V.; Curry, William T.; Martuza, Robert L.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Patel, Anoop P.; Gillespie, Shawn M.; Wakimoto, Hiroaki; Cahill, Daniel P.; Nahed, Brian V.; Curry, William T.; Martuza, Robert L.; Louis, David N.; Suva, Mario L.; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Patel, Anoop P.; Gillespie, Shawn M.; Louis, David N.; Suva, Mario L.; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Patel, Anoop P.; Tirosh, Itay; Trombetta, John J.; Shalek, Alex K.; Gillespie, Shawn M.; Rozenblatt-Rosen, Orit; Suva, Mario L.; Regev, Aviv; Bernstein, Bradley E.] Broad Inst Harvard & Massachusetts Inst Techonol, Cambridge, MA 02142 USA. [Patel, Anoop P.; Gillespie, Shawn M.; Regev, Aviv; Bernstein, Bradley E.] Howard Hughes Med Inst Chevy Chase, Chevy Chase, MD 20815 USA. [Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Suva, ML (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM suva.mario@mgh.harvard.edu; aregev@broadinstitute.org; bernstein.bradley@mgh.harvard.edu OI Shalek, Alex K./0000-0001-5670-8778; Cahill, Daniel/0000-0003-2552-6546 FU NIH- National Institute of Neurological Disorders and Stroke [R25NS065743]; Human Frontier Science Program fellowship; Rothschild fellowship; Medic Foundation; Howard Hughes Medical Institute; Burroughs Wellcome Fund; Harvard Stem Cell Institute; NIH [R01 NS032677, U24 CA180922]; National Brain Tumor Society; Klarman Family Foundation FX We thank E. Shefler for project management, E. Rheinbay for graphical contributions, J. Kim and P. Santos for histology, and P. Bautista and Y. Yagi for slide scanning. A. P. P was supported by NIH- National Institute of Neurological Disorders and Stroke R25NS065743. I. T. was supported by a Human Frontier Science Program fellowship and a Rothschild fellowship. M. L. S was supported by a grant from Medic Foundation. This research was supported by funds from Howard Hughes Medical Institute, Burroughs Wellcome Fund, Harvard Stem Cell Institute, NIH (R01 NS032677 to R. L. M. and U24 CA180922 to A. R.), National Brain Tumor Society, and Klarman Family Foundation. A. R. is a scientific advisory board member for Syros Pharmaceuticals and a consultant for Cancer Therapeutics Innovation Group. B. E. B. is a scientific advisory board member for Syros Pharmaceuticals and a founder and scientific advisor for HiFiBio SAS. RNA-seq data are deposited in Gene Expression Omnibus with accession no. GSE57872. NR 42 TC 393 Z9 397 U1 25 U2 143 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 20 PY 2014 VL 344 IS 6190 BP 1396 EP 1401 DI 10.1126/science.1254257 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ2YQ UT WOS:000337531700040 PM 24925914 ER PT J AU Byrd, JC Brown, JR O'Brien, SM Barrientos, JC Kay, NE Reddy, NM Coutre, SE Tam, C Mulligan, SP Jager, U Devereux, S Barr, PM Furman, RR Kipps, TJ Cymbalista, F Fardis, M McGreivy, JS Clow, F James, DF Hillmen, P AF Byrd, John C. Brown, Jennifer R. O'Brien, Susan Mary Barrientos, Jacqueline Claudia Kay, Neil E. Reddy, Nishitha M. Coutre, Steven E. Tam, Constantine Mulligan, Stephen P. Jaeger, Ulrich Devereux, Steve Barr, Paul M. Furman, Richard R. Kipps, Thomas J. Cymbalista, Florence Fardis, Maria McGreivy, Jesse S. Clow, Fong James, Danelle Frances Hillmen, Peter TI Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Ohio State Univ, Columbus, OH 43210 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Hofstra North Shore LIJ Sch Med, Hempstead, NY USA. Mayo Clin, Rochester, MN USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Stanford Univ, Sch Med, Stanford Canc Ctr, Stanford, CA 94305 USA. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. St Vincents Hosp, Melbourne, Vic, Australia. Royal N Shore Hosp, Sydney, NSW, Australia. Med Univ Vienna, Vienna, Austria. NHS Fdn Trust Denmark Hill, Coll Hosp, London, England. Univ Rochester, Ctr Canc, Rochester, NY USA. Presbyterian Hosp, Cornell Med Ctr, New York, NY USA. Hop Avicenne, Paris, France. Pharmacyclics Inc, Sunnyvale, CA USA. Pharmacyclics, Sunnyvale, CA USA. Pharmacyclics Inc, Sunnyvale, CA USA. Leeds Teaching Hosp, St James Inst Oncol, Leeds, W Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA7008 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900011 ER PT J AU Cmelak, A Li, S Marur, S Zhao, WQ Westra, WH Chung, CH Gillison, ML Gilbert, J Bauman, JE Wagner, LI Ferris, RL Trevarthen, DR Colevas, AD Jahagirdar, BN Burtriess, B AF Cmelak, Anthony Li, Shull Marur, Shanthi Zhao, Weiqiang Westra, William H. Chung, Christine H. Gillison, Maura L. Gilbert, Jill Bauman, Julie E. Wagner, Lynne I. Ferris, Robert L. Trevarthen, David R. Colevas, A. Dimitrios Jahagirdar, Balkrishna N. Burtriess, Barbara TI E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Ohio State Univ, Columbus, OH 43210 USA. Ohio State Univ, James Canc Hosp, Columbus, OH 43210 USA. Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. Vanderbilt Univ, Nashville, TN 37235 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Colorado Canc Res Program, Denver, CO USA. Stanford Univ, Stanford, CA 94305 USA. HealthPartners & Reg Canc Care Ctr, St Paul, MN USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA6006 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900009 ER PT J AU Liu, J Barry, WT Birrer, MJ Lee, JM Buckanovich, RJ Fleming, GF Rime, B Buss, MK Natiam, SR Hurteau, J Luo, WX Quy, P Obermayer, E Whalen, C Lee, H Winer, EP Kohn, EC Ivy, SP Matulonis, U AF Liu, Joyce Barry, William Thomas Birrer, Michael J. Lee, Jung-Min Buckanovich, Ronald J. Fleming, Gini F. Rime, Bj Buss, Mary K. Natiam, Sreenivasa R. Hurteau, Jean Luo, Weixiu Quy, Philippa Obermayer, Elizabeth Whalen, Christin Lee, Hang Winer, Eric P. Kohn, Elise C. Ivy, S. Percy Matulonis, Ursula TI A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Ft Wayne Med Oncol & Hematol, Ft Wayne, IN USA. Univ Chicago, Northshore Univ Hlth Syst, Evanston, IL USA. Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA5500 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900008 ER PT J AU Moore, HCF Unger, JM Phillips, KA Boyle, FM Hitre, E Porter, DJ Francis, PA Minasian, LM Gelber, RD Goldstein, LJ Gomez, HL Vallejos, C Partridge, AH Dakhil, SR Martino, S Barlow, WE Fabian, CJ Meyskens, FL Hortobagyi, GN Albain, KS AF Moore, Halle C. F. Unger, Joseph M. Phillips, Kelly-Anne Boyle, Frances M. Hitre, Erika Porter, David James Francis, Prudence A. Minasian, Lori M. Gelber, Richard D. Goldstein, Lori J. Gomez, Henry Leonidas Vallejos, Carlos Partridge, Ann H. Dakhil, Shaker R. Martino, Silvana Barlow, William E. Fabian, Carol J. Meyskens, Frank L. Hortobagyi, Gabriel N. Albain, Kathy S. TI Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Cleveland Clin, Cleveland, OH 44106 USA. SWOG Stat Ctr, Seattle, WA USA. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. Mater Hosp, Sydney, NSW, Australia. Natl Inst Oncol, Budapest, Hungary. Auckland City Hosp, Dept Oncol, Auckland, New Zealand. Peter MacCallum Canc Ctr, East Melbourne, Australia. NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Inst Nacl Enfermedades Neoplas, Lima, Peru. ONCOSALUD, Lima, Peru. Dana Farber Canc Inst, Boston, MA 02115 USA. Wichita Community Clin Oncol Program, Wichita, KS USA. Angeles Clin & Res Inst, Santa Monica, CA USA. Canc Res & Biostat, Seattle, WA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Chao Family Comprehens Canc Ctr, Orange, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA505 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900006 ER PT J AU Pagani, O Regan, MM Walley, B Fleming, GF Colleoni, M Lang, I Gomez, HL Tondini, C Burstein, HJ Perez, EA Ciruelos, E Stearns, V Bonnefoi, HR Martino, S Geyer, CE Rabaglio-Poretti, M Coates, AS Gelber, RD Goldhirsch, A Francis, PA AF Pagani, Olivia Regan, Meredith M. Walley, Barbara Fleming, Gini F. Colleoni, Marco Lang, Istvan Gomez, Henry Leonidas Tondini, Carlo Burstein, Harold J. Perez, Edith A. Ciruelos, Eva Stearns, Vered Bonnefoi, Herve R. Martino, Silvana Geyer, Charles E. Rabaglio-Poretti, Manuela Coates, Alan S. Gelber, Richard D. Goldhirsch, Aron Francis, Prudence A. CA SOFT TEXT Investigators Int Breast Canc Study Grp TI Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR plus ) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 SAKK, Inst Oncol Southern Switzerland, Lugano Viganello, Switzerland. IBCSG, Lugano Viganello, Switzerland. Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. NCIC Clin Trials Grp, Kingston, ON, Canada. Univ Chicago, Med Ctr & Alliance, Chicago, IL 60637 USA. European Inst Oncol, Milan, Italy. IBCSG, Milan, Italy. Natl Inst Oncol, Budapest, Hungary. Inst Natl Enfermedades Neoplas, Lima, Peru. IBCSG, Lima, Peru. Osp Papa Giovanni XXIII, Bergamo, Italy. Dana Farber Canc Inst & Alliance, Boston, MA USA. Mayo Clin & Alliance, Jacksonville, FL USA. Univ Hosp 12 Octubre, Madrid, Spain. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. ECOG, Baltimore, MD USA. Bergonie Inst, Bordeaux, France. EORTC, Bordeaux, France. Angeles Clin & Res Inst, Santa Monica, CA USA. SWOG, Santa Monica, CA USA. Virginia Commonwealth Univ, Massey Canc Ctr, Sch Med, Richmond, VA USA. NRG Oncol, Richmond, VA USA. Inst Med Oncol, Bern, Switzerland. Int Breast Canc Study Grp, Bern, Switzerland. ANZBCTG, Peter MacCallurn Canc Ctr, Melbourne, Vic, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA1 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900002 ER PT J AU Piccart-Gebhart, MJ Holmes, AP Baselga, J De Azambuja, E Dueck, AC Viale, G Zujewski, JA Goldhirsch, A Santillana, S Pritchard, KI Wolff, AC Jackisch, C Lang, I Untch, M Smith, LE Boyle, F Xu, BH Gomez, HL Gelber, RD Perez, EA AF Piccart-Gebhart, Martine J. Holmes, Andrew Peter Baselga, Jose De Azambuja, Evandro Dueck, Amylou C. Viale, Giuseppe Zujewski, Jo Anne Goldhirsch, Aron Santillana, Sergio Pritchard, Kathleen I. Wolff, Antonio C. Jackisch, Christian Lang, Istvan Untch, Michael Smith, Lan E. Boyle, Frances Xu, Binghe Gomez, Henry Leonidas Gelber, Richard D. Perez, Edith A. TI First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T -> L), or their combination (T plus L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Inst Jules Bordet, Breast Int Grp, B-1000 Brussels, Belgium. Frontier Sci Scotland Ltd, Kincraig, England. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Libre Bruxelles, Inst Jules Bordet, Brussels, Belgium. Mayo Clin, Scottsdale, AZ USA. European Inst Oncol, Div Pathol, Milan, Italy. NCI, Bethesda, MD 20892 USA. European Inst Oncol, Div Med Oncol, Milan, Italy. GlaxoSmithKline, Malvern, PA USA. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Univ Toronto, Toronto, ON, Canada. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. Sana Kliniken Offenbach, Offenbach, Germany. Orszagos Onkol Int, Budapest, Hungary. Helios Klinikum Berlin Buch, Berlin, Germany. Royal Marsden NHS Fdn Trust, London, England. Univ Sydney, Patricia Ritchie Ctr Canc Care & Res, Mater Hosp, Sydney, NSW 2006, Australia. Chinese Acad Med Sci, Canc Hosp, Beijing 100730, Peoples R China. Inst Natl Enfermedades Neoplas, Lima, Peru. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Mayo Clin, Jacksonville, FL 32224 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA4 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900005 ER PT J AU Ribas, A Hodi, FS Kefford, R Hamid, O Daud, A Wolchok, JD Hwu, WJ Gangadhar, TC Patnaik, A Joshua, AM Hersey, P Weber, JS Dronca, RS Zarour, HM Gergich, K Li, XYN Lannone, R Kang, SP Ebbinghaus, S Robert, C AF Ribas, Antoni Hodi, F. Stephen Kefford, Richard Hamid, Omid Daud, Adil Wolchok, Jedd D. Hwu, Wen-Jen Gangadhar, Tara C. Patnaik, Amita Joshua, Anthony M. Hersey, Peter Weber, Jeffrey S. Dronca, Roxana Stefania Zarour, Hassane M. Gergich, Kevin Li, Xiaoyun (Nicole) Lannone, Robert Kang, Soonmo Peter Ebbinghaus, Scot Robert, Caroline TI Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Sydney, Westmead Hosp, Westmead, NSW 2145, Australia. Univ Sydney, Melanoma Inst Australia, Westmead, NSW 2145, Australia. Angeles Clin & Res Inst, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. South Texas Accelerated Res Therapeut START Ctr C, San Antonio, TX USA. Princess Margaret Canc Ctr, Toronto, ON, Canada. Univ Sydney, Sydney, NSW 2006, Australia. H Lee Moffitt Canc Ctr & Res Inst, Comprehens Melanoma Res Ctr, Tampa, FL USA. Mayo Clin, Dept Med Oncol, Rochester, MN USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Merck & Co Inc, N Wales, PA USA. Merck, N Wales, PA USA. Merck & Co Inc, Rahway, NJ 07065 USA. Inst Gustave Roussy, Paris, France. NR 0 TC 9 Z9 9 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA9000 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900013 ER PT J AU Schlumberger, M Tahara, M Wirth, LJ Robinson, B Brose, MS Elisei, R Dutcus, CE de las Heras, B Zhu, JM Habra, MA Newbold, K Shah, MH Hoff, AO Gianoukakis, AG Kiyota, N Taylor, MH Kim, SB Krzyzanowska, MK Sherman, SI AF Schlumberger, Martin Tahara, Makoto Wirth, Lori J. Robinson, Bruce Brose, Marcia S. Elisei, Rossella Dutcus, Corina E. de las Heras, Begoria Zhu, Junming Habra, Mouhammed Amir Newbold, Kate Shah, Manisha H. Hoff, Ana O. Gianoukakis, Andrew G. Kiyota, Naomi Taylor, Matthew Hiram Kim, Sung-Bae Krzyzanowska, Monika K. Sherman, Steven I. TI A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with I-131-refractory differentiated thyroid cancer (SELECT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Gustave Roussy, Dept Nucl Med & Endocrine Oncol, Villejuif, France. Univ Paris 11, Villejuif, France. Natl Canc Ctr Hosp East, Div Head & Neck Med Oncol, Kashiwa, Chiba, Japan. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Univ Sydney, Kolling Inst Med Res, Sydney, NSW 2006, Australia. Univ Penn, Abramson Canc Ctr, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. Univ Pisa, Dept Endocrinol, Pisa, Italy. Eisai, Woodcliff Lake, NJ USA. Eisai, Hatfield, Herts, England. Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Div Internal Med, Houston, TX 77030 USA. Royal Marsden Hosp Natl Hlth Serv Trust, London, England. Ohio State Univ, Dept Internal Med, Ctr Comprehens Canc, Columbus, OH 43210 USA. Univ Sao Paulo, Inst Canc Estado Sao Paulo, Sao Paulo, Brazil. Harbor UCLA Med Ctr, Div Endocrinol & Metab, Torrance, CA 90509 USA. Kobe Univ Hosp, Dept Med Oncol & Hematol, Kobe, Hyogo, Japan. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. Univ Ulsan, Asan Med Ctr, Coll Med, Dept Oncol, Seoul, South Korea. Princess Margaret Canc Ctr, Toronto, ON, Canada. RI Kiyota, Naomi/K-3226-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA6008 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900010 ER PT J AU Sweeney, C Chen, YH Carducci, MA Liu, G Jarrard, DF Eisenberger, MA Wong, YN Hahn, NM Kohli, M Vogelzang, NJ Cooney, MM Dreicer, R Picus, J Shevrin, DH Hussain, M Garcia, JA DiPaola, RS AF Sweeney, Christopher Chen, Yu-Hui Carducci, Michael Anthony Liu, Glenn Jarrard, David Frasier Eisenberger, Mario A. Wong, Yu-Ning Hahn, Noah M. Kohli, Manish Vogelzang, Nicholas J. Cooney, Matthew M. Dreicer, Robert Picus, Joel Shevrin, Daniel H. Hussain, Maha Garcia, Jorge A. DiPaola, Robert S. TI Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrca): An ECOG-led phase III randomized trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Mayo Clin, Rochester, MN USA. Comprehens Canc Ctr Nevada, Las Vegas, NV USA. Case Western Reserve Univ, Univ Hosp Case Med Ctr, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. Cleveland Clin, Cleveland, OH 44106 USA. Washington Univ, Div Oncol, St Louis, MO USA. NorthShore Univ HealthSyst, Evanston, IL USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Rutgers Biomed & Hlth Sci, New Brunswick, NJ USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA2 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900003 ER PT J AU Venook, AP Niedzwiecki, D Lenz, HJ Innocenti, F Mahoney, MR O'Neil, BH Shaw, JE Polite, BN Hochster, HS Atkins, JN Goldberg, RM Mayer, RJ Schilsky, RL Bertagnolli, MM David, C Blanke, CD AF Venook, Alan P. Niedzwiecki, Donna Lenz, Heinz-Josef Innocenti, Federico Mahoney, Michelle R. O'Neil, Bert H. Shaw, James Edward Polite, Blase N. Hochster, Howard S. Atkins, James Norman Goldberg, Richard M. Mayer, Robert J. Schilsky, Richard L. Bertagnolli, Monica M. David, Charles Blanke, Charles David CA Canc Leukemia Grp B Alliance SWOG ECOG TI CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Duke Univ, Durham, NC USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Univ N Carolina, Chapel Hill, NC USA. Mayo Clin, Rochester, MN USA. Indiana Univ Sch Med, Simon Canc Ctr, Indianapolis, IN 46202 USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. Yale Univ, Sch Med, Dept Med Oncol, New Haven, CT USA. CCOP, Southeast Canc Control Consortium, Goldsboro, NC USA. Ohio State Univ, Ctr Comprehens Canc, Arthur G James Canc Hosp, Columbus, OH 43210 USA. Richard J Solove Res Inst, Columbus, OH USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Amer Soc Clin Oncol, Alexandria, VA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. SWOG, Portland, OR USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA3 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900004 ER PT J AU Zhong, QY Gelaye, B Rondon, M Sanchez, SE Garcia, PJ Sanchez, E Barrios, YV Simon, GE Henderson, DC Cripe, SM Williams, MA AF Zhong, Qiuyue Gelaye, Bizu Rondon, Marta Sanchez, Sixto E. Garcia, Pedro J. Sanchez, Elena Barrios, Yasmin V. Simon, Gregory E. Henderson, David C. Cripe, Swee May Williams, Michelle A. TI Comparative performance of Patient Health Questionnaire-9 and Edinburgh Postnatal Depression Scale for screening antepartum depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE PHQ-9; EPDS; Antepartum depression; Peru ID COMMUNITY SAMPLE; PRENATAL DEPRESSION; POSTPARTUM WOMEN; STRESS SYMPTOMS; VALIDATION; ANXIETY; PREGNANCY; RISK; EPDS; VALIDITY AB Objective: We sought to evaluate the psychometric properties of two widely used screening scales: the Patient Health Questionnaire (PHQ-9) and Edinburgh Postnatal Depression Scale (EPDS) among pregnant Peruvian women. Methods: This cross-sectional study included 1517 women receiving prenatal care from February 2012 to March 2013. A structured interview was used to collect data using PHQ-9 and EPDS. We examined reliability, construct and concurrent validity between two scales using internal consistency indices, factor structures, correlations, and Cohen's kappa. Results: Both scales had good internal consistency (Cronbach's alpha > 0.8). Correlation between PHQ-9 and EPDS scores was fair (rho=0.52). Based on exploratory factor analysis (EFA), both scales yielded a two-factor structure. EFA including all items from PHQ-9 and EPDS yielded four factors, namely, "somatization", "depression and suicidal ideation", "anxiety and depression", and "anhedonia". The agreement between the two scales was generally fair at different cutoff scores with the highest Cohen's kappa being 0.46. Conclusions: Both the PHQ-9 and EPDS are reliable and valid scales for antepartum depression assessment. The PHQ-9 captures somatic symptoms, while EPDS detects depressive symptoms comorbid with anxiety during early pregnancy. Our findings suggest simultaneous administration of both scales may improve identification of antepartum depressive disorders in clinical settings. (C) 2014 Elsevier B.V. All rights reserved. C1 [Zhong, Qiuyue; Gelaye, Bizu; Barrios, Yasmin V.; Williams, Michelle A.] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Rondon, Marta] Cayetano Heredia Peruvian Univ, Dept Med, Lima, Peru. [Sanchez, Sixto E.; Garcia, Pedro J.] Univ San Martin de Porres, Lima, Peru. [Sanchez, Elena] Asociac Civil PROESA, Lima, Peru. [Simon, Gregory E.] Grp Hlth Res Inst, Seattle, WA USA. [Henderson, David C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cripe, Swee May] Perdana Univ, Sch Med, Kuala Lumpur, Malaysia. RP Gelaye, B (reprint author), Harvard Univ, Dept Epidemiol, Sch Publ Hlth, 677 Huntington Ave,K505F, Boston, MA 02115 USA. EM bgelaye@hsph.harvard.edu OI Gelaye, Bizu/0000-0001-7934-548X FU National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01-HD-059835] FX This research was supported by an award from the National Institutes of Health (NIH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD-059835). The NIH 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 62 TC 11 Z9 11 U1 2 U2 17 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 JUN 20 PY 2014 VL 162 BP 1 EP 7 DI 10.1016/j.jad.2014.03.028 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AG4JO UT WOS:000335386000001 PM 24766996 ER PT J AU Pietrzak, RH el-Gabalawy, R Tsai, J Sareen, J Neumeister, A Southwick, SM AF Pietrzak, Robert H. el-Gabalawy, Renee Tsai, Jack Sareen, Jitender Neumeister, Alexander Southwick, Steven M. TI Typologies of posttraumatic stress disorder in the US adult population SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Posttraumatic stress disorder; Depression; Trauma ID ALCOHOL-USE-DISORDER; PSYCHIATRIC DIAGNOSTIC MODULES; LATENT CLASS ANALYSIS; IV AUDADIS-IV; INTERNALIZING SUBTYPES; PERSONALITY-DISORDERS; UNITED-STATES; RELIABILITY; MODEL; RISK AB Back,ground: Posttraumatic stress disorder (PTSD) is characterized by heterogeneous clusters of re-experiencing, avoidance, numbing, and hyperarousal symptoms. However, data are lacking regarding the predominant, population-based typologies of this disorder, and how they are linked to trauma-related characteristics, psychiatric comorbidities, and health-related quality of life. Methods: We used latent class analyses (LCAs) to evaluate predominant typologies of PTSD in a nationally representative sample of 2463 U.S. adults with PTSD. Multinomial logistic regression analyses were then conducted to evaluate trauma-related characteristics, psychiatric comorbidities, and health-related quality of life variables associated with these typologies. Results: LCAs revealed three predominant typologies of PTSD Anxious-Re-experiencing (weighted prevalence=32.2%), Dysphoric (32.8%), and High Symptom (35.0%). Compared to the Dysphoric class, the Anxious-Re-experiencing and High Symptom classes were more likely to report sexual assault, physical assault, and military combat as their worst traumatic events; had an earlier age of onset and longer duration of PTSD; and were more likely to be diagnosed with nicotine dependence and borderline personality disorder, to have attempted suicide, and had poorer physical health-related quality of life (HRQoL). The High Symptom class had increased odds of all disorders, suicide attempts, and the poorest HRQoL. Limitations: Diagnoses were based on DSM-IV criteria and cross-sectional analyses preclude examination of how PTSD typologies are temporally related to other variables. Conclusion: PTSD in the general U.S. adult population is characterized by three predominant typologies, which are differentially linked to trauma and clinical characteristics. These findings underscore the importance of personalized approaches to the assessment, monitoring, and treatment of PTSD that take into consideration the heterogeneous manifestations of this disorder. Published by Elsevier B.V. C1 [Pietrzak, Robert H.; Southwick, Steven M.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, VA Connecticut Healthcare Syst, West Haven, CT USA. [Pietrzak, Robert H.; Tsai, Jack; Southwick, Steven M.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [el-Gabalawy, Renee; Sareen, Jitender] Univ Manitoba, Dept Psychol, Winnipeg, MB R3T 2N2, Canada. [Tsai, Jack] US Dept Vet Affairs, New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. [Sareen, Jitender] Univ Manitoba, Dept Psychiat, Winnipeg, MB R3T 2N2, Canada. [Sareen, Jitender] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. [Neumeister, Alexander] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Neumeister, Alexander] NYU, Sch Med, Dept Radiol, New York, NY USA. RP Pietrzak, RH (reprint author), Yale Univ, Sch Med, Natl Ctr PTSD,Dept Psychiat, Clin Neurosci Div,VA Connecticut Hlth Care Syst, 950 Campbell Ave 151E, West Haven, CT 06516 USA. EM robert.pietrzak@yale.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse (NIDA); United States Department of Veterans Affairs National Center for Posttraumatic Stress Disorder FX The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support front the National Institute on Drug Abuse (NIDA). Preparation of this report was supported in part by the United States Department of Veterans Affairs National Center for Posttraumatic Stress Disorder and a private donation. NR 21 TC 9 Z9 9 U1 1 U2 20 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 JUN 20 PY 2014 VL 162 BP 102 EP 106 DI 10.1016/j.jad.2014.03.024 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AG4JO UT WOS:000335386000018 PM 24767013 ER PT J AU Bussel, JB Kuter, DJ Aledort, LM Kessler, CM Cuker, A Pendergrass, KB Tang, SD McIntosh, J AF Bussel, James B. Kuter, David J. Aledort, Louis M. Kessler, Craig M. Cuker, Adam Pendergrass, Kelly B. Tang, Shande McIntosh, Joe TI A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia SO BLOOD LA English DT Article ID AKR-501 YM477; LONG-TERM; PURPURA; ELTROMBOPAG; EFFICACY; ROMIPLOSTIM; MANAGEMENT; SAFETY AB Stimulation of platelet production by thrombopoietin-receptor agonists (TPO-RAs) is an effective second-line treatment in immune thrombocytopenia (ITP). This 28-day phase 2 study assigned subjects with ITP of >= 3 months to once-daily oral avatrombopag (2.5, 5, 10, or 20 mg), an investigational nonpeptide TPO-RA active in humans, or placebo; subjects completing randomized treatment could enroll in a 24-week extension study. Of 64 randomized subjects, 13% (avatrombopag 2.5 mg), 53% (5 mg), 50% (10 mg), and 80% (20 mg), vs 0% for placebo, achieved a platelet count (PC) response of >= 50 x 10(9)/L with >= 20 x 10(9)/L increase above baseline at day 28. Fifty-three subjects (83%) entered the extension: 52% and 76% had a durable (PC response at >= 75% of their platelet assessments over the last 14 weeks) and overall (stable response or response at any >= 2 consecutive visits) response, respectively. All subjects experienced >= 1 adverse event (AE) (most commonly fatigue, headache, and epistaxis); 19% (n = 12) reported >= 1 serious AE; 10 (16%) withdrew due to an AE (5 due to increased PC). Avatrombopag was active and generally well tolerated, with PC response rates and AE incidence comparable with other TPO-RAs. These studies were registered at www.clinicaltrials.gov as #NCT00441090 and NCT00625443. C1 [Bussel, James B.] Cornell Univ, Dept Pediat, Weill Med Coll, Div Hematol, New York, NY 10021 USA. [Bussel, James B.] Cornell Univ, Dept Med, Weill Med Coll, Div Hematol, New York, NY 10021 USA. [Kuter, David J.] Massachusetts Gen Hosp, Dept Hematol, Boston, MA 02114 USA. [Aledort, Louis M.] Mt Sinai Sch Med, Dept Med, Div Hematol Oncol, New York, NY USA. [Kessler, Craig M.] Georgetown Univ, Med Ctr, Div Coagulat, Washington, DC 20007 USA. [Cuker, Adam] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Cuker, Adam] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Pendergrass, Kelly B.] Kansas City Canc Ctr, Kansas City, MO USA. [Tang, Shande; McIntosh, Joe] Eisai Corp North Amer, Woodcliff Lake, NJ USA. RP Bussel, JB (reprint author), Cornell Univ, New York Presbyterian Hosp, Weill Med Coll, Div Hematol Oncol,Dept Pediat & Med, 525 East 68th St,Payson 695, New York, NY 10021 USA. EM jbussel@med.cornell.edu FU Eisai FX This study was sponsored by Eisai. Editorial support was provided by Michael G. Pellegrino and Gary Dever of Complete Medical Communications and was funded by Eisai. NR 20 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 19 PY 2014 VL 123 IS 25 BP 3887 EP 3894 DI 10.1182/blood-2013-07-514398 PG 8 WC Hematology SC Hematology GA AQ2LO UT WOS:000342617800011 PM 24802775 ER PT J AU Flynn, R Du, J Veenstra, RG Reichenbach, DK Panoskaltsis-Mortari, A Taylor, PA Freeman, GJ Serody, JS Murphy, WJ Munn, DH Sarantopoulos, S Luznik, L Maillard, I Koreth, J Cutler, C Soiffer, RJ Antin, JH Ritz, J Dubovsky, JA Byrd, JC MacDonald, KP Hill, GR Blazar, BR AF Flynn, Ryan Du, Jing Veenstra, Rachelle G. Reichenbach, Dawn K. Panoskaltsis-Mortari, Angela Taylor, Patricia A. Freeman, Gordon J. Serody, Jonathan S. Murphy, William J. Munn, David H. Sarantopoulos, Stefanie Luznik, Leo Maillard, Ivan Koreth, John Cutler, Corey Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome Dubovsky, Jason A. Byrd, John C. MacDonald, Kelli P. Hill, Geoff R. Blazar, Bruce R. TI Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; CORD BLOOD TRANSPLANTATION; ANTIBODY-RESPONSES; CLINICAL-TRIALS; CHRONIC GVHD; IL-21; ICOS; DIFFERENTIATION; CRITERIA AB Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donorT cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD. C1 [Flynn, Ryan; Du, Jing; Veenstra, Rachelle G.; Reichenbach, Dawn K.; Panoskaltsis-Mortari, Angela; Taylor, Patricia A.; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Freeman, Gordon J.; Koreth, John; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Boston, MA 02115 USA. [Serody, Jonathan S.; Sarantopoulos, Stefanie] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC 27599 USA. [Murphy, William J.] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Munn, David H.] Georgia Hlth Sci Univ, Dept Pediat, Augusta, GA USA. [Luznik, Leo] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Luznik, Leo] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Maillard, Ivan] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Maillard, Ivan] Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Dubovsky, Jason A.; Byrd, John C.] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [MacDonald, Kelli P.; Hill, Geoff R.] Queensland Inst Med Res, Dept Immunol, Brisbane, Qld 4006, Australia. RP Blazar, BR (reprint author), Univ Minnesota, 420 Delaware St SE,MMC 109, Minneapolis, MN 55455 USA. EM blaza001@umn.edu RI Hill, Geoffrey/O-2630-2016; MacDonald, Kelli/O-2722-2016; OI Hill, Geoffrey/0000-0003-2994-0429; MacDonald, Kelli/0000-0003-3451-4221; Serody, Jonathan/0000-0003-4568-1092; Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health National Cancer Institute grant [P01 CA142106-06A1]; National Institutes of Allergy and Infectious Diseases grants [P01 AI 056299, T32 AI 007313]; National Heart, Lung, and Blood Institute grant [T32 HL 00706237]; National Center for Research Resources Shared Instrumentation [S10 RR16851] FX Supported in part by National Institutes of Health National Cancer Institute grant P01 CA142106-06A1, National Institutes of Allergy and Infectious Diseases grants P01 AI 056299 and T32 AI 007313, and National Heart, Lung, and Blood Institute grant T32 HL 00706237. The use of the confocal microscope was supported by grant S10 RR16851 from the National Center for Research Resources Shared Instrumentation. NR 35 TC 41 Z9 44 U1 0 U2 9 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 19 PY 2014 VL 123 IS 25 BP 3988 EP 3998 DI 10.1182/blood-2014-03-562231 PG 11 WC Hematology SC Hematology GA AQ2LO UT WOS:000342617800023 PM 24820310 ER PT J AU Castillo, JJ Olszewski, AJ Cronin, AM Hunter, ZR Treon, SP AF Castillo, Jorge J. Olszewski, Adam J. Cronin, Angel M. Hunter, Zachary R. Treon, Steven P. TI Survival trends in Waldenstrom macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database SO BLOOD LA English DT Letter ID LYMPHOMA C1 [Castillo, Jorge J.; Hunter, Zachary R.; Treon, Steven P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Olszewski, Adam J.] Brown Univ, Mem Hosp Rhode Isl, Warren Alpert Med Sch, Div Hematol & Oncol, Pawtucket, RI 02860 USA. [Cronin, Angel M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Castillo, JJ (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, 450 Brookline Ave,M221, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Olszewski, Adam/0000-0002-6472-6658; Castillo, Jorge/0000-0001-9490-7532; Hunter, Zachary/0000-0002-1689-1691 NR 10 TC 16 Z9 16 U1 0 U2 4 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 19 PY 2014 VL 123 IS 25 BP 3999 EP 4000 DI 10.1182/blood-2014-05-574871 PG 2 WC Hematology SC Hematology GA AQ2LO UT WOS:000342617800024 PM 24948623 ER PT J AU Huttenhower, C Kostic, AD Xavier, RJ AF Huttenhower, Curtis Kostic, Aleksandar D. Xavier, Ramnik J. TI Inflammatory Bowel Disease as a Model for Translating the Microbiome SO IMMUNITY LA English DT Review ID INNATE LYMPHOID-CELLS; CROHNS-DISEASE; ULCERATIVE-COLITIS; GUT MICROBIOTA; FECAL MICROBIOTA; INTESTINAL INFLAMMATION; COMMENSAL BACTERIA; IMMUNE-SYSTEM; HOST-GENOTYPE; FAECAL FLORA AB The inflammatory bowel diseases (IBDs) are among the most closely studied chronic inflammatory disorders that involve environmental, host genetic, and commensal microbial factors. This combination of features has made IBD both an appropriate and a high-priority platform for translatable research in host-microbiome interactions. Decades of epidemiology have identified environmental risk factors, although most mechanisms of action remain unexplained. The genetic architecture of IBD has been carefully dissected in multiple large populations, identifying several responsible host epithelial and immune pathways but without yet a complete systems-level explanation. Most recently, the commensal gut microbiota have been found to be both ecologically and functionally perturbed during the disease, but with as-yet-unexplained heterogeneity among IBD subtypes and individual patients. IBD thus represents perhaps the most comprehensive current model for understanding the human microbiome's role in complex inflammatory disease. Here, we review the influences of the microbiota on IBD and its potential for translational medicine. C1 [Huttenhower, Curtis; Kostic, Aleksandar D.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Huttenhower, Curtis; Kostic, Aleksandar D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Huttenhower, Curtis; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Huttenhower, Curtis; Kostic, Aleksandar D.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kostic, Aleksandar D.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Huttenhower, C (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM chuttenh@hsph.harvard.edu; xavier@molbio.mgh.harvard.edu OI Kostic, Aleksandar/0000-0002-0837-4360 FU NIDCR NIH HHS [U54 DE023798]; NIDDK NIH HHS [P30 DK043351, R01 DK092405, U54 DK102557] NR 116 TC 71 Z9 73 U1 3 U2 24 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 19 PY 2014 VL 40 IS 6 BP 843 EP 854 DI 10.1016/j.immuni.2014.05.013 PG 12 WC Immunology SC Immunology GA AO6DT UT WOS:000341440200004 PM 24950204 ER PT J AU Visvikis, O Ihuegbu, N Labed, SA Luhachack, LG Alves, AMF Wollenberg, AC Stuart, LM Stormo, GD Irazoqui, JE AF Visvikis, Orane Ihuegbu, Nnamdi Labed, Sid A. Luhachack, Lyly G. Alves, Anna-Maria F. Wollenberg, Amanda C. Stuart, Lynda M. Stormo, Gary D. Irazoqui, Javier E. TI Innate Host Defense Requires TFEB-Mediated Transcription of Cytoprotective and Antimicrobial Genes SO IMMUNITY LA English DT Article ID CAENORHABDITIS-ELEGANS; C. ELEGANS; STAPHYLOCOCCUS-AUREUS; LYSOSOMAL BIOGENESIS; AUTOPHAGY GENES; LIFE-SPAN; DROSOPHILA-MELANOGASTER; PATHOGEN INTERACTIONS; REGULATES AUTOPHAGY; IMMUNE-RESPONSE AB Animal host defense against infection requires the expression of defense genes at the right place and the right time. Understanding such tight control of host defense requires the elucidation of the transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection. C1 [Visvikis, Orane; Labed, Sid A.; Luhachack, Lyly G.; Alves, Anna-Maria F.; Wollenberg, Amanda C.; Irazoqui, Javier E.] Harvard Univ, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Lab Comparat Immunol,Sch Med, Boston, MA 02114 USA. [Ihuegbu, Nnamdi; Stormo, Gary D.] Washington Univ, Sch Med, Ctr Genome Sci, Dept Genet, St Louis, MO 63118 USA. [Stuart, Lynda M.] Bill & Melinda Gates Fdn, Seattle, WA 98109 USA. RP Irazoqui, JE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Lab Comparat Immunol,Sch Med, Boston, MA 02114 USA. EM jirazoqui@mgh.harvard.edu RI di Ronza, Alberto/H-7674-2016; VISVIKIS, ORANE/N-1818-2016; OI di Ronza, Alberto/0000-0002-9813-5143; VISVIKIS, ORANE/0000-0001-7719-5836; Irazoqui, Javier/0000-0001-6553-1329 FU NIH Office of Research Infrastructure Programs [P40-OD010440]; National Institute of General Medical Sciences of the National Institutes of Health from NHGRI [P30-GM092431, R01-GM101056, R01-GM101056-S1, R01-HG000249]; Massachusetts General Hospital FX We thank A. Lacy-Hulbert for helpful discussions, S. Margolis for critical reading of the manuscript, A. Sokolovska and A. Tanne for assistance with macrophage experiments, L.R.Lapierre and M. Hansen for sharing unpublished data, M. Ferron and G. Karsenty for their generous gift of TFEB-3xFLAG RAW264.7 cells, and V. Ambros for the hlh-30(tm1978) strain. We thank the Genome Access Technology Center at Washington University Medical School for their sequencing assistance, especially N. Rockweiler for helpful discussions. Some C. elegans strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (P40-OD010440). This study was funded in part by the National Institute of General Medical Sciences of the National Institutes of Health, under awards numbers P30-GM092431, R01-GM101056, and R01-GM101056-S1 (to J.E.I.) and R01-HG000249 from the NHGRI (to G.D.S.). O.V. was funded by a Fund for Medical Discovery postdoctoral fellowship from the Massachusetts General Hospital. NR 64 TC 36 Z9 36 U1 1 U2 11 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 19 PY 2014 VL 40 IS 6 BP 896 EP 909 DI 10.1016/j.immuni.2014.05.002 PG 14 WC Immunology SC Immunology GA AO6DT UT WOS:000341440200012 PM 24882217 ER PT J AU Fell, GL Robinson, KC Mao, J Woolf, CJ Fisher, DE AF Fell, Gillian L. Robinson, Kathleen C. Mao, Jianren Woolf, Clifford J. Fisher, David E. TI Skin beta-Endorphin Mediates Addiction to UV Light SO CELL LA English DT Article ID FREQUENT INDOOR TANNERS; ULTRAVIOLET-RADIATION; ENDOGENOUS OPIOIDS; NUCLEUS-ACCUMBENS; PLASMA-LEVELS; SUN EXPOSURE; MICE; WITHDRAWAL; INDUCTION; EXERCISE AB UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, beta-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in beta-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. Although primordial UV addiction, mediated by the hedonic action of beta-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in humans. C1 [Fell, Gillian L.; Robinson, Kathleen C.; Fisher, David E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. [Fell, Gillian L.; Robinson, Kathleen C.; Fisher, David E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Mao, Jianren] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res,Dept Anesthesia Critica, Boston, MA 02114 USA. [Woolf, Clifford J.] Childrens Hosp Boston, FM Kirby Neurobiol Ctr, Boston, MA 02114 USA. [Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. EM dfisher3@partners.org FU NIH [R01 AR043369-16, P01CA163222, R01 CA150226-03]; Melanoma Research Alliance; US-Israel Binational Science Foundation; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation FX The authors gratefully acknowledge Dr. Charles Berde, Dr. Jeff Mogil, Ms. Vivien Igras, Mr. John Dellorusso, Ms. Teri Herbert, Ms. Leeza Hargreaves, Dr. Roydon Price, and Dr. Grewo Lim for productive discussions during the early phases of this project and for technical assistance with the experiments and manuscript. The authors thank Dr. Mary Jeanne Kreek for useful discussions. The authors also acknowledge Douglas Hayden from the MGH Biostatistics Center for consultation regarding the statistical analysis. This work was supported by NIH under award numbers R01 AR043369-16, P01CA163222, and R01 CA150226-03 and by grants from the Melanoma Research Alliance, the US-Israel Binational Science Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.E.F.). NR 54 TC 36 Z9 37 U1 5 U2 24 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 19 PY 2014 VL 157 IS 7 BP 1527 EP 1534 DI 10.1016/j.cell.2014.04.032 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QG UT WOS:000340941900009 PM 24949966 ER PT J AU Naetar, N Soundarapandian, V Litovchick, L Goguen, KL Sablina, AA Bowman-Colin, C Sicinski, P Hahn, WC DeCaprio, JA Livingston, DM AF Naetar, Nana Soundarapandian, Velmurugan Litovchick, Larisa Goguen, Kelsey L. Sablina, Anna A. Bowman-Colin, Christian Sicinski, Piotr Hahn, William C. DeCaprio, James A. Livingston, David M. TI PP2A-Mediated Regulation of Ras Signaling in G2 Is Essential for Stable Quiescence and Normal G1 Length SO MOLECULAR CELL LA English DT Article ID HUMAN CELL-TRANSFORMATION; PROTEIN PHOSPHATASE 2A; SMALL-T-ANTIGEN; RESTRICTION POINT; GENE-EXPRESSION; PP2A COMPLEXES; STEM-CELLS; S-PHASE; C-MYC; PROLIFERATION AB Quiescence (G0) allows cycling cells to reversibly cease proliferation. A decision to enter quiescence is suspected of occurring early in G1, before the restriction point (R). Surprisingly, we have identified G2 as an interval during which inhibition of the protein phosphatase PP2A results in failure to exhibit stable quiescence. This effect is accompanied by shortening of the ensuing G1. The PP2A subcomplex required for stable G0 contains the B56 gamma B subunit. After PP2A inhibition in G2, aberrant overexpression of cyclin E occurs during mitosis and is responsible for overriding quiescence. Strikingly, suppression of Ras signaling re-establishes normal cyclin E levels during M and restores G0. These data point to PP2A-B56 gamma-driven Ras signaling modulation in G2 as essential for suppressing aberrant cyclin E expression during mitosis and thereby achieving normal G0 control. Thus, G2 is an interval during which the length and growth factor dependence of the next G1 interval are established. C1 [Naetar, Nana; Soundarapandian, Velmurugan; Bowman-Colin, Christian; Sicinski, Piotr; Livingston, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Litovchick, Larisa; Hahn, William C.; DeCaprio, James A.; Livingston, David M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Litovchick, Larisa; Hahn, William C.; DeCaprio, James A.; Livingston, David M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Naetar, Nana; Soundarapandian, Velmurugan; Goguen, Kelsey L.; Bowman-Colin, Christian; Sicinski, Piotr; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Litovchick, Larisa; Sablina, Anna A.; Hahn, William C.; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Livingston, DM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM david_livingston@dfci.harvard.edu FU National Cancer Institute [NCI-P01CA50661]; Austrian Science Fund (FWF); Austrian Academy of Sciences FX We wish to thank Dr. Charles Sherr for suggesting the G2-Ras hypothesis to us. We also thank Dr. William Kim and members of the D.M.L. laboratory for helpful discussions and Drs. Sergio Nasi, Subhashini Sadasivam, and Wojciech Michowski for providing reagents. This study was supported by grant NCI-P01CA50661 from the National Cancer Institute to D.M.L. N.N.'s work was supported in part by a Schroedinger fellowship from the Austrian Science Fund (FWF) and an APART fellowship of the Austrian Academy of Sciences. NR 42 TC 13 Z9 13 U1 0 U2 9 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 19 PY 2014 VL 54 IS 6 BP 932 EP 945 DI 10.1016/j.molcel.2014.04.023 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5JY UT WOS:000340628000005 PM 24857551 ER PT J AU Bekalu, MA Eggermont, S Ramanadhan, S Viswanath, K AF Bekalu, Mesfin Awoke Eggermont, Steven Ramanadhan, Shoba Viswanath, Kasisomayajula TI Effect of Media Use on HIV-Related Stigma in Sub-Saharan Africa: A Cross-Sectional Study SO PLOS ONE LA English DT Article ID AIDS-RELATED STIGMA; SOUTH-AFRICA; MASS-MEDIA; DEVELOPING-COUNTRIES; HIV/AIDS STIGMA; YOUNG-PEOPLE; CAPE-TOWN; PREVENTION; IMPACT; KENYA AB It is known that HIV-related stigma hinders prevention efforts. Previous studies have documented that HIV-related stigma may be associated with socioeconomic and socioecological factors. Mass media use may moderate this association, but there is limited research addressing that possibility. In this study, based on cross-sectional data pooled from the 2006-2011 Demographic and Health Surveys of 11 sub-Saharan African countries (N = 204,343), we investigated the moderating effects of exposure to mass media on HIV-related stigma. Hierarchical regression analysis indicated that HIV-related stigma tends to be higher among rural residents and individuals with low levels of education and HIV knowledge, as well as those who do not know people living with HIV. Media use was generally associated with low levels of HIV-related stigma, and attenuated the gap between individuals with high and low educational levels. However, the effect of mass media was found to be stronger among urbanites rather than among rural residents, which could lead to a widening gap between the two groups in endorsement of HIV-related stigma. The implication of this study regarding the effect of media use on HIV-related stigma in sub-Saharan Africa is twofold: 1) mass media may have the potential to minimize the gap in HIV-related stigma between individuals with high and low educational levels, and hence future efforts of reducing HIV-related stigma in the region may benefit from utilizing media; 2) due perhaps to low media penetration to rural sub-Saharan Africa, mass media could have the unintended effect of widening the urban-rural gap further unless other more customized and rural-focused communication interventions are put in place. C1 [Bekalu, Mesfin Awoke; Ramanadhan, Shoba; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Bekalu, Mesfin Awoke; Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Bekalu, Mesfin Awoke; Eggermont, Steven] Univ Leuven, Sch Mass Commun Res, Leuven, Belgium. [Bekalu, Mesfin Awoke] Bahir Dar Univ, Dept Journalism & Commun, Bahir Dar, Ethiopia. RP Bekalu, MA (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. EM mesfinawoke.bekalu@soc.kuleuven.be RI Eggermont, Steven/G-5670-2010 OI Eggermont, Steven/0000-0003-0428-092X FU Research Foundation Flanders (FWO) FX The study was made possible through a long term research stay grant from Research Foundation Flanders (FWO) to the first author. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 0 Z9 0 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e100467 DI 10.1371/journal.pone.0100467 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500078 PM 24945251 ER PT J AU Kelly, JF Stout, RL Greene, MC Slaymaker, V AF Kelly, John F. Stout, Robert L. Greene, M. Claire Slaymaker, Valerie TI Young Adults, Social Networks, and Addiction Recovery: Post Treatment Changes in Social Ties and Their Role as a Mediator of 12-Step Participation SO PLOS ONE LA English DT Article ID MULTIVARIATE PROCESS MODEL; SUBSTANCE-ABUSE PATIENTS; SELF-HELP GROUPS; DRINKING OUTCOMES; BEHAVIOR-CHANGE; FRIENDSHIP NETWORKS; EMERGING ADULTHOOD; ALCOHOL; SUPPORT; MECHANISMS AB Background: Social factors play a key role in addiction recovery. Research with adults indicates individuals with substance use disorder (SUD) benefit from mutual-help organizations (MHOs), such as Alcoholics Anonymous, via their ability to facilitate adaptive network changes. Given the lower prevalence of sobriety-conducive, and sobriety-supportive, social contexts in the general population during the life-stage of young adulthood, however, 12-step MHOs may play an even more crucial recovery-supportive social role for young adults, but have not been investigated. Greater knowledge could enhance understanding of recovery-related change and inform young adults' continuing care recommendations. Methods: Emerging adults (N = 302; 18-24 yrs; 26% female; 95% White) enrolled in a study of residential treatment effectiveness were assessed at intake, 1, 3, 6, and 12 months on 12-step attendance, peer network variables ("high [relapse] risk'' and "low [relapse] risk'' friends), and treatment outcomes (Percent Days Abstinent; Percent Days Heavy Drinking). Hierarchical linear models tested for change in social risk over time and lagged mediational analyses tested whether 12-step attendance conferred recovery benefits via change in social risk. Results: High-risk friends were common at treatment entry, but decreased during follow-up; low-risk friends increased. Contrary to predictions, while substantial recovery-supportive friend network changes were observed, this was unrelated to 12-step participation and, thus, not found to mediate its positive influence on outcome. Conclusions: Young adult 12-step participation confers recovery benefit; yet, while encouraging social network change, 12-step MHOs may be less able to provide social network change directly for young adults, perhaps because similar-aged peers are less common in MHOs. Findings highlight the importance of both social networks and 12-step MHOs and raise further questions as to how young adults benefit from 12-step MHOs. C1 [Kelly, John F.; Greene, M. Claire] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Kelly, John F.; Greene, M. Claire] Harvard Univ, Sch Med, Boston, MA USA. [Stout, Robert L.] Pacific Inst Res & Evaluat, Providence, RI USA. [Slaymaker, Valerie] Hazelden Fdn, Ctr City, MN USA. RP Kelly, JF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. EM jkelly11@mgh.harvard.edu FU National Institute of Alcohol Abuse and Alcoholism (NIAAA) [1R21AA018185-01A2] FX This work was was supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) Grant Number: 1R21AA018185-01A2 and by an anonymous donation to the Hazelden Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 10 Z9 10 U1 2 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e100121 DI 10.1371/journal.pone.0100121 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500045 PM 24945357 ER PT J AU Thiagarajah, JR Yildiz, H Carlson, T Thomas, AR Steiger, C Pieretti, A Zukerberg, LR Carrier, RL Goldstein, AM AF Thiagarajah, Jay R. Yildiz, Hasan Carlson, Taylor Thomas, Alyssa R. Steiger, Casey Pieretti, Alberto Zukerberg, Lawrence R. Carrier, Rebecca L. Goldstein, Allan M. TI Altered Goblet Cell Differentiation and Surface Mucus Properties in Hirschsprung Disease SO PLOS ONE LA English DT Article ID ENTERIC NERVOUS-SYSTEM; PATHO-PHYSIOLOGY; ENTEROCOLITIS; MOUSE; INTESTINE; HOMEOSTASIS; SECRETION; TRANSPORT; COLITIS; MATH1 AB Hirschsprung disease-associated enterocolitis (HAEC) leads to significant mortality and morbidity, but its pathogenesis remains unknown. Changes in the colonic epithelium related to goblet cells and the luminal mucus layer have been postulated to play a key role. Here we show that the colonic epithelium of both aganglionic and ganglionic segments are altered in patients and in mice with Hirschsprung disease (HSCR). Structurally, goblet cells were altered with increased goblet cell number and reduced intracellular mucins in the distal colon of biopsies from patients with HSCR. Endothelin receptor B (Ednrb) mutant mice showed increased goblet cell number and size and increased cell proliferation compared to wild-type mice in aganglionic segments, and reduced goblet cell size and number in ganglionic segments. Functionally, compared to littermates, Ednrb(-/-) mice showed increased transepithelial resistance, reduced stool water content and similar chloride secretion in the distal colon. Transcript levels of goblet cell differentiation factors SPDEF and Math1 were increased in the distal colon of Ednrb(-/-) mice. Both distal colon from Ednrb mice and biopsies from HSCR patients showed reduced Muc4 expression as compared to controls, but similar expression of Muc2. Particle tracking studies showed that mucus from Ednrb(-/-) mice provided a more significant barrier to diffusion of 200 nm nanoparticles as compared to wildtype mice. These results suggest that aganglionosis is associated with increased goblet cell proliferation and differentiation and subsequent altered surface mucus properties, prior to the development of inflammation in the distal colon epithelium. Restoration of normal goblet cell function and mucus layer properties in the colonic epithelium may represent a therapeutic strategy for prevention of HAEC. C1 [Thiagarajah, Jay R.] Boston Childrens Hosp, Dept Gastroenterol & Nutr, Boston, MA USA. [Yildiz, Hasan; Carlson, Taylor; Carrier, Rebecca L.] Northeastern Univ, Dept Chem Engn, Boston, MA 02115 USA. [Thomas, Alyssa R.; Steiger, Casey; Pieretti, Alberto; Goldstein, Allan M.] Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Goldstein, AM (reprint author), Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA 02114 USA. EM agoldstein@partners.org FU NIH [5R21EB015750] FX Supported by grant NIH 5R21EB015750 (RC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e99944 DI 10.1371/journal.pone.0099944 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500034 PM 24945437 ER PT J AU Wei, SC Tan, YY Weng, MT Lai, LC Hsiao, JH Chuang, EY Shun, CT Wu, DC Kao, AW Chuang, CS Ni, YH Shieh, MJ Tung, CC Chen, Y Wang, CY Xavier, RJ Podolsky, DK Wong, JM AF Wei, Shu-Chen Tan, Yan-Yin Weng, Meng-Tzu Lai, Liang-Chuan Hsiao, Jen-Hao Chuang, Eric Y. Shun, Chia-Tung Wu, Deng-Cheng Kao, Ai-Wen Chuang, Chiao-Shung Ni, Yen-Hsuan Shieh, Ming-Jium Tung, Chien-Chih Chen, Yun Wang, Cheng-Yi Xavier, Ramnik J. Podolsky, Daniel K. Wong, Jau-Min TI SLCO3A1, a Novel Crohn's Disease-Associated Gene, Regulates NF-kappa B Activity and Associates with Intestinal Perforation SO PLOS ONE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; NICOTINE DEPENDENCE; SCHIZOPHRENIA; POLYMORPHISMS; PATHOGENESIS; ACTIVATION; EXPRESSION; VARIANTS AB Background & Aims: To date, only one gene (TNFSF15) has been identified and validated as a Crohn's disease (CD)-associated gene in non-Caucasian populations. This study was designed to identify novel CD-associated single nucleotide polymorphisms (SNPs)/genes and to validate candidate genes using a functional assay. Methods: SNPs from 16 CD patients and 16 age-and sex-matched control patients were analyzed using Illumina platform analysis. Subsequently, we expanded the study and followed 53 CD patients and 41 control patients by Sequenom MassArray analysis. Quantitative PCR and immunohistochemical staining were performed to assess mRNA and protein expression of the candidate gene on tissue isolated from CD patients. Genotype was correlated with CD phenotypes. Finally, the candidate gene was cloned and its effect on NF-kappa B activity assessed using a reporter luciferase assay. Results: SLCO3A1 (rs207959) reached statistical significance in the first-stage analysis (P = 2.3E-02) and was further validated in the second-stage analysis (P = 1.0E-03). Genotype and phenotype analysis showed that the rs207959 (T) allele is a risk allele that alters SLCO3A1 mRNA expression and is associated with intestinal perforation in CD patients. Higher levels of mRNA and protein expression of SLCO3A1 were seen in CD patients compared with the control group. Overexpression of SLCO3A1 induced increased NF-kappa B activity and increased phosphorylation of P65, ERK, and JNK. Nicotine augmented the activation of NF-kappa B in the presence of SLCO3A1. Conclusions: SLCO3A1, a novel CD-associated gene, mediates inflammatory processes in intestinal epithelial cells through NF-kB transcription activation, resulting in a higher incidence of bowel perforation in CD patients. C1 [Wei, Shu-Chen; Weng, Meng-Tzu; Wang, Cheng-Yi; Wong, Jau-Min] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Tan, Yan-Yin; Wong, Jau-Min] Natl Taiwan Univ, Grad Inst Med Engn, Taipei 10764, Taiwan. [Weng, Meng-Tzu] Far Eastern Mem Hosp, Dept Internal Med, New Taipei, Taiwan. [Lai, Liang-Chuan] Natl Taiwan Univ, Coll Med, Grad Inst Physiol, Taipei, Taiwan. [Lai, Liang-Chuan; Hsiao, Jen-Hao; Chuang, Eric Y.] Natl Taiwan Univ, Bioinformat & Biostat Core, Ctr Genom Med, Taipei 10764, Taiwan. [Chuang, Eric Y.] Natl Taiwan Univ, Grad Inst Biomed Elect & Bioinformat, Taipei 10764, Taiwan. [Shun, Chia-Tung] Natl Taiwan Univ Hosp, Dept Pathol & Forens Med, Taipei, Taiwan. [Wu, Deng-Cheng] Kaohsiung Med Univ, Dept Internal Med, Kaohsiung, Taiwan. [Kao, Ai-Wen; Chuang, Chiao-Shung] Natl Cheng Kung Univ, Dept Internal Med, Tainan 70101, Taiwan. [Ni, Yen-Hsuan] Natl Taiwan Univ Hosp, Dept Pediat, Taipei 10016, Taiwan. [Shieh, Ming-Jium] Natl Taiwan Univ Hosp, Deparment Oncol, Taipei, Taiwan. [Tung, Chien-Chih] Natl Taiwan Univ Hosp, Dept Integrated Diagnost & Therapeut, Taipei, Taiwan. [Chen, Yun] Far Eastern Mem Hosp, New Taipei, Taiwan. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Podolsky, Daniel K.] UT Southwestern Med Ctr, Dallas, TX USA. RP Wong, JM (reprint author), Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. EM jmwong@ntu.edu.tw OI Ni, Yen-Hsuan/0000-0002-1158-5249; SHUN, CHIA-TUNG/0000-0002-0468-4468 FU National Science Council of Taiwan [NSC-98-2314-B-002-139-, 99-2314-B-002-124-MY3]; Liver Disease Prevention & Treatment Research Foundation, Taiwan FX This work was supported by National Science Council of Taiwan (NSC-98-2314-B-002-139-) (99-2314-B-002-124-MY3); Liver Disease Prevention & Treatment Research Foundation, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 3 Z9 3 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e100515 DI 10.1371/journal.pone.0100515 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500084 PM 24945726 ER PT J AU Wang, W Zhong, Q Teng, L Bhatnagar, N Sharma, B Zhang, X Luther, W Haynes, LP Burgoyne, RD Vidal, M Volchenboum, S Hill, DE George, RE AF Wang, W. Zhong, Q. Teng, L. Bhatnagar, N. Sharma, B. Zhang, X. Luther, W., II Haynes, L. P. Burgoyne, R. D. Vidal, M. Volchenboum, S. Hill, D. E. George, R. E. TI Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma SO ONCOGENE LA English DT Article DE PHOX2B; HPCAL1; neuroblastoma; neuronal calcium sensor; differentiation; network perturbation ID CENTRAL-HYPOVENTILATION-SYNDROME; BETA-HYDROXYLASE GENE; NEUROTRANSMITTER BIOSYNTHETIC GENES; ONSET CENTRAL-HYPOVENTILATION; VISININ-LIKE PROTEINS; HOMEOBOX GENE; POLYALANINE EXPANSIONS; FRAMESHIFT MUTATIONS; EDGETIC PERTURBATION; HOMEODOMAIN PROTEINS AB Heterozygous germline mutations in PHOX2B, a transcriptional regulator of sympathetic neuronal differentiation, predispose to diseases of the sympathetic nervous system, including neuroblastoma and congenital central hypoventilation syndrome (CCHS). Although the PHOX2B variants in CCHS largely involve expansions of the second polyalanine repeat within the C-terminus of the protein, those associated with neuroblastic tumors are nearly always frameshift and truncation mutations. To test the hypothesis that the neuroblastoma-associated variants exert their effects through loss or gain of protein-protein interactions, we performed a large-scale yeast two-hybrid screen using both wild-type (WT) and six different mutant PHOX2B proteins against over 10 000 human genes. The neuronal calcium sensor protein HPCAL1 (VILIP-3) exhibited strong binding to WT PHOX2B and a CCHS-associated polyalanine expansion mutant but only weakly or not at all to neuroblastoma-associated frameshift and truncation variants. We demonstrate that both WT PHOX2B and the neuroblastoma-associated R100L missense and the CCHS-associated alanine expansion variants induce nuclear translocation of HPCAL1 in a Ca2+-independent manner, while the neuroblastoma-associated 676delG frameshift and K155X truncation mutants impair subcellular localization of HPCAL1, causing it to remain in the cytoplasm. HPCAL1 did not appreciably influence the ability of WT PHOX2B to transactivate the DBH promoter, nor did it alter the decreased transactivation potential of PHOX2B variants in 293T cells. Abrogation of the PHOX2B-HPCAL1 interaction by shRNA knockdown of HPCAL1 in neuroblastoma cells expressing PHOX2B led to impaired neurite outgrowth with transcriptional profiles indicative of inhibited sympathetic neuronal differentiation. Our results suggest that certain PHOX2B variants associated with neuroblastoma pathogenesis, because of their inability to bind to key interacting proteins such as HPCAL1, may predispose to this malignancy by impeding the differentiation of immature sympathetic neurons. C1 [Wang, W.; Bhatnagar, N.; Sharma, B.; Luther, W., II; George, R. E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Zhong, Q.; Vidal, M.; Hill, D. E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA. [Zhong, Q.; Vidal, M.; Hill, D. E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Teng, L.; Volchenboum, S.] Univ Chicago, Chicago Ctr Childhood Canc & Blood Dis, Chicago, IL 60637 USA. [Zhang, X.] Chinese Acad Sci, High Field Magnet Lab, Hefei, Peoples R China. [Haynes, L. P.; Burgoyne, R. D.] Univ Liverpool, Inst Translat Med, Dept Cellular & Mol Physiol, Liverpool L69 3BX, Merseyside, England. RP George, RE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Dana 640E,450 Brookline Ave, Boston, MA 02115 USA. EM rani_george@dfci.harvard.edu FU Alex's Lemonade Stand Foundation; Abraham Research Fund; National Cancer Institute [R33CA132073]; National Human Genome Research [R01HG001715, P50HG004233]; Ellison Foundation FX We thank Dr Christo Goridis for the generous gift of the PHOX2B antibody. We thank Stacey Frumm and Dr Kimberly Stegmaier for data regarding the neuroblastoma cell differentiation signature before publication. This study was supported by Alex's Lemonade Stand Foundation (to REG), Abraham Research Fund (to WW), National Cancer Institute Grant R33CA132073 (to MV), National Human Genome Research Grants R01HG001715 and P50HG004233 (to MV and DEH) and The Ellison Foundation (to MV). NR 45 TC 4 Z9 4 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 19 PY 2014 VL 33 IS 25 BP 3316 EP 3324 DI 10.1038/onc.2013.290 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AK5DA UT WOS:000338443400011 PM 23873030 ER PT J AU Grover, A Slavin, PL Willson, P AF Grover, Atul Slavin, Peter L. Willson, Peters TI The Economics of Academic Medical Centers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Grover, Atul; Willson, Peters] Assoc Amer Med Coll, Washington, DC 20001 USA. [Slavin, Peter L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Slavin, Peter L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Grover, A (reprint author), Assoc Amer Med Coll, Washington, DC 20001 USA. NR 4 TC 8 Z9 8 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 19 PY 2014 VL 370 IS 25 BP 2360 EP 2362 DI 10.1056/NEJMp1403609 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0OA UT WOS:000337353000003 PM 24826948 ER PT J AU Huybrechts, KF Palmsten, K Avorn, J Cohen, LS Holmes, LB Franklin, JM Mogun, H Levin, R Kowal, M Setoguchi, S Hernandez-Diaz, S AF Huybrechts, Krista F. Palmsten, Kristin Avorn, Jerry Cohen, Lee S. Holmes, Lewis B. Franklin, Jessica M. Mogun, Helen Levin, Raisa Kowal, Mary Setoguchi, Soko Hernandez-Diaz, Sonia TI Antidepressant Use in Pregnancy and the Risk of Cardiac Defects SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEROTONIN-REUPTAKE INHIBITORS; CONGENITAL-MALFORMATIONS; BIRTH-DEFECTS; MATERNAL USE; PAROXETINE; EXPOSURE; 1ST-TRIMESTER; PREVALENCE; COHORT; METAANALYSIS AB BACKGROUND Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. RESULTS A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. C1 [Huybrechts, Krista F.; Avorn, Jerry; Franklin, Jessica M.; Mogun, Helen; Levin, Raisa; Kowal, Mary; Setoguchi, Soko] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Huybrechts, Krista F.; Avorn, Jerry; Franklin, Jessica M.; Mogun, Helen; Levin, Raisa; Kowal, Mary; Setoguchi, Soko] Harvard Univ, Sch Med, Boston, MA USA. [Palmsten, Kristin; Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cohen, Lee S.] Massachusetts Gen Hosp, Ctr Womens Mental Hlth, Boston, MA 02114 USA. [Holmes, Lewis B.] MassGen Hosp Children, Med Genet Unit, Boston, MA USA. [Setoguchi, Soko] Duke Univ, Sch Med, Durham, NC USA. RP Huybrechts, KF (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM khuybrechts@partners.org FU Agency for Healthcare Research and Quality; National Institutes of Health FX Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health. NR 38 TC 75 Z9 76 U1 5 U2 20 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 19 PY 2014 VL 370 IS 25 BP 2397 EP 2407 DI 10.1056/NEJMoa1312828 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0OA UT WOS:000337353000008 PM 24941178 ER PT J AU Gorman, MP Rincon, SP Pierce, VM AF Gorman, Mark P. Rincon, Sandra P. Pierce, Virginia M. TI Case 19-2014: A 19-Year-Old Woman with Headache, Fever, Stiff Neck, and Mental-Status Changes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MYCOPLASMA-PNEUMONIAE; NEUROMYELITIS-OPTICA; INFECTIOUS-DISEASES; CEREBROSPINAL-FLUID; ENCEPHALITIS; MENINGOENCEPHALITIS; SPECTRUM C1 [Gorman, Mark P.] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Rincon, Sandra P.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Pierce, Virginia M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gorman, Mark P.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Rincon, Sandra P.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Pierce, Virginia M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Gorman, MP (reprint author), Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. NR 28 TC 0 Z9 0 U1 0 U2 2 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 19 PY 2014 VL 370 IS 25 BP 2427 EP 2438 DI 10.1056/NEJMcpc1400838 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0OA UT WOS:000337353000012 PM 24941181 ER PT J AU Shalek, AK Satija, R Shuga, J Trombetta, JJ Gennert, D Lu, DN Chen, PL Gertner, RS Gaublomme, JT Yosef, N Schwartz, S Fowler, B Weaver, S Wang, J Wang, XH Ding, RH Raychowdhury, R Friedman, N Hacohen, N Park, H May, AP Regev, A AF Shalek, Alex K. Satija, Rahul Shuga, Joe Trombetta, John J. Gennert, Dave Lu, Diana Chen, Peilin Gertner, Rona S. Gaublomme, Jellert T. Yosef, Nir Schwartz, Schraga Fowler, Brian Weaver, Suzanne Wang, Jing Wang, Xiaohui Ding, Ruihua Raychowdhury, Raktima Friedman, Nir Hacohen, Nir Park, Hongkun May, Andrew P. Regev, Aviv TI Single-cell RNA-seq reveals dynamic paracrine control of cellular variation SO NATURE LA English DT Article ID GENE-EXPRESSION; MAMMALIAN-CELLS; I INTERFERON; RESPONSES; IMMUNE; QUANTIFICATION; STOCHASTICITY; AMPLIFICATION; TRANSCRIPTOME; VARIABILITY AB High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript's level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a 'core' module of antiviral genes is expressed very early by a few 'precocious' cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced 'peaked' inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses. C1 [Shalek, Alex K.; Gertner, Rona S.; Gaublomme, Jellert T.; Ding, Ruihua; Park, Hongkun] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Shalek, Alex K.; Gertner, Rona S.; Gaublomme, Jellert T.; Ding, Ruihua; Park, Hongkun] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Shalek, Alex K.; Satija, Rahul; Trombetta, John J.; Gennert, Dave; Lu, Diana; Yosef, Nir; Schwartz, Schraga; Raychowdhury, Raktima; Hacohen, Nir; Park, Hongkun; Regev, Aviv] Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Shuga, Joe; Chen, Peilin; Fowler, Brian; Weaver, Suzanne; Wang, Jing; Wang, Xiaohui; May, Andrew P.] Fluidigm Corp, San Francisco, CA 94080 USA. [Friedman, Nir] Hebrew Univ Jerusalem, Sch Comp Sci & Engn, IL-91904 Jerusalem, Israel. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Dept Med, Charlestown, MA 02129 USA. [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02140 USA. RP Satija, R (reprint author), Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM rahuls@broadinstitute.org; Hongkun_Park@harvard.edu; apmay1@gmail.com RI Friedman, Nir/H-9692-2012; OI Friedman, Nir/0000-0002-9678-3550; Shalek, Alex K./0000-0001-5670-8778; Schwartz, Schraga/0000-0002-3671-9709 FU NIH [1F32HD075541-01, U54 AI057159, DP2 OD002230, 5DP1OD003893-03, DP1OD003958-01]; NIH CEGS [1P50HG006193-01]; Broad Institute; Klarman Cell Observatory at the Broad Institute; ISF-Broad Grant; ERC FX We thank B. Tilton, T. Rogers and M. Tam for assistance with cell sorting; E. Shefler, C. Guiducci, D. Thompson, and O. Rozenblatt-Rosen for project management and discussions and the Broad Genomics Platform for sequencing. We thank J. West, R. Lebofsky, A. Leyrat, M. Thu, M. Wong, W. Yorza, D. Toppani, M. Norris and B. Clerkson for contributions to C1 system development; B. Alvarado, M. Ray and L. Knuttson for assistance with C1 experiments; and M. Unger for discussions. Work was supported by an NIH Postdoctoral Fellowship (1F32HD075541-01, R.S.), an NIH grant (U54 AI057159, N.H.), an NIH New Innovator Award (DP2 OD002230, N.H.), an NIH CEGS(1P50HG006193-01, H.P., N.H., A.R.), NIH Pioneer Awards (5DP1OD003893-03 to H.P., DP1OD003958-01 to A.R.), the Broad Institute (H.P. and A.R.), HHMI (A.R.), the Klarman Cell Observatory at the Broad Institute (A.R.), an ISF-Broad Grant (N.F.), and the ERC (N.F.). NR 36 TC 186 Z9 191 U1 12 U2 140 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 19 PY 2014 VL 510 IS 7505 BP 363 EP + DI 10.1038/nature13437 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ0NG UT WOS:000337350200028 PM 24919153 ER PT J AU Gitajn, IL Abousayed, M Toussaint, RJ Ting, B Jin, J Kwon, JY AF Gitajn, Ida Leah Abousayed, Mostafa Toussaint, Rull James Ting, Beverlie Jin, Jenny Kwon, John Y. TI Anatomic Alignment and Integrity of the Sustentaculum Tali in Intra-Articular Calcaneal Fractures Is the Sustentaculum Tali Truly Constant? SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID MEDIAL APPROACH TECHNIQUE; OPERATIVE TREATMENT; INTERNAL-FIXATION; NONOPERATIVE TREATMENT; COMPUTED-TOMOGRAPHY; OPEN REDUCTION; FRAGMENT; TRIAL AB Background: In an intra-articular calcaneal fracture, the sustentaculum tali is generally thought to remain tightly bound to the talus by the interosseous talocalcaneal ligaments, spring ligament, and deltoid ligament, providing a "constant'' fragment that remains anatomically aligned. The extensile lateral approach is commonly used for reduction based on this assumption, but because it provides only limited access to the medial aspect of the calcaneus, indirect fracture reduction is required to restore an anatomic relationship of these fragments to the sustentacular fragment. The purpose of this study was to determine the prevalence and displacement of sustentacular fractures in patients with an intra-articular calcaneal fracture, and thus determine whether the sustentacular fragment can be accurately considered as constant and can be consistently relied on to maintain anatomic alignment. Methods: All patients with an intra-articular calcaneal fracture who presented to two level-I trauma centers from 2006 to 2012 were included in the study if computed tomography scanning was performed. The presence or absence of a sustentacular fracture was documented, along with the displacement and the comminution of any such fracture and the subluxation or dislocation of the sustentaculum tali. Results: Sustentacular fractures were present in ninety-four (44.3%) of the 212 patients who met the inclusion criteria. Seventy-two (76.6%) of the sustentacular fractures were nondisplaced, eleven (11.7%) were displaced, and ten (10.6%) were comminuted. The articulation between the sustentaculum tali and the talus was anatomically aligned in 166 (78.3%) of the calcaneal fractures, subluxated in forty-three (20.3%), and dislocated in two (0.9%). Conclusions: This study provides a detailed description of the frequency of sustentacular fractures, the displacement of such fractures, and articular subluxation or dislocation associated with intra-articular calcaneal fractures. Fixation by means of a lateral approach may be compromised when the sustentaculum tali is fractured or subluxated. A medial approach or combined medial and lateral approaches may be considered in such circumstances. Special attention should be paid to the integrity and alignment of the sustentacular fragment prior to surgical fixation. C1 [Gitajn, Ida Leah; Abousayed, Mostafa; Toussaint, Rull James; Ting, Beverlie; Jin, Jenny; Kwon, John Y.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Gitajn, IL (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM igitajn@partners.org NR 26 TC 4 Z9 5 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUN 18 PY 2014 VL 96A IS 12 BP 1000 EP 1005 DI 10.2106/JBJS.M.00330 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AR8AQ UT WOS:000343798400014 PM 24951735 ER PT J AU Kelley, JM AF Kelley, John M. TI The Influence of the Patient-Clinician Relationship on Healthcare Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (vol 9, e94207, 2014) SO PLOS ONE LA English DT Correction C1 [Kelley, John M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Empathy & Relat Sci Program,Psychiat Dept, Boston, MA 02138 USA. [Kelley, John M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Program Placebo Studies & Therapeut Encounter, Boston, MA 02215 USA. [Kelley, John M.] Endicott Coll, Dept Psychol, Beverly, MA USA. RP Kelley, JM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Empathy & Relat Sci Program,Psychiat Dept, Boston, MA 02138 USA. NR 1 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2014 VL 9 IS 6 AR e101191 DI 10.1371/journal.pone.0101191 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6AC UT WOS:000338508200111 ER PT J AU Meijer, DH Sun, Y Liu, T Kane, MF Alberta, JA Adelmant, G Kupp, R Marto, JA Rowitch, DH Nakatani, Y Stiles, CD Mehta, S AF Meijer, Dimphna H. Sun, Yu Liu, Tao Kane, Michael F. Alberta, John A. Adelmant, Guillaume Kupp, Robert Marto, Jarrod A. Rowitch, David H. Nakatani, Yoshihiro Stiles, Charles D. Mehta, Shwetal TI An Amino Terminal Phosphorylation Motif Regulates Intranuclear Compartmentalization of Olig2 in Neural Progenitor Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE bHLH; intranuclear localization; NuRD complex; Olig2; p53; phosphorylation ID HELIX TRANSCRIPTION FACTORS; CENTRAL-NERVOUS-SYSTEM; OLIGODENDROCYTE DIFFERENTIATION; STEM-CELLS; PROTEIN COMPLEXES; MALIGNANT GLIOMA; GENE-EXPRESSION; CHROMATIN; FRACTIONATION; SPECIFICATION AB The bHLH transcription factor Olig2 is expressed in cycling neural progenitor cells but also in terminally differentiated, myelinating oligodendrocytes. Sustained expression of Olig2 is counterintuitive because all known functions of the protein in expansion of neural progenitors and specification of oligodendrocyte progenitors are completed with the formation of mature white matter. How are the biological functions of Olig2 suppressed in terminally differentiated oligodendrocytes? In previous studies, we have shown that a triple serine motif in the amino terminus of Olig2 is phosphorylated in cycling neural progenitors but not in their differentiated progeny. We now show that phosphorylation of the triple serine motif regulates intranuclear compartmentalization of murine Olig2. Phosphorylated Olig2 is preferentially localized to a transcriptionally active "open" chromatin compartment together with coregulator proteins essential for regulation of gene expression. Unphosphorylated Olig2, as seen in mature white matter, is localized mainly within a transcriptionally inactive, chromatin fraction characterized by condensed and inaccessible DNA. Of special note is the observation that the p53 tumor suppressor protein is confined to the open chromatin fraction. Proximity ligation assays show that phosphorylation brings Olig2 within 30 nm of p53 within the open chromatin compartment. The data thus shed light on previously noted promitogenic functions of phosphorylated Olig2, which reflect, at least in part, an oppositional relationship with p53 functions. C1 [Meijer, Dimphna H.; Sun, Yu; Kane, Michael F.; Alberta, John A.; Nakatani, Yoshihiro; Stiles, Charles D.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02215 USA. [Meijer, Dimphna H.; Sun, Yu; Kane, Michael F.; Alberta, John A.; Nakatani, Yoshihiro; Stiles, Charles D.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Liu, Tao] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Liu, Tao] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Pediat, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Neurol Surg, San Francisco, CA 94143 USA. [Kupp, Robert; Mehta, Shwetal] St Josephs Hosp, Dept Neurosurg, Barrow Brain Tumor Res Ctr, Barrow Neurol Inst, Phoenix, AZ 85013 USA. RP Stiles, CD (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM Charles_stiles@dfci.harvard.edu; Shwetal.Mehta@dignityhealth.org RI Liu, Tao/G-3585-2010; OI Liu, Tao/0000-0002-8818-8313; Liu, Tao/0000-0003-0446-9001 FU National Institutes of Health [NS047572, NS057727, NS040511]; Pediatric Low-Grade Astrocytoma Foundation; VSB fonds; Prins Bernard Cultuurfonds FX This work was supported by National Institutes of Health Grants NS047572 and NS057727 to C.D.S. and Grant NS040511 to D.H.R. and the Pediatric Low-Grade Astrocytoma Foundation (to C.D.S.). D.H.M. was supported by VSB fonds and Prins Bernard Cultuurfonds. We thank Dr. Alexander Gimelbrant at Dana-Farber Cancer Institute for helpful conversations. NR 73 TC 5 Z9 5 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 18 PY 2014 VL 34 IS 25 BP 8507 EP 8518 DI 10.1523/JNEUROSCI.0309-14.2014 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AK5FD UT WOS:000338449200013 PM 24948806 ER PT J AU Benaglio, P San Jose, PF Avila-Fernandez, A Ascari, G Harper, S Manes, G Ayuso, C Hamel, C Berson, EL Rivolta, C AF Benaglio, Paola Fernandez San Jose, Patricia Avila-Fernandez, Almudena Ascari, Giulia Harper, Shyana Manes, Gael Ayuso, Carmen Hamel, Christian Berson, Eliot L. Rivolta, Carlo TI Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa SO MOLECULAR VISION LA English DT Article ID TRI-SNRNP; MANDIBULOFACIAL DYSOSTOSIS; PROTEIN; HAPLOINSUFFICIENCY; SPLICEOSOME; PHENOTYPE; VARIANTS; DEFECTS; HOMOLOG; LEADS AB Purpose: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. Methods: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. Results: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. Conclusions: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin. C1 [Benaglio, Paola; Ascari, Giulia; Rivolta, Carlo] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Fernandez San Jose, Patricia; Avila-Fernandez, Almudena; Ayuso, Carmen] Fdn Jimenez Diaz Univ Hosp IIS FJD, UAM, Inst Invest Sanitaria, Dept Genet, Madrid, Spain. [Fernandez San Jose, Patricia; Avila-Fernandez, Almudena; Ayuso, Carmen] ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain. [Harper, Shyana; Berson, Eliot L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA USA. [Manes, Gael; Hamel, Christian] Hop St Eloi, INSERM, Inst Neurosci Montpellier, U1051, Montpellier, France. RP Rivolta, C (reprint author), Univ Lausanne, Dept Med Genet, Rue Bugnon 27, CH-1005 Lausanne, Switzerland. EM carlo.rivolta@unil.ch OI Ayuso, Carmen/0000-0002-9242-7065 FU Swiss National Science Foundation [310030_138346]; Gebert-Ruf Foundation (Rare Diseases - New Technologies Grant); Foundation Fighting Blindness USA [CIBERER 06/07/0036, FIS PI 13/00226, RD 09-0076-00101]; Spanish Ministry of Health, ONCE [Rio Hortega CM12/00013]; FUNDALUCE FX For this study we acknowledge the help of the teams of Drs. Keith Harshman and Marzanna Kunzli from the Lausanne Genomic Technologies Facility and the Functional Genomic Centre Zurich, respectively, for the sequencing experiments; Dr. Peter Rogan (Cytognomix) for providing free access to the Shannon Human Splicing Pipeline, used to analyze the variants of this study. We are grateful for access to exome sequence data from the CoLaus cohort, which was sequenced as part of a partnership between the Wellcome Trust Sanger Institute, the CoLaus principal investigators and the Quantitative Sciences Department of GlaxoSmithKline. This study was supported by the following research grants: the Swiss National Science Foundation (Grant Number 310030_138346), the Gebert-Ruf Foundation (Rare Diseases - New Technologies Grant), the Foundation Fighting Blindness USA, CIBERER 06/07/0036, FIS PI 13/00226, RD 09-0076-00101 (Retics Bionbank) and Rio Hortega CM12/00013 from the Spanish Ministry of Health, ONCE and FUNDALUCE. NR 42 TC 3 Z9 3 U1 1 U2 7 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 18 PY 2014 VL 20 BP 843 EP 851 PG 9 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA AK3KF UT WOS:000338321500001 PM 24959063 ER PT J AU Wu, HY Liu, KH Wang, YC Wu, JF Chiu, WL Chen, CY Wu, SH Sheen, J Lai, EM AF Wu, Hung-Yi Liu, Kun-Hsiang Wang, Yi-Chieh Wu, Jing-Fen Chiu, Wan-Ling Chen, Chao-Ying Wu, Shu-Hsing Sheen, Jen Lai, Erh-Min TI AGROBEST: an efficient Agrobacterium-mediated transient expression method for versatile gene function analyses in Arabidopsis seedlings SO PLANT METHODS LA English DT Article DE Agrobacterium; Arabidopsis; Transient transformation; Gene expression; Innate immunity; Gain-of-function ID MESOPHYLL PROTOPLASTS; PLANT TRANSFORMATION; MOLECULAR-PATTERNS; T-DNA; ARTIFICIAL MICRORNA; DEFENSE RESPONSES; CIRCADIAN CLOCK; INNATE IMMUNITY; TUMEFACIENS; PERCEPTION AB Background: Transient gene expression via Agrobacterium-mediated DNA transfer offers a simple and fast method to analyze transgene functions. Although Arabidopsis is the most-studied model plant with powerful genetic and genomic resources, achieving highly efficient and consistent transient expression for gene function analysis in Arabidopsis remains challenging. Results: We developed a highly efficient and robust Agrobacterium-mediated transient expression system, named AGROBEST (Agrobacterium-mediated enhanced seedling transformation), which achieves versatile analysis of diverse gene functions in intact Arabidopsis seedlings. Using beta-glucuronidase (GUS) as a reporter for Agrobacterium-mediated transformation assay, we show that the use of a specific disarmed Agrobacterium strain with vir gene pre-induction resulted in homogenous GUS staining in cotyledons of young Arabidopsis seedlings. Optimization with AB salts in plant culture medium buffered with acidic pH 5.5 during Agrobacterium infection greatly enhanced the transient expression levels, which were significantly higher than with two existing methods. Importantly, the optimized method conferred 100% infected seedlings with highly increased transient expression in shoots and also transformation events in roots of similar to 70% infected seedlings in both the immune receptor mutant efr-1 and wild-type Col-0 seedlings. Finally, we demonstrated the versatile applicability of the method for examining transcription factor action and circadian reporter-gene regulation as well as protein subcellular localization and protein-protein interactions in physiological contexts. Conclusions: AGROBEST is a simple, fast, reliable, and robust transient expression system enabling high transient expression and transformation efficiency in Arabidopsis seedlings. Demonstration of the proof-of-concept experiments elevates the transient expression technology to the level of functional studies in Arabidopsis seedlings in addition to previous applications in fluorescent protein localization and protein-protein interaction studies. In addition, AGROBEST offers a new way to dissect the molecular mechanisms involved in Agrobacterium-mediated DNA transfer. C1 [Wu, Hung-Yi; Wang, Yi-Chieh; Wu, Jing-Fen; Wu, Shu-Hsing; Lai, Erh-Min] Acad Sinica, Inst Plant & Microbial Biol, Taipei 11529, Taiwan. [Wu, Hung-Yi; Chen, Chao-Ying; Lai, Erh-Min] Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10617, Taiwan. [Liu, Kun-Hsiang; Chiu, Wan-Ling; Sheen, Jen; Lai, Erh-Min] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Liu, Kun-Hsiang; Chiu, Wan-Ling; Sheen, Jen; Lai, Erh-Min] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Liu, Kun-Hsiang; Chiu, Wan-Ling; Sheen, Jen; Lai, Erh-Min] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Chiu, Wan-Ling] Virginia Commonwealth Univ, Ctr Study Biol Complex, Richmond, VA 23284 USA. RP Lai, EM (reprint author), Acad Sinica, Inst Plant & Microbial Biol, Taipei 11529, Taiwan. EM emlai@gate.sinica.edu.tw OI Wu, Shu-Hsing/0000-0002-7179-3138; CHEN, CHAO-YING/0000-0003-0455-832X FU National Science Council of Taiwan [NSC 99-2918-I-001-005, NSC 101-2321-B-001-033, NSC100-2311-B-001-028-MY3]; US National Institutes of Health [R01GM60493, R01GM70567] FX The authors thank Hau-Hsuan Hwang, Lay-Sun Ma, Jer-Sheng Lin, and Po-Yuan Shih for discussion and critical reading of the manuscript; and Yajie Niu and Hoosun Chung for preliminary transient expression tests on different seedling ages. We thank Dr. Inhwan Hwang for NLS-RFP; Drs. Stanton Gelvin and Lan-Ying Lee for pBISN1, Venus-intron and BiFC vectors; and Ms. Mei-Jane Fang from the Cell Biology Core Laboratory at the Institute of Plant and Microbial Biology, Academia Sinica, for excellent technical support on confocal microscopy. This work was supported by research grants from the National Science Council of Taiwan (NSC 99-2918-I-001-005 and NSC 101-2321-B-001-033 to E. M. Lai, NSC100-2311-B-001-028-MY3 to S. H. Wu) and the US National Institutes of Health (R01GM60493 and R01GM70567 to J. Sheen). NR 57 TC 10 Z9 11 U1 4 U2 46 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-4811 J9 PLANT METHODS JI Plant Methods PD JUN 18 PY 2014 VL 10 AR 19 DI 10.1186/1746-4811-10-19 PG 16 WC Biochemical Research Methods; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA AK4DB UT WOS:000338373100001 PM 24987449 ER PT J AU Hyman, BT AF Hyman, Bradley T. TI Tau Propagation, Different Tau Phenotypes, and Prion-like Properties of Tau SO NEURON LA English DT Editorial Material ID ALZHEIMERS-DISEASE; IN-VIVO; PATHOLOGY C1 Massachusetts Gen Hosp, Neurol Serv, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Neurol Serv, 114 16th St, Charlestown, MA 02129 USA. EM bhyman@mgh.harvard.edu NR 14 TC 10 Z9 10 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 18 PY 2014 VL 82 IS 6 BP 1189 EP 1190 DI 10.1016/j.neuron.2014.06.004 PG 2 WC Neurosciences SC Neurosciences & Neurology GA AJ0QO UT WOS:000337360700001 PM 24945760 ER PT J AU Chatterjee, S Chakraborty, A Weinberg, I Kadakia, M Wilensky, RL Sardar, P Kumbhani, DJ Mukherjee, D Jaff, MR Giri, J AF Chatterjee, Saurav Chakraborty, Anasua Weinberg, Ido Kadakia, Mitul Wilensky, Robert L. Sardar, Partha Kumbhani, Dharam J. Mukherjee, Debabrata Jaff, Michael R. Giri, Jay TI Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage A Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CONTROLLED CLINICAL-TRIAL; RANDOMIZED-TRIAL; VENOUS THROMBOEMBOLISM; PLASMINOGEN-ACTIVATOR; SEQUENTIAL-ANALYSIS; INFORMATION SIZE; PROGNOSTIC VALUE; HEPARIN; THERAPY; ALTEPLASE AB IMPORTANCE Thrombolytic therapy may be beneficial in the treatment of some patients with pulmonary embolism. To date, no analysis has had adequate statistical power to determine whether thrombolytic therapy is associated with improved survival, compared with conventional anticoagulation. OBJECTIVE To determine mortality benefits and bleeding risks associated with thrombolytic therapy compared with anticoagulation in acute pulmonary embolism, including the subset of hemodynamically stable patients with right ventricular dysfunction (intermediate-risk pulmonary embolism). DATA SOURCES PubMed, the Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from inception through April 10, 2014. STUDY SELECTION Eligible studies were randomized clinical trials comparing thrombolytic therapy vs anticoagulant therapy in pulmonary embolism patients. Sixteen trials comprising 2115 individuals were identified. Eight trials comprising 1775 patients specified inclusion of patients with intermediate-risk pulmonary embolism. DATA EXTRACTION AND SYNTHESIS Two reviewers independently extracted trial-level data including number of patients, patient characteristics, duration of follow-up, and outcomes. MAIN OUTCOMES AND MEASURES The primary outcomes were all-cause mortality and major bleeding. Secondary outcomes were risk of recurrent embolism and intracranial hemorrhage (ICH). Peto odds ratio (OR) estimates and associated 95% CIs were calculated using a fixed-effects model. RESULTS Use of thrombolytics was associated with lower all-cause mortality (OR, 0.53; 95% CI, 0.32-0.88; 2.17%[23/1061] vs 3.89% [41/1054] with anticoagulants; number needed to treat [NNT] = 59) and greater risks of major bleeding (OR, 2.73; 95% CI, 1.91-3.91; 9.24% [98/1061] vs 3.42%[36/1054]; number needed to harm [NNH] = 18) and ICH (OR, 4.63; 95% CI, 1.78-12.04; 1.46%[15/1024] vs 0.19% [2/1019]; NNH = 78). Major bleeding was not significantly increased in patients 65 years and younger (OR, 1.25; 95% CI, 0.50-3.14). Thrombolysis was associated with a lower risk of recurrent pulmonary embolism (OR, 0.40; 95% CI, 0.22-0.74; 1.17%[12/1024] vs 3.04%[31/1019]; NNT = 54). In intermediate-risk pulmonary embolism trials, thrombolysis was associated with lower mortality (OR, 0.48; 95% CI, 0.25-0.92) and more major bleeding events (OR, 3.19; 95% CI, 2.07-4.92). CONCLUSIONS AND RELEVANCE Among patients with pulmonary embolism, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH. However, findings may not apply to patients with pulmonary embolism who are hemodynamically stable without right ventricular dysfunction. C1 [Chatterjee, Saurav] Mt Sinai Hlth Syst, Div Cardiol, St Lukes Roosevelt Hosp Ctr, New York, NY USA. [Chakraborty, Anasua] Thomas Jefferson Univ Hosp, Div Pulmonol & Crit Care, Philadelphia, PA 19107 USA. [Weinberg, Ido; Jaff, Michael R.] Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. [Kadakia, Mitul; Wilensky, Robert L.; Giri, Jay] Univ Penn, Div Cardiovasc Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sardar, Partha; Mukherjee, Debabrata] Texas Tech Univ, Div Cardiol, El Paso, TX USA. [Kumbhani, Dharam J.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. RP Giri, J (reprint author), Hosp Univ Penn, Div Cardiovasc Med, Gates Pavil,Ninth Floor,3400 Spruce St, Philadelphia, PA 19104 USA. EM giri.jay@gmail.com FU EKOS Corporation; Embolitech; Boston Scientific; Cordis Corporation FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jaff reported having served as a consultant to AstraZeneca; having received support from EKOS Corporation, Embolitech, Boston Scientific, and Cordis Corporation; and being a board member for VIVA Physicians, a 501(c)(3) not-for profit education and research organization. Dr Wilensky reported being a member of the scientific advisor boards of Cardiostem, GenWay, Soteria, and Vascular Magnetics and having equity interest in Johnson & Johnson. No other disclosures were reported. NR 42 TC 99 Z9 101 U1 0 U2 10 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 18 PY 2014 VL 311 IS 23 BP 2414 EP 2421 DI 10.1001/jama.2014.5990 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AI9XV UT WOS:000337301500022 PM 24938564 ER PT J AU Fling, BW Cohen, RG Mancini, M Carpenter, SD Fair, DA Nutt, JG Horak, FB AF Fling, Brett W. Cohen, Rajal G. Mancini, Martina Carpenter, Samuel D. Fair, Damien A. Nutt, John G. Horak, Fay B. TI Functional Reorganization of the Locomotor Network in Parkinson Patients with Freezing of Gait SO PLOS ONE LA English DT Article ID SUPPLEMENTARY MOTOR AREA; HUMAN BASAL GANGLIA; COGNITIVE CONTROL; DISEASE; BRAIN; CONNECTIVITY; MOVEMENT; CORTEX; PEDUNCULOPONTINE; NEUROPHYSIOLOGY AB Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accompanies advanced Parkinson's disease (PD) and significantly impairs mobility. The current study uses a multimodal neuroimaging approach to assess differences in the functional and structural locomotor neural network in PD patients with and without FoG and relates these findings to measures of FoG severity. Twenty-six PD patients and fifteen age-matched controls underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging along with self-reported and clinical assessments of FoG. After stringent movement correction, fifteen PD patients and fourteen control participants were available for analysis. We assessed functional connectivity strength between the supplementary motor area (SMA) and the following locomotor hubs: 1) subthalamic nucleus (STN), 2) mesencephalic and 3) cerebellar locomotor region (MLR and CLR, respectively) within each hemisphere. Additionally, we quantified structural connectivity strength between locomotor hubs and assessed relationships with metrics of FoG. FoG+ patients showed greater functional connectivity between the SMA and bilateral MLR and between the SMA and left CLR compared to both FoG- and controls. Importantly, greater functional connectivity between the SMA and MLR was positively correlated with i) clinical, ii) self-reported and iii) objective ratings of freezing severity in FoG+, potentially reflecting a maladaptive neural compensation. The current findings demonstrate a reorganization of functional communication within the locomotor network in FoG+ patients whereby the higher-order motor cortex (SMA) responsible for gait initiation communicates with the MLR and CLR to a greater extent than in FoG- patients and controls. The observed pattern of altered connectivity in FoG+ may indicate a failed attempt by the CNS to compensate for the loss of connectivity between the STN and SMA and may reflect a loss of lower-order, automatic control of gait by the basal ganglia. C1 [Fling, Brett W.; Mancini, Martina; Nutt, John G.; Horak, Fay B.] Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, Portland, OR 97201 USA. [Carpenter, Samuel D.; Fair, Damien A.] Oregon Hlth & Sci Univ, Sch Med, Dept Behav Neurosci, Portland, OR 97201 USA. [Fair, Damien A.] Oregon Hlth & Sci Univ, Sch Med, Dept Psychiat, Portland, OR 97201 USA. [Cohen, Rajal G.] Univ Idaho, Dept Psychol & Commun Studies, Moscow, ID 83843 USA. [Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. RP Fling, BW (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, Portland, OR 97201 USA. EM fling@ohsu.edu FU Pacific Northwest Udall Center (PANUC); National Institute on Aging [R37 AG006457]; National Multiple Sclerosis Society [MB0011]; Oregon Clinical and Translational Research Institute (OCTRI) from the National Center for Research Resources (NCRR) a component of the National Institutes of Health (NIH) [UL1 RR024140]; NIH Roadmap for Medical Research FX This work was supported by pilot awards from the Pacific Northwest Udall Center (PANUC; RC), a MERIT award from the National Institute on Aging (FH: R37 AG006457), and a postdoctoral Mentored Research Award from the National Multiple Sclerosis Society (Horak #MB0011). Additional support was provided from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 43 Z9 43 U1 3 U2 16 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 17 PY 2014 VL 9 IS 6 AR e100291 DI 10.1371/journal.pone.0100291 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5YM UT WOS:000338503400101 PM 24937008 ER PT J AU Fuchs, MA Sato, K Niedzwiecki, D Ye, X Saltz, LB Mayer, RJ Mowat, RB Whittom, R Hantel, A Benson, A Atienza, D Messino, M Kindler, H Venook, A Ogino, S Wu, KN Willett, WC Giovannucci, EL Meyerhardt, JA AF Fuchs, Michael A. Sato, Kaori Niedzwiecki, Donna Ye, Xing Saltz, Leonard B. Mayer, Robert J. Mowat, Rex B. Whittom, Renaud Hantel, Alexander Benson, Al Atienza, Daniel Messino, Michael Kindler, Hedy Venook, Alan Ogino, Shuji Wu, Kana Willett, Walter C. Giovannucci, Edward L. Meyerhardt, Jeffrey A. TI Sugar-Sweetened Beverage Intake and Cancer Recurrence and Survival in CALGB 89803 (Alliance) SO PLOS ONE LA English DT Article ID III COLON-CANCER; FOOD FREQUENCY QUESTIONNAIRE; DIETARY GLYCEMIC LOAD; GROWTH-FACTOR-I; COLORECTAL-CANCER; BODY-WEIGHT; EPIDEMIOLOGIC EVIDENCE; PHYSICAL-ACTIVITY; CELL-LINE; C-PEPTIDE AB Background: In colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown. Methods: We assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models. Results: Patients consuming >= 2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04-2.68), compared with those consuming <2 servings per month (P-trend = 0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index >= 25 kg/m(2)) and less physically active (metabolic equivalent task-hours per week < 18) (HR = 2.22; 95% CI, 1.29-3.81, P-trend = 0.0025). Conclusion: Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients. C1 [Fuchs, Michael A.] Brown Univ, Providence, RI 02912 USA. [Sato, Kaori; Mayer, Robert J.; Ogino, Shuji; Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Niedzwiecki, Donna; Ye, Xing] Duke Univ, Med Ctr, Alliance Stat & Data Ctr, Durham, NC USA. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mowat, Rex B.] Toledo Community Hosp, Oncol Program, Toledo, OH USA. [Whittom, Renaud] Hop Sacre Coeur, Montreal, PQ H4J 1C5, Canada. [Hantel, Alexander] Loyola Univ, Stritch Sch Med, Naperville, IL USA. [Benson, Al] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Atienza, Daniel] Virginia Oncol Associates, Norfolk, VA USA. [Messino, Michael] Mission Hosp Inc, Southeast Canc Control Consortium, Asheville, NC USA. [Kindler, Hedy] Univ Chicago, Chicago, IL 60637 USA. [Venook, Alan] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wu, Kana; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM jmeyerhardt@partners.org OI Saltz, Leonard/0000-0001-8353-4670 FU National Cancer Institute [CA31946, R01 CA118553, R01 CA149222, R01 CA169141, P50 CA127003, CA33601]; Pfizer Oncology FX CALGB 89803 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica Bertagnolli, M. D., Chairman) and to the Alliance Statistical Center (Daniel Sargent, PhD, CA33601 as well as support from Pharmacia & Upjohn Company, now Pfizer Oncology. Dr. Meyerhardt is supported in part by grants from the National Cancer Institute (R01 CA118553, R01 CA149222, R01 CA169141, and P50 CA127003). The sponsors did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 48 TC 6 Z9 6 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 17 PY 2014 VL 9 IS 6 AR e99816 DI 10.1371/journal.pone.0099816 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5YM UT WOS:000338503400040 PM 24937507 ER PT J AU Kim, YM Lee, SW Chun, SM Kim, DY Kim, JH Kim, KR Kim, YT Nam, JH van Hummelen, P MacConaill, LE Hahn, WC Jang, SJ AF Kim, Yong-Man Lee, Shin-Wha Chun, Sung-Min Kim, Dae-Yeon Kim, Jong-Hyeok Kim, Kyu-Rae Kim, Young-Tak Nam, Joo-Hyun van Hummelen, Paul MacConaill, Laura E. Hahn, William C. Jang, Se Jin TI Analysis and Comparison of Somatic Mutations in Paired Primary and Recurrent Epithelial Ovarian Cancer Samples SO PLOS ONE LA English DT Article ID FACTOR-RECEPTOR MUTATIONS; CELL LUNG-CANCER; COLORECTAL-CANCER; K-RAS; ADENOCARCINOMA; EXPRESSION; TUMORS; HETEROGENEITY; CARCINOMAS; GEFITINIB AB The TP53 mutations have been proved to be predominated in ovarian cancer in a study from The Cancer Genome Atlas (TCGA). However, the molecular characteristics of recurrent ovarian cancers following initial treatment have been poorly estimated. This study was to investigate the pattern of somatic point mutations in matched paired samples of primary and recurrent epithelial ovarian cancers, using the OncoMap mutation detection protocol. We have adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. OncoMap v. 4.4 was used to evaluate genomic DNA isolated from a set of 92 formalin-fixed, paraffin-embedded (FFPE) tumors, consisting of matched paired samples of initially diagnosed and recurrent tumors from 46 epithelial ovarian cancer (EOC) patients. Mutations were observed in 33.7% of the samples, with 29.3% of these samples having a single mutation and the remaining 4.3% having two or more mutations. Among the 41 genes analyzed, 35 mutations were found in four genes, namely, CDKN2A (2.2%), KRAS (6.5%), MLH1 (8.2%) and TP53 (20.7%). TP53 was the most frequently mutated gene, but there was no correlation between the presence of mutation in any gene and clinical prognosis. Furthermore, somatic mutations did not differ between primary and recurrent ovarian carcinomas. Every mutation present in recurrent samples was detected in the corresponding primary sample. In conclusion, these OncoMap data of Korean EOC samples provide that somatic mutations were found in CDKN2A, KRAS, MLH1, and TP53. No differences in mutational status between primary and recurrent samples were detected. To understand the biology of tumor recurrence in epithelial ovarian cancer, more studies are necessary, including epigenetic modifications or additional mutations in other genes. C1 [Kim, Yong-Man; Lee, Shin-Wha; Kim, Dae-Yeon; Kim, Jong-Hyeok; Kim, Young-Tak; Nam, Joo-Hyun] Univ Ulsan, ASAN Med Ctr, Dept Obstet & Gynecol, Seoul, South Korea. [Chun, Sung-Min; Kim, Kyu-Rae; Jang, Se Jin] Univ Ulsan, ASAN Med Ctr, Dept Pathol, Seoul, South Korea. [van Hummelen, Paul; MacConaill, Laura E.; Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [van Hummelen, Paul; MacConaill, Laura E.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, Yong-Man; Lee, Shin-Wha; Chun, Sung-Min; Jang, Se Jin] ASAN Med Ctr, ASAN Ctr Canc Genome Discovery, Seoul, South Korea. RP Jang, SJ (reprint author), Univ Ulsan, ASAN Med Ctr, Dept Pathol, Seoul, South Korea. EM jangsejin@amc.seoul.kr FU Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology (MEST) [2011-0030105] FX This study was supported by a grant of the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) (2011-0030105). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 6 Z9 6 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 17 PY 2014 VL 9 IS 6 AR e99451 DI 10.1371/journal.pone.0099451 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5YM UT WOS:000338503400019 PM 24936796 ER PT J AU Zhang, QX Ren, H Baker, GL AF Zhang, Quanxuan Ren, Hong Baker, Gregory L. TI An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards 'clickable' biodegradable polylactide SO BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY LA English DT Article DE alkylation; 'click' chemistry; 'clickable' polylactide; decomposition; diethyl 2-acetamidomalonate; 2-hydroxy-4-pentynoic acid; one-pot; optimization; propargyl bromide; propargyl tosylate; safe and economical ID RING-OPENING POLYMERIZATION; IN-VITRO SYNTHESIS; POLY(ALPHA-HYDROXY ACID); EPSILON-CAPROLACTONE; AMINO-ACIDS; COPOLYMERS; ANALOGS; ALCOHOLS; HYDROXY; DESIGN AB 2-Hydroxy-4-pentynoic acid (1) is a key intermediate towards 'clickable' polylactide which allows for efficient introduction of a broad range of pendant functional groups onto polymers from a single monomer via convenient 'click' chemistry with organic azides. The incorporation of various pendant functional groups could effectively tailor the physicochemical properties of polylactide. The reported synthesis of 1 started from propargyl bromide and ethyl glyoxylate. However, both of starting materials are expensive and unstable; especially, propargyl bromide is shock-sensitive and subjected to thermal explosive decomposition, which makes the preparation of 1 impractical with high cost and high risk of explosion. Herein, we report a simple, economical and safe synthetic route to prepare 1 using cheap and commercially available diethyl 2-acetamidomalonate (4) and propargyl alcohol. The desired product 1 was obtained via alkylation of malonate 4 with propargyl tosylate followed by a one-pot four-step sequence of hydrolysis, decarboxylation, diazotization and hydroxylation of propargylic malonate 5 without work-up of any intermediate. C1 [Zhang, Quanxuan; Baker, Gregory L.] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Ren, Hong] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Ren, Hong] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Med Sch, Charlestown, MA 02129 USA. RP Zhang, QX (reprint author), Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. EM zhangqua@msu.edu RI Ren, Hong/J-5191-2015 OI Ren, Hong/0000-0003-0375-0360 NR 47 TC 2 Z9 2 U1 4 U2 36 PU BEILSTEIN-INSTITUT PI FRANKFURT AM MAIN PA TRAKEHNER STRASSE 7-9, FRANKFURT AM MAIN, 60487, GERMANY SN 1860-5397 J9 BEILSTEIN J ORG CHEM JI Beilstein J. Org. Chem. PD JUN 17 PY 2014 VL 10 BP 1365 EP 1371 DI 10.3762/bjoc.10.139 PG 7 WC Chemistry, Organic SC Chemistry GA AK6XA UT WOS:000338569400001 PM 24991290 ER PT J AU Roussakis, E Spencer, JA Lin, CP Vinogradov, SA AF Roussakis, Emmanuel Spencer, Joel A. Lin, Charles P. Vinogradov, Sergei A. TI Two-Photon Antenna-Core Oxygen Probe with Enhanced Performance SO ANALYTICAL CHEMISTRY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; IN-VIVO; PHOSPHORESCENCE LIFETIME; TISSUE OXYGENATION; ELECTRON-TRANSFER; REDOX POTENTIALS; PARTIAL-PRESSURE; QUANTUM YIELDS; TRIPLET-STATES; PD COMPLEXES AB Recent development of two-photon phosphorescence lifetime microscopy (2PLM) of oxygen enabled first noninvasive high-resolution measurements of tissue oxygenation in vivo in 3D, providing valuable physiological information. The so far developed two-photon-enhanced phosphorescent probes comprise antenna-core constructs, in which two-photon absorbing chromophores (antenna) capture and channel excitation energy to a phosphorescent core (metalloporphyrin) via intramolecular excitation energy transfer (EET). These probes allowed demonstration of the methods' potential; however, they suffer from a number of limitations, such as partial loss of emissivity to competing triplet state deactivation pathways (e.g., electron transfer) and suboptimal sensitivity to oxygen, thereby limiting spatial and temporal resolution of the method. Here we present a new probe, PtTCHP-C307, designed to overcome these limitations. The key improvements include significant increase in the phosphorescence quantum yield, higher efficiency of the antenna-core energy transfer, minimized quenching of the phosphorescence by electron transfer and increased signal dynamic range. For the same excitation flux, the new probe is able to produce up to 6-fold higher signal output than previously reported molecules. Performance of PtTCHP-C307 was demonstrated in vivo in pO(2) measurements through the intact mouse skull into the bone marrow, where all blood cells are made from hematopoietic stem cells. C1 [Roussakis, Emmanuel; Vinogradov, Sergei A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Roussakis, Emmanuel; Spencer, Joel A.; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Roussakis, Emmanuel; Spencer, Joel A.; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. RP Vinogradov, SA (reprint author), Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. EM vinograd@mail.med.upenn.edu FU Penn Medicine Neuroscience Center; Penn Abramson Cancer Center; Regional Laser and Biomedical Technology Laboratories (RLBL) (NIH/NCRR) [P41RR001348] FX Support of the Penn Medicine Neuroscience Center and the Penn Abramson Cancer Center are gratefully acknowledged. Fluorescence lifetime measurements were performed in the Regional Laser and Biomedical Technology Laboratories (RLBL) (NIH/NCRR Grant P41RR001348) with assistance of Dr. Thomas Troxler. Ms. Abigail Cember and Dr. Tomoyasu Mani are acknowledged for their help in measuring photo-physical properties of probe PtTCHP-C307. The authors are grateful to Mr. Erich Beuerman and Prof. Mikhail Drobizhev of the Department of Physics of Montana State University for measurements of the two-photon absorption spectra of coumarines C307 and C343. NR 73 TC 22 Z9 23 U1 1 U2 30 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 17 PY 2014 VL 86 IS 12 BP 5937 EP 5945 DI 10.1021/ac501028m PG 9 WC Chemistry, Analytical SC Chemistry GA AJ4JX UT WOS:000337643500050 PM 24848643 ER PT J AU Goldfine, AB Phua, EJ Abrahamson, MJ AF Goldfine, Allison B. Phua, Eng-Joo Abrahamson, Martin J. TI Glycemic Management in Patients With Coronary Artery Disease and Prediabetes or Type 2 Diabetes Mellitus SO CIRCULATION LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; 10-YEAR FOLLOW-UP; PREVENTION; METFORMIN; OUTCOMES; ROSIGLITAZONE; PIOGLITAZONE; TRIALS C1 [Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Goldfine, AB (reprint author), Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM allison.goldfine@joslin.harvard.edu FU NIH Diabetes Endocrinology Research Center (DERC) [NIH P30-DK-0368-36] FX This work was supported by a NIH Diabetes Endocrinology Research Center (DERC) grant to Joslin Diabetes Center (NIH P30-DK-0368-36). NR 19 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 17 PY 2014 VL 129 IS 24 BP 2567 EP 2573 DI 10.1161/CIRCULATIONAHA.113.006634 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AJ5ET UT WOS:000337705900015 PM 24934464 ER PT J AU Malik, MT Healy, BC Benson, LA Kivisakk, P Musallam, A Weiner, HL Chitnis, T AF Malik, Muhammad Taimur Healy, Brian C. Benson, Leslie A. Kivisakk, Pia Musallam, Alexander Weiner, Howard L. Chitnis, Tanuja TI Factors associated with recovery from acute optic neuritis in patients with multiple sclerosis SO NEUROLOGY LA English DT Article ID VITAMIN-D STATUS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; NATURAL-HISTORY; TREATMENT TRIAL; RELAPSE RATE; FOLLOW-UP; ONSET; RISK; MS; TESTOSTERONE AB Objective:To identify clinical and demographic features associated with the severity and recovery from acute optic neuritis (AON) episodes in patients with multiple sclerosis (MS).Methods:Adult (n = 253) and pediatric (n = 38) patients whose first symptom was AON were identified from our MS database. Severity measured by loss of visual acuity (mild attack 20/40, moderate attack 20/50-20/190, and severe attack 20/200) and recovery in visual acuity at 1 year after the attack (complete recovery 20/20, fair recovery 20/40, and poor recovery 20/50) were recorded. Demographic and clinical features associated with attack severity and recovery were identified using proportional odds logistic regression. For another group of patients, blood samples were available within 6 months of an AON attack. In this group, the impact of vitamin D level on the severity/recovery was also assessed.Results:Men (adjusted odds ratio [OR] = 2.28, p = 0.03) and subjects with severe attacks (adjusted OR = 5.24, p < 0.001) had worse recovery. AON severity was similar between the pediatric and adult subjects, but recovery was significantly better in pediatric subjects in the unadjusted analysis (p = 0.041) and the analysis adjusted for sex (p = 0.029). Season-adjusted vitamin D level was significantly associated with attack severity (OR for 10-U increase in vitamin D level = 0.47; 95% confidence interval: 0.32, 0.68; p < 0.001). Vitamin D level was not associated with recovery from the attack (p = 0.98) in univariate analysis or after accounting for attack severity (p = 0.10).Conclusion:Vitamin D levels affect AON severity, whereas younger age, attack severity, and male sex affect AON recovery. Underlying mechanisms and potential therapeutic targets may identify new measures to mitigate disability accrual in MS. C1 [Malik, Muhammad Taimur; Healy, Brian C.; Benson, Leslie A.; Musallam, Alexander; Weiner, Howard L.; Chitnis, Tanuja] Harvard Univ, Brigham & Womens Hosp, Sch Med, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. [Kivisakk, Pia; Weiner, Howard L.; Chitnis, Tanuja] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Benson, Leslie A.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Benson, Leslie A.; Chitnis, Tanuja] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. RP Chitnis, T (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. EM tchitnis@partners.org FU National Multiple Sclerosis Society [RG 4256A4/2]; Clinical Translational Science Award [UL1RR025758]; Brigham and Women's Hospital from the National Center for Research Resources FX Supported by National Multiple Sclerosis Society RG 4256A4/2 (T. C.). This research was also supported by Clinical Translational Science Award UL1RR025758 to Harvard University and Brigham and Women's Hospital from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the NIH. NR 31 TC 12 Z9 12 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 17 PY 2014 VL 82 IS 24 BP 2173 EP 2179 DI 10.1212/WNL.0000000000000524 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AJ5FA UT WOS:000337706700010 PM 24850491 ER PT J AU Abel, GA AF Abel, Gregory A. TI Public Advertising by Cancer Centers: Are More Data Needed? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID EXPECTATIONS C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM gregory_abel@dfci.harvard.edu NR 10 TC 4 Z9 4 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 17 PY 2014 VL 160 IS 12 BP 870 EP 871 DI 10.7326/M14-1081 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0VR UT WOS:000337374900026 PM 24862947 ER PT J AU Chow, MJ Turcotte, R Lin, CP Zhang, YH AF Chow, Ming-Jay Turcotte, Raphael Lin, Charles P. Zhang, Yanhang TI Arterial Extracellular Matrix: A Mechanobiological Study of the Contributions and Interactions of Elastin and Collagen SO BIOPHYSICAL JOURNAL LA English DT Article ID IN-SITU CHARACTERIZATION; MECHANICAL-PROPERTIES; FIBER ORIENTATION; FLUORESCENCE MICROSCOPY; MULTIPHOTON MICROSCOPY; ADVENTITIA; TISSUES; WALL; MICROSTRUCTURE; QUANTIFICATION AB The complex network structure of elastin and collagen extracellular matrix (ECM) forms the primary load bearing components in the arterial wall. The structural and mechanobiological interactions between elastin and collagen are important for properly functioning arteries. Here, we examined the elastin and collagen organization, realignment, and recruitment by coupling mechanical loading and multiphoton imaging. Two-photon excitation fluorescence and second harmonic generation methods were performed with a multiphoton video-rate microscope to capture real time changes to the elastin and collagen structure during biaxial deformation. Enzymatic removal of elastin was performed to assess the structural changes of the remaining collagen structure. Quantitative analysis of the structural changes to elastin and collagen was made using a combination of two-dimensional fast Fourier transform and fractal analysis, which allows for a more complete understanding of structural changes. Our study provides new quantitative evidence, to our knowledge on the sequential engagement of different arterial ECM components in response to mechanical loading. The adventitial collagen exists as large wavy bundles of fibers that exhibit fiber engagement after 20% strain. The medial collagen is engaged throughout the stretching process, and prominent elastic fiber engagement is observed up to 20% strain after which the engagement plateaus. The fiber orientation distribution functions show remarkably different changes in the ECM structure in response to mechanical loading. The medial collagen shows an evident preferred circumferential distribution, however the fiber families of adventitial collagen are obscured by their waviness at no or low mechanical strains. Collagen fibers in both layers exhibit significant realignment in response to unequal biaxial loading. The elastic fibers are much more uniformly distributed and remained relatively unchanged due to loading. Removal of elastin produces similar structural changes in collagen as mechanical loading. Our study suggests that the elastic fibers are under tension and impart an intrinsic compressive stress on the collagen. C1 [Chow, Ming-Jay; Zhang, Yanhang] Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. [Turcotte, Raphael; Zhang, Yanhang] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Turcotte, Raphael; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Wellman Ctr Photomed, Ctr Syst Biol,Sch Med,Adv Microscopy Program, Boston, MA 02114 USA. RP Zhang, YH (reprint author), Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. EM yanhang@bu.edu FU National Institutes of Health (NIH) [P41 EB015903-02S1, R01HL098028]; FRQNT PhD Fellowship; Wellman Center for Photomedicine Graduate Student Fellowship FX This work was supported by a grant from the NIH (R01HL098028) that was provided to KY. The imaging work was made possible through a grant to CPL at Wellman Center for Photomedicine from the National Institutes of Health (NIH) (P41 EB015903-02S1). RT was supported by a FRQNT PhD Fellowship and a Wellman Center for Photomedicine Graduate Student Fellowship. NR 53 TC 18 Z9 18 U1 4 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUN 17 PY 2014 VL 106 IS 12 BP 2684 EP 2692 DI 10.1016/j.bpj.2014.05.014 PG 9 WC Biophysics SC Biophysics GA AJ4QY UT WOS:000337662100018 PM 24940786 ER PT J AU Yeh, RW Wimmer, NJ AF Yeh, Robert W. Wimmer, Neil J. TI Bleeding After PCI, Vascular Access, and Falsification Endpoints in Observational Studies Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Yeh, RW (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,GRB800, Boston, MA 02114 USA. EM ryeh@mgh.harvard.edu NR 2 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 17 PY 2014 VL 63 IS 23 BP 2587 EP 2588 DI 10.1016/j.jacc.2014.02.570 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ0PR UT WOS:000337358100019 PM 24681135 ER PT J AU Felgentreff, K Du, LK Weinacht, KG Dobbs, K Bartish, M Giliani, S Schlaeger, T DeVine, A Schambach, A Woodbine, LJ Davies, G Baxi, SN van der Burg, M Bleesing, J Gennery, A Manis, J Pan-Hammarstrom, Q Notarangelo, LD AF Felgentreff, Kerstin Du, Likun Weinacht, Katja G. Dobbs, Kerry Bartish, Margarita Giliani, Silvia Schlaeger, Thorsten DeVine, Alexander Schambach, Axel Woodbine, Lisa J. Davies, Graham Baxi, Sachin N. van der Burg, Mirjam Bleesing, Jack Gennery, Andrew Manis, John Pan-Hammarstrom, Qiang Notarangelo, Luigi D. TI Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LIGASE IV DEFICIENCY; DOUBLE-STRAND BREAKS; HEMATOPOIETIC PROGENITORS; HOMOLOGOUS RECOMBINATION; V(D)J RECOMBINATION; IONIZING-RADIATION; MAMMALIAN-CELLS; DSB REPAIR; PATHWAY; P53 AB Nonhomologous end-joining (NHEJ) is a key pathway for efficient repair of DNA double-strand breaks (DSBs) and V(D)J recombination. NHEJ defects in humans cause immunodeficiency and increased cellular sensitivity to ionizing irradiation (IR) and are variably associated with growth retardation, microcephaly, and neurodevelopmental delay. Repair of DNA DSBs is important for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). To compare the specific contribution of DNA ligase 4 (LIG4), Artemis, and DNA-protein kinase catalytic subunit (PKcs) in this process and to gain insights into phenotypic variability associated with these disorders, we reprogrammed patient-derived fibroblast cell lines with NHEJ defects. Deficiencies of LIG4 and of DNA-PK catalytic activity, but not Artemis deficiency, were associated with markedly reduced reprogramming efficiency, which could be partially rescued by genetic complementation. Moreover, we identified increased genomic instability in LIG4-deficient iPSCs. Cell cycle synchronization revealed a severe defect of DNA repair and a G0/G1 cell cycle arrest, particularly in LIG4- and DNA-PK catalytically deficient iPSCs. Impaired myeloid differentiation was observed in LIG4-, but not Artemis-or DNA-PK-mutated iPSCs. These results indicate a critical importance of the NHEJ pathway for somatic cell reprogramming, with a major role for LIG4 and DNA-PKcs and a minor, if any, for Artemis. C1 [Felgentreff, Kerstin; Weinacht, Katja G.; Dobbs, Kerry; Baxi, Sachin N.; Notarangelo, Luigi D.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Du, Likun; Bartish, Margarita; Pan-Hammarstrom, Qiang] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Lab Med, Div Clin Immunol & Transfus Med, SE-14186 Stockholm, Sweden. [Weinacht, Katja G.; Schlaeger, Thorsten; DeVine, Alexander; Schambach, Axel] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Weinacht, Katja G.; Schlaeger, Thorsten; DeVine, Alexander; Schambach, Axel] Dana Farber Canc Inst, Boston, MA 02115 USA. [Giliani, Silvia] Univ Brescia, Spedali Civili, Pediat Clin, A Nocivelli Inst Mol Med, I-25123 Brescia, Italy. [Schambach, Axel] Hannover Med Sch, Inst Expt Hematol, D-30625 Hannover, Germany. [Woodbine, Lisa J.] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. [Davies, Graham] Great Ormond St Hosp Sick Children, Ctr Immunodeficiency, London WC1N 3JH, England. [Davies, Graham] Inst Child Hlth, London WC1N 3JH, England. [van der Burg, Mirjam] Erasmus MC, Dept Immunol, NL-3015 GE Rotterdam, Netherlands. [Bleesing, Jack] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplant & Immunodeficiency, Cincinnati, OH 45229 USA. [Gennery, Andrew] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Manis, John] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Transfus Med, Boston, MA 02115 USA. [Notarangelo, Luigi D.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Notarangelo, LD (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. EM Luigi.Notarangelo@childrens.harvard.edu RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [1R01AI100887, 5P01AI076210-04]; German Research Foundation [FE1253/1-1]; networks of Bundesministerium fur Bildung und Forschung (PidNet); European Union (Cellpid); Swedish Research Council, European Research Council [242551]; University of Brescia and Fondazione A. Nocivelli; Manton Foundation FX We thank the patients and their families for collaboration and Dr. Penny Jeggo for supplying the cell line NM720 and providing helpful comments on the manuscript. We thank Ms. Giulia Notarangelo for technical help. This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grants 1R01AI100887 and 5P01AI076210-04 (to L.D.N.). K.F. was supported by the German Research Foundation (FE1253/1-1), A. S. was supported by networks of Bundesministerium fur Bildung und Forschung (PidNet) and European Union (Cellpid), Q.P.-H. was supported by the Swedish Research Council, European Research Council (242551-ImmunoSwitch), S.G. was partially supported by the University of Brescia and Fondazione A. Nocivelli, and L.D.N. was partially supported by the Manton Foundation. NR 42 TC 14 Z9 14 U1 0 U2 10 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 17 PY 2014 VL 111 IS 24 BP 8889 EP 8894 DI 10.1073/pnas.1323649111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI9XO UT WOS:000337300100048 PM 24889605 ER PT J AU Hunter, JC Gurbani, D Ficarro, SB Carrasco, MA Lim, SM Choi, HG Xie, T Marto, JA Chen, Z Gray, NS Westover, KD AF Hunter, John C. Gurbani, Deepak Ficarro, Scott B. Carrasco, Martin A. Lim, Sang Min Choi, Hwan Geun Xie, Ting Marto, Jarrod A. Chen, Zhe Gray, Nathanael S. Westover, Kenneth D. TI In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CPM assay; ActivX ID SMALL-CELL LUNG; PROTEIN-KINASE INHIBITORS; MEDIATED NUCLEOTIDE EXCHANGE; GROWTH-FACTOR RECEPTOR; RHO GTPASES; EVOLUTIONARY CONSERVATION; FUNCTIONAL-ANALYSIS; SMALL MOLECULES; COVALENT DRUGS; PHASE-II AB Directly targeting oncogenic V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras) with small-molecule inhibitors has historically been considered prohibitively challenging. Recent reports of compounds that bind directly to the K-Ras G12C mutant suggest avenues to overcome key obstacles that stand in the way of developing such compounds. We aim to target the guanine nucleotide (GN)-binding pocket because the natural contents of this pocket dictate the signaling state of K-Ras. Here, we characterize the irreversible inhibitor SML-8-73-1 (SML), which targets the GN-binding pocket of K-Ras G12C. We report a high-resolution X-ray crystal structure of G12C K-Ras bound to SML, revealing that the compound binds in a manner similar to GDP, forming a covalent linkage with Cys-12. The resulting conformation renders K-Ras in the open, inactive conformation, which is not predicted to associate productively with or activate downstream effectors. Conservation analysis of the Ras family GN-binding pocket reveals variability in the side chains surrounding the active site and adjacent regions, especially in the switch I region. This variability may enable building specificity into new iterations of Ras and other GTPase inhibitors. High-resolution in situ chemical proteomic profiling of SML confirms that SML effectively discriminates between K-Ras G12C and other cellular GTP-binding proteins. A biochemical assay provides additional evidence that SML is able to compete with millimolar concentrations of GTP and GDP for the GN-binding site. C1 [Hunter, John C.; Gurbani, Deepak; Carrasco, Martin A.; Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Hunter, John C.; Gurbani, Deepak; Carrasco, Martin A.; Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Chen, Zhe] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Ficarro, Scott B.; Lim, Sang Min; Choi, Hwan Geun; Marto, Jarrod A.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Lim, Sang Min; Choi, Hwan Geun; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Lim, Sang Min; Xie, Ting] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RP Westover, KD (reprint author), Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. EM kenneth.westover@utsouthwestern.edu FU CPRIT [R1207]; Welch Foundation [I1829]; US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357] FX This work was supported by CPRIT Grant R1207 (to K.D.W.) and Grant I1829 from The Welch Foundation (to K.D.W.). Results shown in this report are derived from work performed at the Structural Biology Center at the Advanced Photon Source, Argonne National Laboratory. The Argonne National Laboratory is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research, under Contract DE-AC02-06CH11357. NR 52 TC 37 Z9 38 U1 1 U2 25 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 17 PY 2014 VL 111 IS 24 BP 8895 EP 8900 DI 10.1073/pnas.1404639111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI9XO UT WOS:000337300100049 PM 24889603 ER PT J AU Kovacs-Bogdan, E Sancak, Y Kamer, KJ Plovanich, M Jambhekar, A Huber, RJ Myre, MA Blower, MD Mootha, VK AF Kovacs-Bogdan, Erika Sancak, Yasemin Kamer, Kimberli J. Plovanich, Molly Jambhekar, Ashwini Huber, Robert J. Myre, Michael A. Blower, Michael D. Mootha, Vamsi K. TI Reconstitution of the mitochondrial calcium uniporter in yeast SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT KIDNEY MITOCHONDRIA; CA2+ UPTAKE; COMPLEX-I; PROTEIN; MICU1; MEMBRANE; TISSUES; DICTYOSTELIUM; TRANSPORT; DISEASE AB The mitochondrial calcium uniporter is a highly selective calcium channel distributed broadly across eukaryotes but absent in the yeast Saccharomyces cerevisiae. The molecular components of the human uniporter holocomplex (uniplex) have been identified recently. The uniplex consists of three membrane-spanning subunits-mitochondrial calcium uniporter (MCU), its paralog MCUb, and essential MCU regulator (EMRE)- and two soluble regulatory components-MICU1 and its paralog MICU2. The minimal components sufficient for in vivo uniporter activity are unknown. Here we consider Dictyostelium discoideum (Dd), a member of the Amoebazoa outgroup of Metazoa and Fungi, and show that it has a highly simplified uniporter machinery. We show that D. discoideum mitochondria exhibit membrane potential-dependent calcium uptake compatible with uniporter activity, and also that expression of DdMCU complements the mitochondrial calcium uptake defect in human cells lacking MCU or EMRE. Moreover, expression of DdMCU in yeast alone is sufficient to reconstitute mitochondrial calcium uniporter activity. Having established yeast as an in vivo reconstitution system, we then reconstituted the human uniporter. We show that coexpression of MCU and EMRE is sufficient for uniporter activity, whereas expression of MCU alone is insufficient. Our work establishes yeast as a powerful in vivo reconstitution system for the uniporter. Using this system, we confirm that MCU is the pore-forming subunit, define the minimal genetic elements sufficient for metazoan and nonmetazoan uniporter activity, and provide valuable insight into the evolution of the uniporter machinery. C1 [Kovacs-Bogdan, Erika; Sancak, Yasemin; Kamer, Kimberli J.; Plovanich, Molly; Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Kovacs-Bogdan, Erika; Sancak, Yasemin; Kamer, Kimberli J.; Plovanich, Molly; Jambhekar, Ashwini; Blower, Michael D.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Kovacs-Bogdan, Erika; Sancak, Yasemin; Kamer, Kimberli J.; Plovanich, Molly; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02446 USA. [Jambhekar, Ashwini; Blower, Michael D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02446 USA. [Huber, Robert J.; Myre, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Huber, Robert J.; Myre, Michael A.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Mootha, Vamsi K.] Broad Inst, Cambridge, MA 02142 USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM vamsi@hms.harvard.edu FU National Science Foundation; Helen Hay Whitney Foundation; National Institutes of Health [R01 DK080261] FX We thank Abbas Yaseen for technical guidance, Sarah Calvo for bioinformatics assistance, and Zenon Grabarek for helpful discussions. K.J.K. was supported by a graduate research fellowship from the National Science Foundation. Y.S. received support from Helen Hay Whitney Foundation. This work was supported by National Institutes of Health Grant R01 DK080261 (to V.K.M.). V.K.M. is an Investigator of the Howard Hughes Medical Institute. NR 37 TC 34 Z9 35 U1 1 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 17 PY 2014 VL 111 IS 24 BP 8985 EP 8990 DI 10.1073/pnas.1400514111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI9XO UT WOS:000337300100064 PM 24889638 ER PT J AU Lin, FJ Pickard, AS Krishnan, JA Joo, MJ Au, DH Carson, SS Gillespie, S Henderson, AG Lindenauer, PK McBurnie, MA Mularski, RA Naureckas, ET Vollmer, WM Lee, TA AF Lin, Fang-Ju Pickard, A. Simon Krishnan, Jerry A. Joo, Min J. Au, David H. Carson, Shannon S. Gillespie, Suzanne Henderson, Ashley G. Lindenauer, Peter K. McBurnie, Mary Ann Mularski, Richard A. Naureckas, Edward T. Vollmer, William M. Lee, Todd A. CA CONCERT Consortium TI Measuring health-related quality of life in chronic obstructive pulmonary disease: properties of the EQ-5D-5L and PROMIS-43 short form SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE COPD; EQ-5D-5L; PROMIS; Psychometric properties ID FUNCTIONAL LIMITATIONS; CHRONIC ILLNESS; COPD SEVERITY; ITEM BANKS; DYSPNEA; ASTHMA; DISABILITY; VALIDITY AB Background: The Patient Reported Outcomes Measurement Information System 43-item short form (PROMIS-43) and the five-level EQ-5D (EQ-5D-5L) are recently developed measures of health-related quality of life (HRQL) that have potentially broad application in evaluating treatments and capturing burden of respiratory-related diseases. The aims of this study were: (1) to examine their psychometric properties in patients with chronic obstructive pulmonary disease (COPD), and (2) to identify dimensions of HRQL that differ and do not differ by lung function. Methods: We conducted a multi-center, cross-sectional study ("COPD Outcomes-based Network for Clinical Effectiveness & Research Translation" [CONCERT]). We analyzed patients who met spirometric criteria for COPD, and completed EQ-5D-5L and PROMIS questionnaires. Disease severity was graded based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. Pulmonary function test, PROMIS-43, EQ-5D (index score and EQ-Visual Analog Scale [EQ-VAS]), six minute walk test (6MWT), and three dyspnea scales (mMRC, Borg, FACIT-Dyspnea) were administered. Validity and reliability of EQ-5D-5L and PROMIS-43 were examined, and differences in HRQL by GOLD grade were assessed. Results: Data from 670 patients with COPD were analyzed (mean age 68.5 years; 58% male). More severe COPD was associated with more problems with mobility, self-care and usual activities (all p-values <0.01) according to EQ-5D-5L. Related domains on EQ-5D-5L, PROMIS and clinical measures were moderately (r = 0.30-0.49) to strongly (r = 0.50) correlated. A statistically significant trend of decreasing HRQL with more severe lung functions was observed for EQ-5D-5L index scores, EQ-VAS scores, and PROMIS physical function and social roles. Conclusions: Results supported the validity of EQ-5D-5L and PROMIS-43 in COPD patients, and indicate that physical function and social activities decrease with level of lung function by GOLD grade, but not pain, mental health, sleep or fatigue as reported by patients. C1 [Lin, Fang-Ju; Pickard, A. Simon; Krishnan, Jerry A.; Lee, Todd A.] Univ Illinois, Chicago, IL 60607 USA. [Krishnan, Jerry A.; Joo, Min J.] Univ Illinois Hosp & Hlth Sci Syst, Chicago, IL USA. [Au, David H.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Au, David H.] Univ Washington, Seattle, WA 98195 USA. [Carson, Shannon S.; Henderson, Ashley G.] Univ N Carolina, Chapel Hill, NC USA. [Gillespie, Suzanne; McBurnie, Mary Ann; Mularski, Richard A.; Vollmer, William M.] Kaiser Permanente Northwest Ctr Hlth Res, Portland, OR USA. [Lindenauer, Peter K.] Baystate Med Ctr, Springfield, MA USA. [Lindenauer, Peter K.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Naureckas, Edward T.] Univ Chicago, Chicago, IL 60637 USA. [Pickard, A. Simon] Univ Illinois, Coll Pharm, Dept Pharm Syst Outcomes & Policy, Chicago, IL 60612 USA. RP Pickard, AS (reprint author), Univ Illinois, Chicago, IL 60607 USA. EM pickard1@uic.edu OI LIN, FANG-JU/0000-0002-8249-7481 FU National Heart, Lung, and Blood Institute [NHLBI RC2 HL101618]; Graduate College of the University of Illinois at Chicago; Veteran Affairs Health Services Research & Development (VA HSRD) FX The COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) was funded by the National Heart, Lung, and Blood Institute (NHLBI RC2 HL101618). Fang-Ju Lin was supported by the Graduate College of the University of Illinois at Chicago (2012/2013 Dean's Scholar Award). The sponsors had no role in the design of the study, collection and analysis of the data, interpretation of results or the writing of this manuscript. Dr. David Au received funding from the Veteran Affairs Health Services Research & Development (VA HSR&D). The opinions expressed represent those of the authors and do not necessarily reflect those of the Department of Veterans Affairs. NR 42 TC 9 Z9 9 U1 3 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD JUN 16 PY 2014 VL 14 AR 78 DI 10.1186/1471-2288-14-78 PG 12 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AK3DX UT WOS:000338304400001 PM 24934150 ER PT J AU Jaiswal, S Ebert, BL AF Jaiswal, Siddhartha Ebert, Benjamin L. TI MDS Is a Stem Cell Disorder After All SO CANCER CELL LA English DT Editorial Material ID MYELODYSPLASTIC SYNDROMES; CLONAL ANALYSIS; MUTATIONS C1 [Jaiswal, Siddhartha] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Jaiswal, Siddhartha; Ebert, Benjamin L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Jaiswal, Siddhartha; Ebert, Benjamin L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol,Dept Med, Boston, MA 02115 USA. RP Ebert, BL (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM bebert@partners.org NR 11 TC 7 Z9 7 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUN 16 PY 2014 VL 25 IS 6 BP 713 EP 714 DI 10.1016/j.ccr.2014.06.001 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AJ5GB UT WOS:000337709600002 PM 24937455 ER PT J AU Ozdemir, BC Pentcheva-Hoang, T Carstens, JL Zheng, XF Wu, CC Simpson, TR Laklai, H Sugimoto, H Kahlert, C Novitskiy, SV De Jesus-Acosta, A Sharma, P Heidari, P Mahmood, U Chin, L Moses, HL Weaver, VM Maitra, A Allison, JP LeBleu, VS Kalluri, R AF Oezdemir, Berna C. Pentcheva-Hoang, Tsvetelina Carstens, Julienne L. Zheng, Xiaofeng Wu, Chia-Chin Simpson, Tyler R. Laklai, Hanane Sugimoto, Hikaru Kahlert, Christoph Novitskiy, Sergey V. De Jesus-Acosta, Ana Sharma, Padmanee Heidari, Pedram Mahmood, Umar Chin, Lynda Moses, Harold L. Weaver, Valerie M. Maitra, Anirban Allison, James P. LeBleu, Valerie S. Kalluri, Raghu TI Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival SO CANCER CELL LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; DUCTAL ADENOCARCINOMA; STEM-CELLS; EXTRACELLULAR-MATRIX; PROGRESSION; METASTASIS; INFLAMMATION; PATHWAY; TUMORS; MOUSE AB Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stomal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete alpha SMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp(3+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC. C1 [Oezdemir, Berna C.; Carstens, Julienne L.; Zheng, Xiaofeng; Sugimoto, Hikaru; Kahlert, Christoph; LeBleu, Valerie S.; Kalluri, Raghu] Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77054 USA. [Oezdemir, Berna C.; Sugimoto, Hikaru; Kahlert, Christoph; LeBleu, Valerie S.; Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02115 USA. [Oezdemir, Berna C.; Sugimoto, Hikaru; Kahlert, Christoph; LeBleu, Valerie S.; Kalluri, Raghu] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Pentcheva-Hoang, Tsvetelina; Simpson, Tyler R.; Sharma, Padmanee; Allison, James P.] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77054 USA. [Wu, Chia-Chin; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA. [Laklai, Hanane; Weaver, Valerie M.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Novitskiy, Sergey V.; Moses, Harold L.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. [De Jesus-Acosta, Ana] Johns Hopkins Univ Hosp, Dept Med Oncol, Baltimore, MD 21287 USA. [Heidari, Pedram; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Ahmad Ctr Pancreat Canc Res, Dept Pathol, Houston, TX 77030 USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Ahmad Ctr Pancreat Canc Res, Dept Translat Mol Pathol, Houston, TX 77030 USA. RP Kalluri, R (reprint author), Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77054 USA. EM rkalluri@mdanderson.org RI LeBleu, Valerie /E-2991-2015 FU NIH [UO1 CA151925, CA113669]; OncoSuisse MD/PhD Scholarship [323630-128865/1]; Swiss National Science Foundation [PBBEP3_144809]; Deutsche Forschungsgemeinschaft; Cancer Prevention and Research Institute of Texas; Metastasis Research Center at MD Anderson Cancer Center, NIH [DK55001, DK81976, CA125550, CA155370, CA163191] FX We wish to thank Travis Hardcastle, Lauren Bizarro, Judith Kaye, Laura Gibson, and Sara Lovisa for genotyping and animal husbandry support; Donna Reynolds for IHC stainings; and Travis Hardcastle, Dr. Ganiraju C. Manyam, Dr. Jing Wang, and the Bioinformatics and Computational Biology Department at MDACC for bioinformatic support. This study was supported primarily by NIH grant UO1 CA151925. B.C.O. received funding from the OncoSuisse MD/PhD Scholarship (323630-128865/1) and the Swiss National Science Foundation Fellowship (PBBEP3_144809). C.K. is funded by a Research Fellowship of Deutsche Forschungsgemeinschaft. A.M. is supported by NIH grant CA113669. R.K. is supported by the Cancer Prevention and Research Institute of Texas and the Metastasis Research Center at MD Anderson Cancer Center, NIH grants DK55001, DK81976, CA125550, CA155370, and CA163191. J.P.A. is an inventor of intellectual property owned by the University of California, Berkeley, and licensed to Bristol Myers-Squibb. NR 56 TC 300 Z9 304 U1 19 U2 91 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUN 16 PY 2014 VL 25 IS 6 BP 719 EP 734 DI 10.1016/j.ccr.2014.04.005 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AJ5GB UT WOS:000337709600005 PM 24856586 ER PT J AU Yamamoto, S Wu, ZH Russnes, HG Takagi, S Peluffo, G Vaske, C Zhao, X Vollan, HKM Maruyama, R Ekram, MB Sun, HF Kim, JH Carver, K Zucca, M Feng, JX Almendro, V Bessarabova, M Rueda, OM Nikolsky, Y Caldas, C Liu, XS Polyak, K AF Yamamoto, Shoji Wu, Zhenhua Russnes, Hege G. Takagi, Shinji Peluffo, Guillermo Vaske, Charles Zhao, Xi Vollan, Hans Kristian Moen Maruyama, Reo Ekram, Muhammad B. Sun, Hanfei Kim, Jee Hyun Carver, Kristopher Zucca, Mattia Feng, Jianxing Almendro, Vanessa Bessarabova, Marina Rueda, Oscar M. Nikolsky, Yuri Caldas, Carlos Liu, X. Shirley Polyak, Kornelia TI JARID1B Is a Luminal Lineage-Driving Oncogene in Breast Cancer SO CANCER CELL LA English DT Article ID GENE-EXPRESSION PATTERNS; MELANOMA-CELLS; TRANSCRIPTION FACTORS; MOLECULAR PORTRAITS; MAMMARY-GLAND; SELF-RENEWAL; RNA-SEQ; GENOME; BINDING; CHROMATIN AB Recurrent mutations in histone-modifying enzymes imply key roles in tumorigenesis, yet their functional relevance is largely unknown. Here, we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGF beta pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARD1B activity is associated with poor outcome in patients with hormone receptor-positive breast tumors. C1 [Yamamoto, Shoji; Russnes, Hege G.; Takagi, Shinji; Peluffo, Guillermo; Maruyama, Reo; Ekram, Muhammad B.; Kim, Jee Hyun; Carver, Kristopher; Zucca, Mattia; Almendro, Vanessa; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wu, Zhenhua; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G.; Takagi, Shinji; Peluffo, Guillermo; Maruyama, Reo; Ekram, Muhammad B.; Sun, Hanfei; Kim, Jee Hyun; Carver, Kristopher; Zucca, Mattia; Almendro, Vanessa; Liu, X. Shirley; Polyak, Kornelia] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Yamamoto, Shoji; Russnes, Hege G.; Takagi, Shinji; Peluffo, Guillermo; Maruyama, Reo; Ekram, Muhammad B.; Kim, Jee Hyun; Carver, Kristopher; Almendro, Vanessa; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Yamamoto, Shoji; Russnes, Hege G.; Takagi, Shinji; Peluffo, Guillermo; Maruyama, Reo; Ekram, Muhammad B.; Kim, Jee Hyun; Carver, Kristopher; Almendro, Vanessa; Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wu, Zhenhua; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Russnes, Hege G.; Vollan, Hans Kristian Moen] Radiumhosp, Oslo Univ Hosp, N-0310 Oslo, Norway. [Vaske, Charles] Five3 Genom, Santa Cruz, CA 95060 USA. [Zhao, Xi] Stanford Univ, Sch Med, Dept Radiol, Stanford Ctr Canc Syst Biol, Stanford, CA 94305 USA. [Maruyama, Reo] Sapporo Med Univ, Sch Med, Sapporo, Hokkaido 0608556, Japan. [Sun, Hanfei; Feng, Jianxing] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. [Kim, Jee Hyun] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110799, South Korea. [Zucca, Mattia] San Raffaele Univ, I-20132 Milan, Italy. [Bessarabova, Marina; Nikolsky, Yuri] Thomson Reuters Healthcare & Sci, Encinitas, CA 92024 USA. [Rueda, Oscar M.; Caldas, Carlos] Univ Cambridge, Cambridge Inst, Canc Res UK, Cambridge CB2 0RE, England. [Liu, X. Shirley; Polyak, Kornelia] Broad Inst, Cambridge, MA 02141 USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM kornelia_polyak@dfci.harvard.edu RI Russnes, Hege/N-6170-2015; Vaske, Charles/D-6018-2013 OI Russnes, Hege/0000-0001-8724-1891; Vaske, Charles/0000-0001-8151-6612 FU National Cancer Institute [CA080111, GM099409]; Norwegian Cancer Society; Radiumhospitalets Foundation; Novartis Oncology; Susan G. Komen Foundation; DFCI-Novartis drug discovery program FX We thank members of our laboratories for their critical reading of this manuscript and useful discussions. We thank Dr. Jonathan Yingling (Eli Lilly) for providing the LY2109761 TGBR kinase inhibitor, Dr. P. Senthupathy (University of North Carolina) for providing the list of paused genes in MCF7 cells, and Chenfei Wang for his help with GEO submission. This research was supported by the National Cancer Institute (CA080111 to K.P. and GM099409 to X.S.L.), the Norwegian Cancer Society (to H.G.R.), the Radiumhospitalets Foundation (to H.G.R.), Novartis Oncology (to K.P.), and the Susan G. Komen Foundation (to R.M. and K.P.). This work was supported in part by the DFCI-Novartis drug discovery program. K.P. receives research support from Novartis Oncology and is a consultant to Novartis Oncology. NR 72 TC 35 Z9 35 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUN 16 PY 2014 VL 25 IS 6 BP 762 EP 777 DI 10.1016/j.ccr.2014.04.024 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AJ5GB UT WOS:000337709600008 PM 24937458 ER PT J AU Turer, AT Lewis, GD O'Sullivan, JF Elmariah, S Mega, JL Addo, TA Sabatine, MS de Lemos, JA Gerszten, RE AF Turer, Aslan T. Lewis, Gregory D. O'Sullivan, John F. Elmariah, Sammy Mega, Jessica L. Addo, Tayo A. Sabatine, Marc S. de Lemos, James A. Gerszten, Robert E. TI Increases in Myocardial Workload Induced by Rapid Atrial Pacing Trigger Alterations in Global Metabolism SO PLOS ONE LA English DT Article ID BILE-ACIDS; ISCHEMIA; ADENOSINE; HUMANS; BLOOD; FAT AB Objective: To determine whether increases in cardiac work lead to alterations in the plasma metabolome and whether such changes arise from the heart or peripheral organs. Background: There is growing evidence that the heart influences systemic metabolism through endocrine effects and affecting pathways involved in energy homeostasis. Methods: Nineteen patients referred for cardiac catheterization were enrolled. Peripheral and selective coronary sinus (CS) blood sampling was performed at serial timepoints following the initiation of pacing, and metabolite profiling was performed by liquid chromatography-mass spectrometry (LC-MS). Results: Pacing-stress resulted in a 225% increase in the median rate? pressure product from baseline. Increased myocardial work induced significant changes in the peripheral concentration of 43 of 125 metabolites assayed, including large changes in purine [ adenosine (+99%, p = 0.006), ADP (+42%, p = 0.01), AMP (+79%, p = 0.004), GDP (+69%, p = 0.003), GMP (+58%, p = 0.01), IMP (+50%, p = 0.03), xanthine (+61%, p = 0.0006)], and several bile acid metabolites. The CS changes in metabolites qualitatively mirrored those in the peripheral blood in both timing and magnitude, suggesting the heart was not the major source of the metabolite release. Conclusions: Isolated increases in myocardial work can induce changes in the plasma metabolome, but these changes do not appear to be directly cardiac in origin. A number of these dynamic metabolites have known signaling functions. Our study provides additional evidence to a growing body of literature on metabolic 'cross-talk' between the heart and other organs. C1 [Turer, Aslan T.; de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Dept Med, Div Cardiol, Dallas, TX 75390 USA. [Lewis, Gregory D.; O'Sullivan, John F.; Elmariah, Sammy; Addo, Tayo A.; Gerszten, Robert E.] Massachusetts Gen Hosp, Dept Internal Med, Div Cardiol, Boston, MA 02114 USA. [Mega, Jessica L.; Sabatine, Marc S.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Turer, AT (reprint author), Univ Texas SW Med Ctr Dallas, Dept Med, Div Cardiol, Dallas, TX 75390 USA. EM aslan.turer@utsouthwestern.edu FU Abbott Laboratories; Ortho-Clinical Diagnostics; Roche Diagnostics; Singulex; National Institutes of Health [K23 HL 091106, R01HL098280, R01DK081572, HHSN268201000033C]; American Heart Association Established Investigator Award FX Dr. Sabatine: Abbott Laboratories, Ortho-Clinical Diagnostics, Roche Diagnostics, Singulex; Dr. de Lemos: Abbott Diagnostics, Roche Diagnostics; Dr Lewis: National Institutes of Health Grant: #K23 HL 091106; Dr Gerszten: National Institutes of Health Grants #R01HL098280 and #R01DK081572, National Institutes of Health contract #HHSN268201000033C, and American Heart Association Established Investigator Award; the other authors have no relevant disclosures. No companies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 1 Z9 1 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2014 VL 9 IS 6 AR e99058 DI 10.1371/journal.pone.0099058 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ5PV UT WOS:000337738600020 PM 24932507 ER PT J AU Vetter, ML Zhang, ZJ Liu, S Wang, JH Cho, H Zhang, JM Zhang, W Gray, NS Yang, PL AF Vetter, Michael L. Zhang, Zijuan Liu, Shuai Wang, Jinhua Cho, HaeYeon Zhang, Jianming Zhang, Wei Gray, Nathanael S. Yang, Priscilla L. TI Fluorescent Visualization of Src by Using Dasatinib-BODIPY SO CHEMBIOCHEM LA English DT Article DE cell recognition; fluorescent probes; kinase inhibitors; proteins; signal transduction ID SRC/ABL KINASE INHIBITOR; TYROSINE KINASE; SARACATINIB AZD0530; PHASE-II; C-SRC; CELLS; BMS-354825; PROTEIN; CANCER; PROBE AB Many biological experiments are not compatible with the use of immunofluorescence, genetically encoded fluorescent tags, or FRET-based reporters. Conjugation of existing kinase inhibitors to cell-permeable fluorophores can provide a generalized approach to develop fluorescent probes of intracellular kinases. Here, we report the development of a small molecule probe of Src through conjugation of BODIPY to two well-established dual Src-Abl kinase inhibitors, dasatinib and saracatinib. We show that this approach is not successful for saracatinib but that dasatinib-BODIPY largely retains the biological activity of its parent compound and can be used to monitor the presence of Src kinase in individual cells by flow cytometry. It can also be used to track the localization of Src by fixed and live-cell fluorescence microscopy. This strategy could enable generation of additional kinase-specific probes useful in systems not amenable to genetic manipulation or could be used together with fluorescent proteins to enable a multiplexed assay readout. C1 [Vetter, Michael L.; Yang, Priscilla L.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Zhang, Zijuan; Liu, Shuai; Zhang, Wei] Univ Massachusetts, Dept Chem, Boston, MA 02125 USA. [Wang, Jinhua; Cho, HaeYeon; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Wang, Jinhua; Cho, HaeYeon; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Zhang, W (reprint author), Univ Massachusetts, Dept Chem, 100 Morrissey Blvd, Boston, MA 02125 USA. EM wei2.zhang@umb.edu; nathanael_gray@dfci.harvard.edu; priscilla_yang@hms.harvard.edu FU NIH/NCI grant [U54 CA156732]; NIH/NIAID [AI076442] FX This work was supported by NIH/NCI grant U54 CA156732 (PIs: Emmons and Colon) to the University of Massachusetts Boston-Dana-Farber/Harvard Cancer Center (UMB-DFHCC) U54 Comprehensive Partnership to Reduce Cancer Health Disparities and by NIH/NIAID grant AI076442 (PI: P.L. Yang). Hong Zeng and Dian-rong Zhu are gratefully acknowledged for their participation in synthetic work. We also acknowledge the Live-Cell Imaging Core of the New England Regional Center of Excellence Biodefense and Emerging Infectious Diseases (U54 AI057159) and the ICCB-Longwood Screening Facility for use of equipment and technical support. DNA sequencing was performed by the DNA Resource Core of the Dana-Farber/Harvard Cancer Center. Flow cytometry was performed at the Dana-Farber Cancer Institute Flow Cytometry Facility. NR 36 TC 3 Z9 3 U1 5 U2 23 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD JUN 16 PY 2014 VL 15 IS 9 BP 1317 EP 1324 DI 10.1002/cbic.201402010 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AJ4IK UT WOS:000337638400014 PM 24828915 ER PT J AU Overduin, J Tylee, TS Frayo, RS Cummings, DE AF Overduin, Joost Tylee, Tracy S. Frayo, R. Scott Cummings, David E. TI Hyperosmolarity in the small intestine contributes to postprandial ghrelin suppression SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE ghrelin; intestinal osmolarity; 3-O-methylglucose; lactulose; satiation ID GASTRIC BYPASS-SURGERY; NUTRIENT-DRIVEN SATIETY; GLUCAGON-LIKE PEPTIDE-1; PLASMA GHRELIN; FOOD-INTAKE; SHORT-TERM; INGESTIVE BEHAVIOR; BARIATRIC SURGERY; ANOREXIA-NERVOSA; LIDOCAINE SPRAY AB Plasma levels of the orexigenic hormone ghrelin are suppressed by meals with an efficacy dependent on their macronutrient composition. We hypothesized that heterogeneity in osmolarity among macronutrient classes contributes to these differences. In three studies, the impact of small intestinal hyperosmolarity was examined in Sprague-Dawley rats. In study 1, isotonic, 2.5X, and 5X hypertonic solutions of several agents with diverse absorption and metabolism properties were infused duodenally at a physiological rate (3 ml/10 min). Jugular vein blood was sampled before and at 30, 60, 90, 120, 180, 240, and 300 min after infusion. Plasma ghrelin was suppressed dose dependently and most strongly by glucose. Hyperosmolar infusions of lactulose, which transits the small intestine unabsorbed, and 3-O-methylglucose (3-O-MG), which is absorbed like glucose but remains unmetabolized, also suppressed ghrelin. Glucose, but not lactulose or 3-O-MG, infusions increased plasma insulin. In study 2, intestinal infusions of hyperosmolar NaCl suppressed ghrelin, a response that was not attenuated by coinfusion with the neural blocker lidocaine. In study 3, we reconfirmed that the low-osmolar lipid emulsion Intralipid suppresses ghrelin more weakly than isocaloric (but hypertonic) glucose. Importantly, raising Intralipid's osmolarity to that of the glucose solution by nonabsorbable lactulose supplementation enhanced ghrelin suppression to that seen after glucose. Hyperosmolar ghrelin occurred particularly during the initial 3 postinfusion hours. We conclude that small intestinal hyperosmolarity 1) is sufficient to suppress ghrelin, 2) may combine with other postprandial mechanisms to suppress ghrelin, 3) might contribute to altered ghrelin regulation after gastric bypass surgery, and 4) may inform dietary modifications for metabolic health. C1 Univ Washington, Sch Med, Seattle, WA 98195 USA. [Cummings, David E.] VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Cummings, DE (reprint author), VA Puget Sound Hlth Care Syst, Box 358280 Mail Stop 111, Seattle, WA 98195 USA. EM davidec@u.washington.edu FU National Institute of Health [NIDDK RO1 DK61516] FX The studies in this paper were supported by National Institute of Health grant NIDDK RO1 DK61516 awarded to D. E. Cummings. NR 96 TC 1 Z9 1 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUN 15 PY 2014 VL 306 IS 12 BP C1108 EP C1116 DI 10.1152/ajpgi.00072.2014 PG 9 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA AK4UZ UT WOS:000338420900008 PM 24789208 ER PT J AU Belzil, C Asada, N Ishiguro, K Nakaya, T Parsons, K Pendolino, V Neumayer, G Mapelli, M Nakatani, Y Sanada, K Nguyen, MD AF Belzil, Camille Asada, Naoyuki Ishiguro, Kei-ichiro Nakaya, Takeo Parsons, Kari Pendolino, Valentina Neumayer, Gernot Mapelli, Marina Nakatani, Yoshihiro Sanada, Kamon Minh Dang Nguyen TI p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex SO BIOLOGY OPEN LA English DT Article DE p600; UBR4; Ndel1; Neurogenesis; Apical neural progenitors; Spindle orientation ID CEREBRAL CORTICAL DEVELOPMENT; ASYMMETRIC DIVISION; UBIQUITIN LIGASES; CELL-SURVIVAL; CNS NEURONS; RADIAL GLIA; STEM-CELLS; PROTEIN; LIS1; GENERATION AB Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis. C1 [Belzil, Camille; Parsons, Kari; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Parsons, Kari; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Hotchkiss Brain Inst, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Parsons, Kari; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Hotchkiss Brain Inst, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [Asada, Naoyuki; Sanada, Kamon] Univ Tokyo, Mol Genet Res Lab, Grad Sch Sci, Bunkyo Ku, Tokyo 1130033, Japan. [Ishiguro, Kei-ichiro; Nakaya, Takeo; Nakatani, Yoshihiro] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pendolino, Valentina; Mapelli, Marina] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy. [Ishiguro, Kei-ichiro] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan. RP Nguyen, MD (reprint author), Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, 3330 Hosp Dr NW,Heritage Med Res Bldg, Calgary, AB T2N 4N1, Canada. EM kamon_sanada@gen.s.u-tokyo.ac.jp; mdnguyen@ucalgary.ca FU Canadian Institute of Health Research; Alberta Innovates-Health Solutions (AI-HS); Ministry of Education, Culture, Sports, Science and Technology of Japan; Daiichi-Sankyo Foundation of Life Science; NCI [CA138866]; Italian Association for Cancer Research (AIRC); Italian Ministry of Health; Human Frontier Science Program Organization; CIHR; AI-HS; University of Calgary; Ted Fong Hotchkiss Brain Institute doctoral scholarship; AI-HS scholarship; JSPS fellowship FX This work was supported by the Canadian Institute of Health Research and the Alberta Innovates-Health Solutions (AI-HS) (to M.D.N.), Grant-in-Aid for Scientific Research on Innovative Areas "Neural Diversity and Neocortical Organization" from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Daiichi-Sankyo Foundation of Life Science (to K.S.), the NCI [grant no. CA138866 to Y.N.] and by the Italian Association for Cancer Research (AIRC) and the Italian Ministry of Health (to M.M.). M.D.N. held a Career Development Award from the Human Frontier Science Program Organization, a New Investigator Award from the CIHR and a Scholar Award from the AI-HS. C.B. received an Achievers in Medical Sciences award from the University of Calgary, a Ted Fong Hotchkiss Brain Institute doctoral scholarship and a AI-HS scholarship. K.-i.I. received a JSPS fellowship for research abroad, the Grant-in-Aid for Scientific Research on Priority Areas, and Grant-in-Aid for Young Scientists. K.P. received an AI-HS scholarship. NR 46 TC 1 Z9 1 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD JUN 15 PY 2014 VL 3 IS 6 BP 475 EP 485 DI 10.1242/bio.20147807 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AZ2NC UT WOS:000348069200007 PM 24812355 ER PT J AU Pathak, N Austin-Tse, CA Liu, Y Vasilyev, A Drummond, IA AF Pathak, Narendra Austin-Tse, Christina A. Liu, Yan Vasilyev, Aleksandr Drummond, Iain A. TI Cytoplasmic carboxypeptidase 5 regulates tubulin glutamylation and zebrafish cilia formation and function SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PURKINJE-CELL DEGENERATION; DIFFERENTIAL DISTRIBUTION; ALPHA-TUBULIN; IFT PARTICLE; POLYGLUTAMYLATION; TRANSPORT; GENE; MECHANISM; MOTILITY; MICE AB Glutamylation is a functionally important tubulin posttranslational modification enriched on stable microtubules of neuronal axons, mitotic spindles, centrioles, and cilia. In vertebrates, balanced activities of tubulin glutamyl ligase and cytoplasmic carboxypeptidase deglutamylase enzymes maintain organelle-and cell type-specific tubulin glutamylation patterns. Tubulin glutamylation in cilia is regulated via restricted subcellular localization or expression of tubulin glutamyl ligases (ttlls) and nonenzymatic proteins, including the zebrafish TPR repeat protein Fleer/Ift70. Here we analyze the expression patterns of ccp deglutamylase genes during zebrafish development and the effects of ccp gene knockdown on cilia formation, morphology, and tubulin glutamylation. The deglutamylases ccp2, ccp5, and ccp6 are expressed in ciliated cells, whereas ccp1 expression is restricted to the nervous system. Only ccp5 knockdown increases cilia tubulin glutamylation, induces ciliopathy phenotypes, including axis curvature, hydrocephalus, and pronephric cysts, and disrupts multicilia motility, suggesting that Ccp5 is the principal tubulin deglutamylase that maintains functional levels of cilia tubulin glutamylation. The ability of ccp5 knockdown to restore cilia tubulin glutamylation in fleer/ift70 mutants and rescue pronephric multicilia formation in both fleer- and ift88-deficient zebrafish indicates that tubulin glutamylation is a key driver of ciliogenesis. C1 [Pathak, Narendra; Liu, Yan; Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. [Vasilyev, Aleksandr] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. [Austin-Tse, Christina A.; Drummond, Iain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Pathak, N (reprint author), Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. EM NPATHAK@mgh.harvard.edu OI Austin-Tse, Christina/0000-0001-6492-6716 FU National Institutes of Health [K01DK078741, K08DK08272, R03DK097443, RO1DK053093] FX We acknowledge Mohamed Adan for technical assistance, Tjakko Van Ham for the gift of UAS: annexin-V-GFP transgenic fish, and members of the Drummond lab for critical input to the manuscript. We also thank Carsten Janke for the GT335 antibody and Zhaoxia Sun for the Arl13b antibody. This work was supported by National Institutes of Health Grants K01DK078741 (N.P.), K08DK08272 and R03DK097443 (A.V.), and RO1DK053093 (I.A.D.). NR 51 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN 15 PY 2014 VL 25 IS 12 BP 1836 EP 1844 DI 10.1091/mbc.E13-01-0033 PG 9 WC Cell Biology SC Cell Biology GA AM2AW UT WOS:000339651500003 PM 24743595 ER PT J AU Kumar, M Gupta, D Singh, G Sharma, S Bhat, M Prashant, CK Dinda, AK Kharbanda, S Kufe, D Singh, H AF Kumar, Manoj Gupta, Dikshi Singh, Gurpal Sharma, Sapna Bhat, Madhusudan Prashant, C. K. Dinda, A. K. Kharbanda, Surender Kufe, Donald Singh, Harpal TI Novel Polymeric Nanoparticles for Intracellular Delivery of Peptide Cargos: Antitumor Efficacy of the BCL-2 Conversion Peptide NuBCP-9 SO CANCER RESEARCH LA English DT Article ID DRUG-DELIVERY; IN-VIVO; HYDROLYTIC DEGRADATION; THERAPEUTIC PEPTIDES; INSULIN DELIVERY; CANCER-CELLS; FAMILY; INHIBITOR; PLA; NANOCARRIERS AB The preclinical development of peptidyl drugs for cancer treatment is hampered by their poor pharmacologic properties and cell penetrative capabilities in vivo. In this study, we report a nanoparticle-based formulation that overcomes these limitations, illustrating their utility in studies of the anticancer peptide NuBCP-9, which converts BCL-2 from a cell protector to a cell killer. NuBCP-9 was encapsulated in polymeric nanoparticles composed of a polyethylene glycol (PEG)-modified polylactic acid (PLA) diblock copolymer (NuBCP-9/PLA-PEG) or PEG-polypropylene glycol-PEG-modified PLA-tetrablock copolymer (NuBCP-9/PLA-PEG-PPG-PEG). We found that peptide encapsulation was enhanced by increasing the PEG chain length in the block copolymers. NuBCP-9 release from the nanoparticles was controlled by both PEG chain length and the PLA molecular weight, permitting time-release over sustained periods. Treatment of human cancer cells with these nanoparticles in vitro triggered apoptosis by NuBCP-9-mediated mechanism, with a potency similar to NuBCP-9 linked to a cell-penetrating poly-Arg peptide. Strikingly, in vivo administration of NuBCP-9/nanoparticles triggered complete regressions in the Ehrlich syngeneic mouse model of solid tumor. Our results illustrate an effective method for sustained delivery of anticancer peptides, highlighting the superior qualities of the novel PLA-PEG-PPG-PEG tetrablock copolymer formulation as a tool to target intracellular proteins. (C)2014 AAGR. C1 [Kumar, Manoj; Gupta, Dikshi; Singh, Gurpal; Sharma, Sapna; Singh, Harpal] Indian Inst Technol, Ctr Biomed Engn, Hauz Khas, India. [Bhat, Madhusudan; Prashant, C. K.; Dinda, A. K.] All India Inst Med Sci, Dept Pathol, New Delhi 110029, India. [Kharbanda, Surender; Kufe, Donald] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA. RP Kufe, D (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu; harpal2000@yahoo.com FU National Cancer Institute of the NIH [CA97098]; Lung Cancer Research Foundation; Department of Science and Technology, Government of India FX This work was supported by the National Cancer Institute of the NIH under award number CA97098, by the Lung Cancer Research Foundation, and by a grant from the Department of Science and Technology, Government of India. NR 50 TC 14 Z9 14 U1 3 U2 38 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2014 VL 74 IS 12 BP 3271 EP 3281 DI 10.1158/0008-5472.CAN-13-2015 PG 11 WC Oncology SC Oncology GA AL1IA UT WOS:000338877900008 PM 24741005 ER PT J AU Schoumacher, M Hurov, KE Lehar, J Yan-Neale, Y Mishina, Y Sonkin, D Korn, JM Flemming, D Jones, MD Antonakos, B Cooke, VG Steiger, J Ledell, J Stump, MD Sellers, WR Danial, NN Shao, WL AF Schoumacher, Marie Hurov, Kristen E. Lehar, Joseph Yan-Neale, Yan Mishina, Yuji Sonkin, Dmitriy Korn, Joshua M. Flemming, Daisy Jones, Michael D. Antonakos, Brandon Cooke, Vesselina G. Steiger, Janine Ledell, Jebediah Stump, Mark D. Sellers, William R. Danial, Nika N. Shao, Wenlin TI Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling SO CANCER RESEARCH LA English DT Article ID WNT PATHWAY; ADP-RIBOSYLATION; ACTIVATION; MOLECULE; PI3K; RESISTANCE; POLY(ADP-RIBOSE); THERAPEUTICS; CHERUBISM; THERAPY AB Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism. (C) 2014 AACR. C1 [Schoumacher, Marie; Hurov, Kristen E.; Lehar, Joseph; Yan-Neale, Yan; Mishina, Yuji; Sonkin, Dmitriy; Korn, Joshua M.; Flemming, Daisy; Jones, Michael D.; Antonakos, Brandon; Cooke, Vesselina G.; Stump, Mark D.; Sellers, William R.; Shao, Wenlin] Novartis Inst BioMed Res, Dept Oncol, Cambridge, MA 02139 USA. [Steiger, Janine; Ledell, Jebediah] Zalicus Inc, Cambridge, MA USA. [Danial, Nika N.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Shao, WL (reprint author), Novartis Inst BioMed Res, Dept Oncol, 250 Massachusetts Ave, Cambridge, MA 02139 USA. EM wenlin.shao@novartis.com OI Sonkin, Dmitriy/0000-0002-1649-0652 FU Novartis Institutes for BioMedical Research (NIBR); NIBR FX All studies were funded by Novartis Institutes for BioMedical Research (NIBR). M. Schoumacher is a recipient of the presidential postdoctoral fellowship from NIBR. NR 43 TC 5 Z9 5 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2014 VL 74 IS 12 BP 3294 EP 3305 DI 10.1158/0008-5472.CAN-14-0138-T PG 12 WC Oncology SC Oncology GA AL1IA UT WOS:000338877900010 PM 24747911 ER PT J AU Wang, RR Liu, W Helfer, CM Bradner, JE Hornick, JL Janicki, SM French, CA You, JX AF Wang, Ranran Liu, Wei Helfer, Christine M. Bradner, James E. Hornick, Jason L. Janicki, Susan M. French, Christopher A. You, Jianxin TI Activation of SOX2 Expression by BRD4-NUT Oncogenic Fusion Drives Neoplastic Transformation in NUT Midline Carcinoma SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; HUMAN PROSTATE-CANCER; EMBRYONIC STEM-CELLS; SELECTIVE-INHIBITION; BET BROMODOMAINS; INITIATING CELLS; SUPER-ENHANCERS; GENE-EXPRESSION; OVARIAN-CANCER; BREAST-CANCER AB BRD4 is implicated in the pathogenesis of a number of different cancers. It is also the target of translocation t(15;19) that accounts for the highly aggressive NUT midline carcinoma (NMC). We discovered that t(15;19) NMC cells display the ability to grow into stem cell-like spheres and express an exceptionally high level of the stem cell marker, SOX2. The BRD4-NUT fusion oncogene resulting from t(15;19) translocation is required for the abnormal activation of SOX2, which drives the stem cell-like proliferation and cellular transformation in NMC cells. SOX2 knockdown phenocopies the effects of BRD4-NUT inhibition, whereas ectopic SOX2 expression rescues the phenotype. The BRD4-NUT-induced abnormal SOX2 activation was observed in multiple NMC cell lines as well as in NMC primary tumors. We further demonstrate that BRD4-NUT oncoprotein recruits p300 to stimulate transcription activation and that inhibition of p300 represses SOX2 transcription in NMC cells. These studies identify this stem cell marker as a novel BRD4-NUT target that supports the highly aggressive transforming activity of t(15;19) carcinomas. Our study provides new mechanistic insights for understanding how alteration of BRD4 function by BRD4-NUT oncogene leads to the highly malignant NMC carcinoma. Because abnormal stem cell self-renewal is frequently observed during tumor formation and metastasis, the aberrant stem cell-like proliferation associated with BRD4 dysregulation observed in NMC carcinoma may have implications for studying the oncogenic mechanism of other BRD4-associated tumors. (C) 2014 AACR. C1 [Wang, Ranran; Liu, Wei; Helfer, Christine M.; You, Jianxin] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Janicki, Susan M.] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hornick, Jason L.; French, Christopher A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP You, JX (reprint author), Dept Microbiol, 3610 Hamilton Walk, Philadelphia, PA 19104 USA. EM jianyou@mail.med.upenn.edu RI LIU, WEI/J-5000-2012 FU NIH [R01CA148768, R01CA142723] FX This work has been supported by the NIH grants R01CA148768 and R01CA142723 to J. You. NR 50 TC 8 Z9 8 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2014 VL 74 IS 12 BP 3332 EP 3343 DI 10.1158/0008-5472.CAN-13-2658 PG 12 WC Oncology SC Oncology GA AL1IA UT WOS:000338877900013 PM 24736545 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO SPINE LA English DT Article DE low back pain; chronic low back pain; research standards; minimum data set; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a research task force to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum data set to describe research participants (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The research task force believes that these recommendations will advance the field, help resolve controversies, and facilitate future research addressing the genomic, neurological, and other mechanistic substrates of cLBP. We expect that the research task force recommendations will become a dynamic document and undergo continual improvement. Perspective: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for cLBP. The results included recommendations for definitions, a minimum data set, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony; Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony; Weiner, Debra K.] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis and Musculoskeletal and Skin Diseases FX Supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. NR 127 TC 13 Z9 13 U1 9 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD JUN 15 PY 2014 VL 39 IS 14 BP 1128 EP 1143 DI 10.1097/BRS.0000000000000434 PG 16 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AL5HL UT WOS:000339164300014 PM 24887571 ER PT J AU Fondell, E O'Reilly, EJ Fitzgerald, KC Falcone, GJ Kolonel, LN Park, Y McCullough, ML Ascherio, A AF Fondell, Elinor O'Reilly, Eilis J. Fitzgerald, Kathryn C. Falcone, Guido J. Kolonel, Laurence N. Park, Yikyung McCullough, Marjorie L. Ascherio, Alberto TI Dietary Fiber and Amyotrophic Lateral Sclerosis: Results From 5 Large Cohort Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; fiber; longitudinal cohort studies; motor neuron disease ID FOOD FREQUENCY QUESTIONNAIRE; C-REACTIVE PROTEIN; SOCIETY CANCER PREVENTION; BASE-LINE CHARACTERISTICS; GLYCEMIC LOAD; SYSTEMIC INFLAMMATION; ALCOHOL-CONSUMPTION; MULTIETHNIC COHORT; CIGARETTE-SMOKING; NUTRITION COHORT AB Amyotrophic lateral sclerosis (ALS) is a fast-progressing neurodegenerative disease with a median survival time from diagnosis of 1.5-3 years. The cause of ALS is unknown, but inflammation may play a role. Fiber has been shown to lower inflammatory markers, and a high fiber intake was associated with a lower risk of ALS in a case-control study; however, prospective studies are lacking. We explored the relation between dietary intake of fiber and the risk of ALS in 5 large prospective cohort studies comprising over 1,050,000 US citizens who contributed 1,133 ALS cases during a mean of 15 years of follow-up (1980-2008). Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. We found that intakes of total fiber, cereal fiber, vegetable fiber, and fruit fiber were not associated with ALS risk when comparing the highest quintile of intake with the lowest (for total fiber, pooled multivariable relative risk (RR) = 0.99, 95% confidence interval (CI): 0.80, 1.24; for cereal fiber, RR = 1.13, 95% CI: 0.94, 1.37; for vegetable fiber, RR = 0.97, 95% CI: 0.77, 1.23; and for fruit fiber, RR = 1.05, 95% CI: 0.86, 1.29). These findings do not support the hypothesis that fiber intake is a major determinant of ALS risk. C1 [Fondell, Elinor; O'Reilly, Eilis J.; Fitzgerald, Kathryn C.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fondell, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM efondell@hsph.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU National Institute of Neurological Diseases and Stroke [R01 NS045893]; National Cancer Institute [P01 CA87969, P01 CA055075] FX This work was supported by grant R01 NS045893 from the National Institute of Neurological Diseases and Stroke and grants P01 CA87969 and P01 CA055075 from the National Cancer Institute. NR 40 TC 0 Z9 0 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2014 VL 179 IS 12 BP 1442 EP 1449 DI 10.1093/aje/kwu089 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AK0MC UT WOS:000338106100008 PM 24816788 ER PT J AU Tsai, AC Lucas, M Okereke, OI O'Reilly, EJ Mirzaei, F Kawachi, I Ascherio, A Willett, WC AF Tsai, Alexander C. Lucas, Michel Okereke, Olivia I. O'Reilly, EIlis J. Mirzaei, Fariba Kawachi, Ichiro Ascherio, Alberto Willett, Walter C. TI Suicide Mortality in Relation to Dietary Intake of n-3 and n-6 Polyunsaturated Fatty Acids and Fish: Equivocal Findings From 3 Large US Cohort Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; docosahexaenoic acid; eicosapentaenoic acid; fish; linoleic acid; n-3 polyunsaturated fatty acids; suicide ID CORONARY-HEART-DISEASE; FOOD FREQUENCY QUESTIONNAIRE; NATIONAL DEATH INDEX; TOTAL-ENERGY-INTAKE; CARDIOVASCULAR-DISEASE; UNITED-STATES; CONTROLLED-TRIALS; CLINICAL-TRIALS; DEPRESSED MOOD; OMEGA-3-FATTY-ACIDS AB Intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs) has been implicated in the pathogenesis of depression. We sought to estimate the association between intake of fish and n-3 and n-6 PUFAs and suicide mortality over the course of long-term follow-up. In this prospective cohort study, biennial questionnaires were administered to 42,290 men enrolled in the Health Professionals Follow-up Study (1988-2008), 72,231 women enrolled in the Nurses' Health Study (1986-2008), and 90,836 women enrolled in Nurses' Health Study II (1993-2007). Dietary fish and n-3 and n-6 PUFA intakes were assessed every 4 years using a validated food-frequency questionnaire. Suicide mortality was ascertained through blind physician review of death certificates and hospital or pathology reports. Adjusted relative risks of suicide mortality were estimated with multivariable Cox proportional hazards models and pooled across cohorts using random-effects meta-analysis. The pooled multivariable relative risks for suicide among persons in the highest quartile of intake of n-3 or n-6 PUFAs, relative to the lowest quartile, ranged from 1.08 to 1.46 for n-3 PUFAs (P-trend = 0.11-0.52) and from 0.68 to 1.19 for n-6 PUFAs (P-trend = 0.09-0.54). We did not find evidence that intake of n-3 PUFAs or fish lowered the risk of completed suicide. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.; Okereke, Olivia I.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Lucas, Michel; O'Reilly, EIlis J.; Mirzaei, Fariba; Ascherio, Alberto; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Lucas, Michel] Univ Laval, Dept Social & Prevent Med, Quebec City, PQ, Canada. [Okereke, Olivia I.; O'Reilly, EIlis J.; Kawachi, Ichiro; Ascherio, Alberto; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Okereke, Olivia I.; Ascherio, Alberto; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Okereke, Olivia I.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Kawachi, Ichiro] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org RI Okereke, Olivia/R-9934-2016; OI Tsai, Alexander/0000-0001-6397-7917 FU National Cancer Institute (National Institutes of Health (NIH)) [P01CA087969, U19CA055075, R01CA050385]; National Institute of Mental Health (NIH) [K23MH096620, R01MH091448]; National Institute of Neurological Disorders and Stroke (NIH) [R01NS061858] FX Follow-up of the cohorts whose data were included in this study was supported by the National Cancer Institute (National Institutes of Health (NIH) grants P01CA087969, U19CA055075, and R01CA050385). Several authors received salary support from the National Institute of Mental Health (NIH grants K23MH096620 to A. C. T. and R01MH091448 to O.I.O.) and the National Institute of Neurological Disorders and Stroke (NIH grant R01NS061858 to A.A.). NR 76 TC 10 Z9 10 U1 3 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2014 VL 179 IS 12 BP 1458 EP 1466 DI 10.1093/aje/kwu086 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AK0MC UT WOS:000338106100010 PM 24812159 ER PT J AU An, D Lessard, SJ Toyoda, T Lee, MY Koh, HJ Qi, L Hirshman, MF Goodyear, LJ AF An, Ding Lessard, Sarah J. Toyoda, Taro Lee, Min-Young Koh, Ho-Jin Qi, Ling Hirshman, Michael F. Goodyear, Laurie J. TI Overexpression of TRB3 in muscle alters muscle fiber type and improves exercise capacity in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE TRB3; exercise capacity; muscle; microRNAs; PPAR-alpha ID MOUSE SKELETAL-MUSCLE; GLUCOSE-HOMEOSTASIS; INSULIN-RESISTANCE; METABOLIC SYNDROME; ENERGY-METABOLISM; TRIBBLES HOMOLOG; EXPRESSION; GENE; DIFFERENTIATION; PERFORMANCE AB Increasing evidence suggests that TRB3, a mammalian homolog of Drosophila tribbles, plays an important role in cell growth, differentiation, and metabolism. In the liver, TRB3 binds and inhibits Akt activity, whereas in adipocytes, TRB3 upregulates fatty acid oxidation. In cultured muscle cells, TRB3 has been identified as a potential regulator of insulin signaling. However, little is known about the function and regulation of TRB3 in skeletal muscle in vivo. In the current study, we found that 4 wk of voluntary wheel running (6.6 +/- 0.4 km/day) increased TRB3 mRNA by 1.6-fold and protein by 2.5-fold in the triceps muscle. Consistent with this finding, muscle-specific transgenic mice that overexpress TRB3 (TG) had a pronounced increase in exercise capacity compared with wild-type (WT) littermates (TG: 1,535 +/- 283; WT: 644 +/- 67 joules). The increase in exercise capacity in TRB3 TG mice was not associated with changes in glucose uptake or glycogen levels; however, these mice displayed a dramatic shift toward a more oxidative/fatigue-resistant (type I/IIA) muscle fiber type, including threefold more type I fibers in soleus muscles. Skeletal muscle from TRB3 TG mice had significantly decreased PPAR alpha expression, twofold higher levels of miR208b and miR499, and corresponding increases in the myosin heavy chain isoforms Myh7 and Myb7b, which encode these microRNAs. These findings suggest that TRB3 regulates muscle fiber type via a peroxisome proliferator-activated receptor-alpha (PPAR-alpha)-regulated miR499/miR208b pathway, revealing a novel function for TRB3 in the regulation of skeletal muscle fiber type and exercise capacity. C1 [An, Ding; Lessard, Sarah J.; Toyoda, Taro; Lee, Min-Young; Koh, Ho-Jin; Hirshman, Michael F.; Goodyear, Laurie J.] Brigham & Womens Hosp, Joslin Diabet Ctr, Res Div, Boston, MA 02115 USA. [An, Ding; Lessard, Sarah J.; Toyoda, Taro; Lee, Min-Young; Koh, Ho-Jin; Goodyear, Laurie J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Qi, Ling] Salk Inst, San Diego, CA 92186 USA. RP Goodyear, LJ (reprint author), One Joslin Pl, Boston, MA 02215 USA. EM laurie.goodyear@joslin.harvard.edu FU National Institutes of Health [R01 DK101043, AR42238]; Diabetes Research Center [P30 DK36836]; American Diabetes Association Mentor-Based Award [7-12-MN-22]; American Physiological Society (Physiological Genomics); Canadian Diabetes Association FX This work was supported by funding from the National Institutes of Health Grants R01 DK101043 and AR42238 (L. J. Goodyear) and Diabetes Research Center Grant P30 DK36836 (Joslin Diabetes Center). M.-Y. Lee was supported by an American Diabetes Association Mentor-Based Award (Grant 7-12-MN-22) to L. J. Goodyear. S. J. Lessard was supported by postdoctoral fellowships from the American Physiological Society (Physiological Genomics) and the Canadian Diabetes Association. NR 27 TC 7 Z9 7 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JUN 15 PY 2014 VL 306 IS 12 BP R925 EP R933 DI 10.1152/ajpregu.00027.2014 PG 9 WC Physiology SC Physiology GA AK4VK UT WOS:000338422000007 PM 24740654 ER PT J AU Zhang, Z Duckart, J Slatore, CG Fu, Y Petrik, AF Thorp, ML Cohen, DM AF Zhang, Zheng Duckart, Jonathan Slatore, Christopher G. Fu, Yi Petrik, Amanda F. Thorp, Micah L. Cohen, David M. TI Individuality of the plasma sodium concentration SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE human; hyponatremia; osmoregulation; population ID NEPHROGENIC DIABETES-INSIPIDUS; DAY-TO-DAY; SERUM CONSTITUENTS; INAPPROPRIATE ANTIDIURESIS; INTRAINDIVIDUAL VARIATION; INDUCED HYPONATREMIA; ANALYTIC COMPONENTS; WATER-DEPRIVATION; RECEPTOR GENE; LONG-TERM AB Older literature has suggested that the plasma sodium concentration is not individual, that it is neither intrinsic to an individual nor reproducible, longitudinally. We recently observed that the plasma sodium concentration is heritable. Because demonstrable heritability requires individuality of the relevant phenotype, we hypothesized that the plasma sodium concentration was substantially individual. In two large health plan-based cohorts, we demonstrated individuality of the plasma sodium concentration over a 10-yr interval; the intraclass correlation coefficient (ICC) averaged 0.4-0.5. The individuality of plasma sodium increased significantly with age. Plasma sodium individuality was equal to or only slightly less than that for plasma glucose but was less than the individuality for creatinine. The individuality of plasma sodium was further confirmed by comparing the Pearson correlation coefficient for within-individual versus between-individual pairs of sodium determinations and via application of the agreement index. Furthermore, the distribution of all sodium determinations for all participants within a population was similar to the distribution for the mean sodium concentration for individuals within that population. Therefore, the near-normal distribution of plasma sodium measurements within a population is likely not attributable to assay-specific factors but rather to genuine and durable biological variability in the osmotic set point. In aggregate, these data strongly support the individuality of the plasma sodium concentration. They further indicate that serial plasma sodium values for any given individual tend to cluster around a patient-specific set point and that these set points vary among individuals. C1 [Fu, Yi; Cohen, David M.] Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97239 USA. [Petrik, Amanda F.; Thorp, Micah L.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Zhang, Zheng] Brown Univ, Sch Med, Dept Biostat, Providence, RI 02912 USA. [Slatore, Christopher G.] Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97239 USA. [Fu, Yi; Cohen, David M.] Portland VA Med Ctr, Sect Nephrol, Portland, OR USA. [Slatore, Christopher G.] Portland VA Med Ctr, Sect Pulm & Crit Care Med, Portland, OR USA. [Duckart, Jonathan] Portland VA Med Ctr, Portland, OR USA. RP Cohen, DM (reprint author), Oregon Hlth & Sci Univ, Mailcode CH12R,3303 SW Bond Ave, Portland, OR 97239 USA. EM cohend@ohsu.edu RI Zhang, Zheng/J-2388-2014; OI Zhang, Zheng/0000-0003-2497-0362; Slatore, Christopher/0000-0003-0958-8122 FU National Institutes of Health; Department of Veterans Affairs; American Heart Association; Kaiser Permanente Northwest Center for Health Research; Veterans Administration Health Services Research and Development Career Development Award; Portland Veterans Affairs Medical Center (Portland, OR) FX This work was supported by grants from the National Institutes of Health, Department of Veterans Affairs, and American Heart Association (to D. M. Cohen) and by the Kaiser Permanente Northwest Center for Health Research (to A. F. Petrik and M. L. Thorp). C. G. Slatore is supported by a Veterans Administration Health Services Research and Development Career Development Award and resources from the Portland Veterans Affairs Medical Center (Portland, OR). NR 52 TC 9 Z9 9 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN 15 PY 2014 VL 306 IS 12 BP F1534 EP F1543 DI 10.1152/ajprenal.00585.2013 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AK3VW UT WOS:000338354200014 PM 24717732 ER PT J AU Lamas, DJ Owens, RL Bernacki, RE Block, SD AF Lamas, Daniela J. Owens, Robert L. Bernacki, Rachelle E. Block, Susan D. TI Palliative Care: A Core Competency for Intensive Care Unit Doctors SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID CONSULTATION; MODEL C1 [Lamas, Daniela J.; Owens, Robert L.; Bernacki, Rachelle E.; Block, Susan D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bernacki, Rachelle E.; Block, Susan D.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lamas, DJ (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 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 JUN 15 PY 2014 VL 189 IS 12 BP 1569 EP 1569 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AK3KI UT WOS:000338322000027 PM 24930536 ER PT J AU Bernau, C Riester, M Boulesteix, AL Parmigiani, G Huttenhower, C Waldron, L Trippa, L AF Bernau, Christoph Riester, Markus Boulesteix, Anne-Laure Parmigiani, Giovanni Huttenhower, Curtis Waldron, Levi Trippa, Lorenzo TI Cross-study validation for the assessment of prediction algorithms SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Student Council Symposium of the International-Society-for-Computational-Biology (ISCB) held in conjunction with the 22nd Annual Meeting of Intelligent Systems for Molecular Biology (ISMB) CY JUL 11, 2014 CL Boston, MA SP Int Soc Computat Biol ID NEGATIVE BREAST-CANCER; HIGH-DIMENSIONAL DATA; PROGNOSTIC SIGNATURE; ERROR ESTIMATION; CLASSIFIERS; SURVIVAL; MODELS; LUNG; BIOINFORMATICS; METASTASIS AB Motivation: Numerous competing algorithms for prediction in high-dimensional settings have been developed in the statistical and machine-learning literature. Learning algorithms and the prediction models they generate are typically evaluated on the basis of cross-validation error estimates in a few exemplary datasets. However, in most applications, the ultimate goal of prediction modeling is to provide accurate predictions for independent samples obtained in different settings. Cross-validation within exemplary datasets may not adequately reflect performance in the broader application context. Methods: We develop and implement a systematic approach to 'cross-study validation', to replace or supplement conventional cross-validation when evaluating high-dimensional prediction models in independent datasets. We illustrate it via simulations and in a collection of eight estrogen-receptor positive breast cancer microarray gene-expression datasets, where the objective is predicting distant metastasis-free survival (DMFS). We computed the C-index for all pairwise combinations of training and validation datasets. We evaluate several alternatives for summarizing the pairwise validation statistics, and compare these to conventional cross-validation. Results: Our data-driven simulations and our application to survival prediction with eight breast cancer microarray datasets, suggest that standard cross-validation produces inflated discrimination accuracy for all algorithms considered, when compared to cross-study validation. Furthermore, the ranking of learning algorithms differs, suggesting that algorithms performing best in cross-validation may be suboptimal when evaluated through independent validation. C1 [Bernau, Christoph] Leibniz Supercomp Ctr, Garching, Germany. [Bernau, Christoph; Boulesteix, Anne-Laure] Dept Med Informat Biometry & Epidemiol, Cambridge, MA USA. [Riester, Markus; Parmigiani, Giovanni; Trippa, Lorenzo] Dana Farber Canc Inst, Boston, MA 02115 USA. [Riester, Markus; Parmigiani, Giovanni; Trippa, Lorenzo] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Waldron, Levi] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. RP Waldron, L (reprint author), CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. EM levi.waldron@hunter.cuny.edu OI Riester, Markus/0000-0002-4759-8332; Waldron, Levi/0000-0003-2725-0694 FU German Science Foundation [BO3139/2-2]; National Science Foundation [CAREER DBI-1053486, DMS-1042785]; National Cancer Institute [5P30 CA006516-46, 1RC4 CA156551-01] FX German Science Foundation [BO3139/2-2 to A.L.B.]. National Science Foundation [grant number CAREER DBI-1053486 to C.H. and DMS-1042785 to G.P.]; National Cancer Institute [grant 5P30 CA006516-46 to G.P. and 1RC4 CA156551-01 to L.W. G.P. and L.T.]. NR 41 TC 11 Z9 11 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2014 VL 30 IS 12 BP 105 EP 112 DI 10.1093/bioinformatics/btu279 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AK0NF UT WOS:000338109200013 PM 24931973 ER PT J AU Leslie, R O'Donnell, CJ Johnson, AD AF Leslie, Richard O'Donnell, Christopher J. Johnson, Andrew D. TI GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Student Council Symposium of the International-Society-for-Computational-Biology (ISCB) held in conjunction with the 22nd Annual Meeting of Intelligent Systems for Molecular Biology (ISMB) CY JUL 11, 2014 CL Boston, MA SP Int Soc Computat Biol ID PROSTATE-CANCER SUSCEPTIBILITY; EUROPEAN POPULATIONS; GENETIC ASSOCIATION; PARKINSONS-DISEASE; COMMON VARIANTS; LOCI; MULTIPLE; TRAITS; RISK; IDENTIFICATION AB We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains 46.2 million SNP-phenotype association from among 1390 GWAS studies. We re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs). Motivation: To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions. Results: GWAS have grown exponentially, with increases in sample sizes and markers tested, and continuing bias toward European ancestry samples. GRASP contains > 100 000 phenotypes, roughly: eQTLs (71.5%), metabolite QTLs (21.2%), methylation QTLs (4.4%) and diseases, biomarkers and other traits (2.8%). c/s-eQTLs, meQTLs, mQTLs and MHC region SNPs are highly enriched among significant results. After removing these categories, GRASP still contains a greater proportion of studies and results than comparable GWAS catalogs. Cardiovascular disease and related risk factors pre-dominate remaining GWAS results, followed by immunological, neurological and cancer traits. Significant results in GWAS display a highly gene-centric tendency. Sex chromosome X (OR= 0.18[0.16-0.20]) and Y (OR= 0.003[0.001-0.01]) genes are depleted for GWAS results. Gene length is correlated with GWAS results at nominal significance (P <= 0.05) levels. We show this gene-length correlation decays at increasingly more stringent P-value thresholds. Potential pleotropic genes and SNPs enriched for multi-phenotype association in GWAS are identified. However, we note possible population stratification at some of these loci. Finally, via re-annotation we identify compelling functional hypotheses at GWAS loci, in some cases unrealized in studies to date. Conclusion: Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights. C1 [Leslie, Richard; O'Donnell, Christopher J.; Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Leslie, Richard] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Johnson, AD (reprint author), NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU National Heart, Lung and Blood Institute intramural funds FX National Heart, Lung and Blood Institute intramural funds to R. L., C.J.O. and A.D.J. NR 58 TC 30 Z9 30 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2014 VL 30 IS 12 BP 185 EP 194 DI 10.1093/bioinformatics/btu273 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AK0NF UT WOS:000338109200022 PM 24931982 ER PT J AU Gross, ND Bauman, JE Gooding, WE Denq, W Thomas, SM Wang, L Chiosea, S Hood, BL Flint, MS Sun, M Conrads, TP Ferris, RL Johnson, JT Kim, S Argiris, A Wirth, L Nikiforova, MN Siegfried, JM Grandis, JR AF Gross, Neil D. Bauman, Julie E. Gooding, William E. Denq, William Thomas, Sufi M. Wang, Lin Chiosea, Simion Hood, Brian L. Flint, Melanie S. Sun, Mai Conrads, Thomas P. Ferris, Robert L. Johnson, Jonas T. Kim, Seungwon Argiris, Athanassios Wirth, Lori Nikiforova, Marina N. Siegfried, Jill M. Grandis, Jennifer R. TI Erlotinib, Erlotinib-Sulindac versus Placebo: A Randomized, Double-Blind, Placebo-Controlled Window Trial in Operable Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; EPIDERMAL-GROWTH-FACTOR; CHEMOTHERAPY PLUS CETUXIMAB; FACTOR RECEPTOR EXPRESSION; GENE COPY NUMBER; PHASE-II; BREAST-CANCER; PREDICTIVE-VALUE; TYROSINE KINASE; NUCLEAR ANTIGEN AB Purpose: The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo. Experimental Design: Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates. Results: From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R-2 = 0.312, P = 0.024). Conclusions: Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target. (C) 2014 AACR. C1 [Gross, Neil D.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Div Head & Neck Surg, Portland, OR 97201 USA. [Bauman, Julie E.; Argiris, Athanassios] Univ Pittsburgh, Inst Canc, Div Hematol Oncol, Dept Internal Med, Pittsburgh, PA 15232 USA. [Hood, Brian L.; Flint, Melanie S.; Sun, Mai; Conrads, Thomas P.; Siegfried, Jill M.] Univ Pittsburgh, Inst Canc, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15232 USA. [Gooding, William E.] Univ Pittsburgh, Inst Canc, Biostat Facil, Pittsburgh, PA 15232 USA. [Denq, William; Thomas, Sufi M.; Chiosea, Simion; Ferris, Robert L.; Johnson, Jonas T.; Kim, Seungwon; Grandis, Jennifer R.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15232 USA. [Wang, Lin; Chiosea, Simion; Nikiforova, Marina N.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15232 USA. [Thomas, Sufi M.] Univ Kansas, Med Ctr, Dept Otolaryngol, Kansas City, KS 66103 USA. [Hood, Brian L.; Conrads, Thomas P.] Gynecol Canc Ctr Excellence, Womens Hlth Integrated Res Ctr, Annandale, VA USA. [Argiris, Athanassios] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol Oncol, San Antonio, TX 78229 USA. [Wirth, Lori] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Siegfried, Jill M.] Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. RP Bauman, JE (reprint author), Univ Pittsburgh, Inst Canc, 5150 Ctr Ave,5th Floor, Pittsburgh, PA 15232 USA. EM baumanje@upmc.edu OI Flint, Melanie/0000-0001-5311-3023; Thomas, Sufi/0000-0001-5370-0842 FU NIH [R01CA098372]; NIH [UPCI Head and Neck Cancer SPORE] [P50CA097190]; NIH [UPCI Cancer Center Support Grant] [P30CA47904]; American Cancer Society Distinguished Professorship; OSI Pharmaceuticals FX This work was supported by grants from the NIH [R01CA098372; the UPCI Head and Neck Cancer SPORE (P50CA097190), the UPCI Cancer Center Support Grant (P30CA47904)], the American Cancer Society Distinguished Professorship (to J.R. Grandis), and OSI Pharmaceuticals. NR 50 TC 16 Z9 17 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2014 VL 20 IS 12 BP 3289 EP 3298 DI 10.1158/1078-0432.CCR-13-3360 PG 10 WC Oncology SC Oncology GA AK3SG UT WOS:000338344400025 PM 24727329 ER PT J AU Wilson, MA Zhao, FM Letrero, R D'Andrea, K Rimm, DL Kirkwood, JM Kluger, HM Lee, SJ Schuchter, LM Flaherty, KT Nathanson, KL AF Wilson, Melissa A. Zhao, Fengmin Letrero, Richard D'Andrea, Kurt Rimm, David L. Kirkwood, John M. Kluger, Harriet M. Lee, Sandra J. Schuchter, Lynn M. Flaherty, Keith T. Nathanson, Katherine L. TI Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib SO CLINICAL CANCER RESEARCH LA English DT Article ID REFRACTORY SOLID TUMORS; METASTATIC MELANOMA; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; BRAF MUTATIONS; MULTIKINASE INHIBITOR; IMPROVED SURVIVAL; PHASE-II; NRAS; TRIAL AB Purpose: Sorafenib is an inhibitor of VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAF kinases, amongst others. We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603, comparing treatment with carboplatin, paclitaxel +/- sorafenib (CP vs. CPS). Experimental Design: Pretreatment tumor samples from 179 unique individuals enrolled on E2603 were analyzed. Genotyping was performed using a custom iPlex panel interrogating 74 mutations in 13 genes. Statistical analysis was performed using Fisher exact test, logistic regression, and Cox proportional hazards models. Progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier methods. Results: BRAF and NRAS mutations were found at frequencies consistent with other metastatic melanoma cohorts. BRAF-mutant melanoma was associated with worse performance status, increased number of disease sites, and younger age at diagnosis. NRAS-mutant melanoma was associated with better performance status, fewer sites of disease, and female gender. BRAF and NRAS mutations were not significantly predictive of response or survival when treated with CPS versus CP. However, patients with NRAS-mutant melanoma trended toward a worse response and PFS on CP than those with BRAF-mutant or WT/WT melanoma, an association that was reversed for this group on the CPS arm. Conclusions: This study of somatic mutations in melanoma is the last prospectively collected phase III clinical trial population before the era of BRAF-targeted therapy. A trend toward improved clinical response in patients with NRAS-mutant melanoma treated with CPS was observed, possibly due to the effect of sorafenib on CRAF. Clin Cancer Res; 20(12); 3328-37. (C) 2014 AACR. C1 [Wilson, Melissa A.; Schuchter, Lynn M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Letrero, Richard; D'Andrea, Kurt; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Schuchter, Lynn M.; Nathanson, Katherine L.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA USA. [Zhao, Fengmin; Lee, Sandra J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Kluger, Harriet M.] Yale Canc Ctr, Sect Med Oncol, New Haven, CT USA. RP Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, 351 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM knathans@exchange.upenn.edu OI Wilson, Melissa/0000-0002-5391-7838 FU Public Health Service Grants [CA23318, CA66636, CA21115, CA15488, CA14958, CA39229]; National Cancer Institute, NIH; Department of Health and Human Services; NCI Cancer Center Research Training Program [T32 CA009615]; NIH [R01 CA115756, RO1 CA118871] FX This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA15488, CA14958, CA39229 and from the National Cancer Institute, NIH and the Department of Health and Human Services. This research was funded in part by a NCI Cancer Center Research Training Program Grant T32 CA009615 (PI: Dr. John Maris; to M. A. Wilson), NIH Grant R01 CA115756 (to H. M. Kluger), and NIH GRANT RO1 CA118871 (to K. T. Flaherty and K. L. Nathanson). NR 42 TC 16 Z9 16 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2014 VL 20 IS 12 BP 3328 EP 3337 DI 10.1158/1078-0432.CCR-14-0093 PG 10 WC Oncology SC Oncology GA AK3SG UT WOS:000338344400029 PM 24714776 ER PT J AU Abrahamson, EE Foley, LM Hitchens, TK Dixon, CE Ikonomovic, MD AF Abrahamson, E. E. Foley, L. M. Hitchens, T. K. Dixon, C. E. Ikonomovic, M. D. TI MEMANTINE HYDROCHLORIDE AS A THERAPY FOR TRAUMATIC BRAIN INJURY: A PRECLINICAL STUDY USING THE CCI INJURY MODEL IN RATS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE cerebral blood flow; controlled cortical impact; excitotoxicity; glutamate C1 [Abrahamson, E. E.; Ikonomovic, M. D.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Abrahamson, E. E.; Ikonomovic, M. D.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Ikonomovic, M. D.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Dixon, C. E.] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA USA. [Foley, L. M.; Hitchens, T. K.] Carnegie Mellon Univ, Pittsburgh NMR Ctr, Pittsburgh, PA 15213 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA C2-31 BP A87 EP A87 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600236 ER PT J AU Dixon, CE Yan, HQ Ma, X Empey, P Poloyac, S Feldman, K Kochanek, PM AF Dixon, C. E. Yan, H. Q. Ma, X. Empey, P. Poloyac, S. Feldman, K. Kochanek, P. M. TI DOSE-RESPONSE EVALUATION OF SIMVASTATIN IN THE CONTROLLED CORTICAL IMPACT MODEL: OPERATION BRAIN TRAUMA THERAPY CONSORTIUM SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE consortium; controlled cortical impact; rats; simvastatin C1 [Dixon, C. E.; Yan, H. Q.; Ma, X.; Empey, P.; Poloyac, S.] Univ Pittsburgh, Pittsburgh, PA USA. [Dixon, C. E.; Feldman, K.; Kochanek, P. M.] Univ Pittsburgh, CCM, Safar Ctr Resuscitat, Pittsburgh, PA USA. [Dixon, C. E.; Yan, H. Q.; Ma, X.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RI Kochanek, Patrick/D-2371-2015 OI Kochanek, Patrick/0000-0002-2627-913X NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D1-19 BP A107 EP A107 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600291 ER PT J AU Folmer, RL Hutter, M Belding, H Papesh, M Grush, L Leek, M Gallun, F AF Folmer, R. L. Hutter, M. Belding, H. Papesh, M. Grush, L. Leek, M. Gallun, F. TI ELECTROPHYSIOLOGICAL EVIDENCE OF AUDITORY AND COGNITIVE DYSFUNCTION IN VETERANS EXPOSED TO HIGH-INTENSITY BLASTS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE auditory brainstem response; auditory processing; event-related potentials; N200; P300 C1 [Folmer, R. L.; Hutter, M.; Belding, H.; Papesh, M.; Gallun, F.] NCRAR, Portland VA Med Ctr, Portland, OR USA. [Folmer, R. L.; Gallun, F.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. [Grush, L.] Univ Colorado, Boulder, CO 80309 USA. [Leek, M.] VA Loma Linda, Loma Linda, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA B3-05 BP A57 EP A57 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600152 ER PT J AU Hsieh, CL Niemi, EC Wang, SH Lee, C Bingham, D Zhang, J Charo, I Huang, EJ Liu, J Nakamura, MC AF Hsieh, C. L. Niemi, E. C. Wang, S. H. Lee, C. Bingham, D. Zhang, J. Charo, I Huang, E. J. Liu, J. Nakamura, M. C. TI CCR2 DEFICIENCY IMPAIRS MACROPHAGE INFILTRATION AND IMPROVES COGNITIVE FUNCTION AFTER TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE behavior studies; CCR2; flow cytometry; inflammation; macrophage; traumatic brain injury C1 [Hsieh, C. L.; Niemi, E. C.; Wang, S. H.; Lee, C.; Bingham, D.; Zhang, J.; Charo, I; Huang, E. J.; Liu, J.; Nakamura, M. C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hsieh, C. L.; Niemi, E. C.; Lee, C.; Bingham, D.; Zhang, J.; Huang, E. J.; Liu, J.; Nakamura, M. C.] San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D1-31 BP A111 EP A111 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600303 ER PT J AU Mannix, R Iverson, GL Maxwell, B Atkins, J Berkner, P AF Mannix, R. Iverson, G. L. Maxwell, B. Atkins, J. Berkner, P. TI MULTIPLE PRIOR CONCUSSIONS ARE ASSOCIATED WITH SYMPTOMS IN HIGH SCHOOL ATHLETES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE baseline neurocognitive test; ImPact (R) Test; multiple concussion; self report; symptoms C1 [Mannix, R.] Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Iverson, G. L.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, G. L.] Red Sox Fdn, Boston, MA USA. [Iverson, G. L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. [Maxwell, B.] Colby Coll, Dept Comp Sci, Waterville, ME 04901 USA. [Atkins, J.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. [Berkner, P.] Colby Coll, Hlth Serv, Waterville, ME 04901 USA. NR 0 TC 0 Z9 0 U1 3 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA OC5-03 BP A15 EP A15 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600036 ER PT J AU McGuone, D Smith, C Costine, BA Duhaime, AC AF McGuone, D. Smith, C. Costine, B. A. Duhaime, A. C. TI CHALLENGES IN ASSESSING TAU IN A LARGE ANIMAL MODEL OF TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE immaturity; large animal model; tauopathy; TBI C1 [McGuone, D.; Smith, C.; Costine, B. A.; Duhaime, A. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D2-27 BP A122 EP A123 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600333 ER PT J AU Papesh, MA Gallun, F Leek, M Billings, CJ Folmer, R Storzbach, D AF Papesh, M. A. Gallun, F. Leek, M. Billings, C. J. Folmer, R. Storzbach, D. TI BLAST EXPOSURE IMPAIRS THE BRAIN'S ABILITY TO MODULATE SENSITIVITY TO SENSORY INFORMATION: EVIDENCE FROM THE VETERAN POPULATION SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE auditory; blast exposure; sensory processing; traumatic brain injury; veterans C1 [Papesh, M. A.; Gallun, F.; Leek, M.; Billings, C. J.; Folmer, R.; Storzbach, D.] OHSU, Portland, OR USA. [Gallun, F.; Leek, M.; Billings, C. J.; Folmer, R.; Storzbach, D.] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA A5-02 BP A43 EP A43 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600113 ER PT J AU Tagge, CA Fisher, AM Gaudreau, AB Wojnarowicz, MW Minaeva, O Moncaster, JA Casey, N Stein, TD Moss, WC Moir, RD Tanzi, RE Stanton, PK Mckee, AC Goldstein, LE AF Tagge, C. A. Fisher, A. M. Gaudreau, A. B. Wojnarowicz, M. W. Minaeva, O. Moncaster, J. A. Casey, N. Stein, T. D. Moss, W. C. Moir, R. D. Tanzi, R. E. Stanton, P. K. McKee, A. C. Goldstein, L. E. TI ELUCIDATING THE PATHOBIOLOGY OF IMPACT CONCUSSION IN A MOUSE MODEL OF MILD TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE traumatic brain injury C1 [Tagge, C. A.; Fisher, A. M.; Gaudreau, A. B.; Wojnarowicz, M. W.; Minaeva, O.; Moncaster, J. A.; Casey, N.; Stein, T. D.; McKee, A. C.; Goldstein, L. E.] Boston Univ, Coll Engn, Sch Med, Boston, MA 02215 USA. [Stein, T. D.; Goldstein, L. E.] Boston Univ, Alzheimers Dis Ctr, Boston, MA 02215 USA. [Stein, T. D.; McKee, A. C.] Boston VA Healthcare Syst, Boston, MA USA. [Moss, W. C.] Lawrence Livermore Natl Lab, Livermore, CA USA. [Stanton, P. K.] New York Med Coll, Valhalla, NY 10595 USA. [Moir, R. D.; Tanzi, R. E.] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D2-25 BP A122 EP A122 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600331 ER PT J AU Wojnarowicz, MW Fisher, AM Tagge, CA Gaudreau, AB Minaeva, O Moncaster, JA Casey, N Stein, TD Moss, WC Moir, RD Tanzi, RE Stanton, PK McKee, AC Goldstein, LE AF Wojnarowicz, M. W. Fisher, A. M. Tagge, C. A. Gaudreau, A. B. Minaeva, O. Moncaster, J. A. Casey, N. Stein, T. D. Moss, W. C. Moir, R. D. Tanzi, R. E. Stanton, P. K. McKee, A. C. Goldstein, L. E. TI ELUCIDATING THE KINEMATICS AND PATHOBIOLOGY OF BLAST-RELATED TRAUMATIC BRAIN INJURY AND SEQUELAE IN A MOUSE MODEL SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE blast; CTE; murine model; neuropathology C1 [Wojnarowicz, M. W.; Fisher, A. M.; Tagge, C. A.; Gaudreau, A. B.; Minaeva, O.; Moncaster, J. A.; Casey, N.; Stein, T. D.; McKee, A. C.; Goldstein, L. E.] Boston Univ, Coll Engn, Sch Med, Boston, MA 02215 USA. [Stein, T. D.; McKee, A. C.; Goldstein, L. E.] Boston Univ, Alzheimers Dis Ctr, Boston, MA 02215 USA. [Stein, T. D.; McKee, A. C.] Boston VA Healthcare Syst, Boston, MA USA. [Moss, W. C.] Lawrence Livermore Natl Lab, Livermore, CA USA. [Stanton, P. K.] New York Med Coll, Valhalla, NY 10595 USA. [Moir, R. D.; Tanzi, R. E.] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D2-07 BP A115 EP A115 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600313 ER PT J AU Wu, L Leung, W Wang, X Wu, J Lo, EH Lok, J AF Wu, L. Leung, W. Wang, X. Wu, J. Lo, E. H. Lok, J. TI NEUREGULIN-1 INFUSION AFTER TBI IN ADOLESCENT MICE IMPROVES COGNITIVE PERFORMANCE DURING ADULTHOOD SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE neuregulin-1; neuroprotection; pediatric; trauma C1 [Wu, L.; Leung, W.; Wang, X.; Lo, E. H.; Lok, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wu, L.; Wu, J.] Jilin Univ, Hosp 1, Changchun 130023, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D1-26 BP A110 EP A110 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600298 ER PT J AU Yan, HQ Carlson, S Li, Y Henchir, J Ma, X Dixon, CE AF Yan, H. Q. Carlson, S. Li, Y. Henchir, J. Ma, X. Dixon, C. E. TI EFFECT OF TRAUMATIC BRAIN INJURY ON WILD-TYPE ALPHA-SYNUCLEIN EXPRESSION IN RAT HIPPOCAMPUS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE alpha-synuclein; immunofluorescence; traumatic brain injury; Western blot C1 [Yan, H. Q.; Carlson, S.; Li, Y.; Henchir, J.; Ma, X.; Dixon, C. E.] Univ Pittsburgh, Pittsburgh, PA USA. [Yan, H. Q.; Carlson, S.; Li, Y.; Henchir, J.; Ma, X.; Dixon, C. E.] VA Pittsburgh Healthcare Syst, 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 JUN 15 PY 2014 VL 31 IS 12 MA C3-23 BP A97 EP A97 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600263 ER PT J AU Deschenes-Simard, X Lessard, F Gaumont-Leclerc, MF Bardeesy, N Ferbeyre, G AF Deschenes-Simard, Xavier Lessard, Frederic Gaumont-Leclerc, Marie-France Bardeesy, Nabeel Ferbeyre, Gerardo TI Cellular senescence and protein degradation Breaking down cancer SO CELL CYCLE LA English DT Article DE E3 ligases; ERK kinases; Ras oncogene; ubiquitin; SASP ID ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE-RESPONSE; E3 UBIQUITIN LIGASES; HEAT-SHOCK-PROTEIN; LEUKEMIA-NUCLEAR-BODIES; SRM160/300 SPLICING COACTIVATOR; TUMOR-SUPPRESSOR ACTIVITY; RAS-INDUCED SENESCENCE; C-MYC; REPLICATIVE SENESCENCE AB Autophagy and the ubiquitin-proteasome pathway (UPP) are the major protein degradation systems in eukaryotic cells. Whereas the former mediate a bulk nonspecific degradation, the UPP allows a rapid degradation of specific proteins. Both systems have been shown to play a role in tumorigenesis, and the interest in developing therapeutic agents inhibiting protein degradation is steadily growing. However, emerging data point to a critical role for autophagy in cellular senescence, an established tumor suppressor mechanism. Recently, a selective protein degradation process mediated by the UPP was also shown to contribute to the senescence phenotype. This process is tightly regulated by E3 ubiquitin ligases, deubiquitinases, and several post-translational modifications of target proteins. Illustrating the complexity of UPP, more than 600 human genes have been shown to encode E3 ubiquitin ligases, a number which exceeds that of the protein kinases. Nevertheless, our knowledge of proteasome-dependent protein degradation as a regulated process in cellular contexts such as cancer and senescence remains very limited. Here we discuss the implications of protein degradation in senescence and attempt to relate this function to the protein degradation pattern observed in cancer cells. C1 [Deschenes-Simard, Xavier; Lessard, Frederic; Gaumont-Leclerc, Marie-France; Ferbeyre, Gerardo] Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ, Canada. [Bardeesy, Nabeel] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Ferbeyre, G (reprint author), Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ, Canada. EM g.ferbeyre@umontreal.ca FU National Institutes of Health [R01 CA133557-05, P01 CA117969-07]; Linda J. Verville Cancer Research Foundation FX X.D.-S. is a fellow of the Vanier Canada Graduate Scholarships Program and Michael Smith Foreign Study Supplements Program. F. L. is a fellow of FRQS (Fonds de recherche du Quebec - Sante). N.B. is supported by grants from the National Institutes of Health (R01 CA133557-05 and P01 CA117969-07) and the Linda J. Verville Cancer Research Foundation. G. F. is a FRSQ national research fellow. NR 268 TC 4 Z9 5 U1 0 U2 8 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2014 VL 13 IS 12 BP 1840 EP 1858 DI 10.4161/cc.29335 PG 19 WC Cell Biology SC Cell Biology GA AJ8HN UT WOS:000337944100008 PM 24866342 ER PT J AU Conrotto, F Scacciatella, P D'Ascenzo, F Chieffo, A Latib, A Park, SJ Kim, YH Onuma, Y Capranzano, P Jegere, S Makkar, R Palacios, I Buszman, P Chakravarty, T Mehran, R Naber, C Margey, R Leon, M Moses, J Fajadet, J Lefevre, T Morice, MC Erglis, A Tamburino, C Alfieri, O D'Amico, M Marra, S Serruys, PW Colombo, A Meliga, E AF Conrotto, Federico Scacciatella, Paolo D'Ascenzo, Fabrizio Chieffo, Alaide Latib, Azeem Park, Seung Jung Kim, Young Hak Onuma, Yoshinobu Capranzano, Piera Jegere, Sanda Makkar, Raj Palacios, Igor Buszman, Pawel Chakravarty, Tarun Mehran, Roxana Naber, Christoph Margey, Ronan Leon, Martin Moses, Jeffrey Fajadet, Jean Lefevre, Thierry Morice, Marie Claude Erglis, Andrejs Tamburino, Corrado Alfieri, Ottavio D'Amico, Maurizio Marra, Sebastiano Serruys, Patrick W. Colombo, Antonio Meliga, Emanuele TI Long-Term Outcomes of Percutaneous Coronary Interventions or Coronary Artery Bypass Grafting for Left Main Coronary Artery Disease in Octogenarians (from a Drug-Eluting stent for LefT main Artery Registry Substudy) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID AGED GREATER-THAN-OR-EQUAL-TO-75 YEARS; SURGERY; IMPLANTATION AB Percutaneous coronary intervention (PCI) with drug-eluting stents is an accepted alternative to surgery for the treatment of unprotected left main coronary artery (ULMCA) disease, but the long-term outcome in elderly patients is unclear. Aim of our study was to compare the clinical outcomes of octogenarians with ULMCA disease treated either with PCI with drug-eluting stents or coronary artery bypass grafting (CABG). The primary study end point was the composite of death, cerebrovascular accident, and myocardial infarction at follow-up. A total of 304 consecutive patients with ULMCA stenosis treated with PCI or CABG and aged 80 years were selected and analyzed in a large multinational registry. Two hundred eighteen were treated with PCI and 86 with CABG. During the hospitalization, a trend toward a higher mortality rate was reported in PCI-treated patients (3.5% vs 7.3%, p = 0.32). At a median follow-up of 1,088 days, the incidence of the primary end point was similar in the 2 groups (32.6% vs 30.2%, p = 0.69). Incidence of target vessel revascularization at follow-up was higher in PCI-treated patients (10% vs 4.2%, p = 0.05). At multivariate analysis, left ventricular ejection fraction was the only independent predictor of the primary end point (hazard ratio 0.95, 95% confidence interval 0.91 to 0.98, p = 0.001). After adjustment with propensity score, the revascularization strategy was not significantly correlated to the incidence of the primary end point (hazard ratio 0.98, 95% confidence interval 0.57 to 1.71, p = 0.95). In octogenarians, no difference was observed in the occurrence of the primary end point after PCI or CABG for the treatment of ULMCA disease. However, the rate of target vessel revascularization was higher in the PCI group. (C) 2014 Elsevier Inc. All rights reserved. C1 [Conrotto, Federico; Scacciatella, Paolo; D'Amico, Maurizio; Marra, Sebastiano] Citta Salute & Sci Hosp, Dept Cardiol, Turin, Italy. [D'Ascenzo, Fabrizio] Univ Turin, Dept Internal Med, Div Cardiol, Turin, Italy. [Chieffo, Alaide; Latib, Azeem; Alfieri, Ottavio; Colombo, Antonio] Ist Sci San Raffaele, Dept Cardiothorac & Vasc Dis, I-20132 Milan, Italy. [Park, Seung Jung; Kim, Young Hak] Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Med Res & Informat,Dept Cardiol, Seoul, South Korea. [Onuma, Yoshinobu; Serruys, Patrick W.] Erasmus MC, Thoraxctr, Rotterdam, Netherlands. [Capranzano, Piera; Tamburino, Corrado] Univ Catania, Ferrarotto Hosp, Catania, Italy. [Jegere, Sanda; Erglis, Andrejs] Pauls Stradins Clin Univ Hosp, Latvian Ctr Cardiol, Riga, Latvia. [Jegere, Sanda; Erglis, Andrejs] Univ Latvia, Inst Cardiol, Riga, Latvia. [Makkar, Raj; Chakravarty, Tarun] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Los Angeles, CA 90048 USA. [Palacios, Igor; Margey, Ronan] Massachusetts Gen Hosp, Cardiac Catheterizat Lab, Boston, MA 02114 USA. [Palacios, Igor; Margey, Ronan] Harvard Univ, Sch Med, Boston, MA USA. [Buszman, Pawel] Med Univ Silesia, Amer Heart Poland, Katowice, Poland. [Mehran, Roxana; Leon, Martin; Moses, Jeffrey] Columbia Univ, Med Ctr, New York, NY USA. [Mehran, Roxana; Leon, Martin; Moses, Jeffrey] Cardiovasc Res Fdn, New York, NY USA. [Naber, Christoph] Univ Hosp, Dept Cardiol, Essen, Germany. [Fajadet, Jean] Clin Pasteur, Toulouse, France. [Lefevre, Thierry; Morice, Marie Claude] Inst Hosp Jacques Cartier, Massy, France. [Meliga, Emanuele] AO Ordine Mauriziano Umberto I, Intervent Cardiol Unit, Turin, Italy. RP Conrotto, F (reprint author), Citta Salute & Sci Hosp, Dept Cardiol, Turin, Italy. EM federico.conrotto@gmail.com OI TAMBURINO, Corrado/0000-0002-4940-9742 FU St. Jude Medical, Sadra Medical (Los Gatos California); Stentys, and Icon (Dublin, Ireland); Bristol-Myers Squibb/Sanofi (Paris, France); Medicines Company, and Lilly/Daiichi Sankyo (Tokyo, Japan); Abbott Vascular, Biotronik, Direct Flow (Santa Rosa, California) FX Dr. Mehran is a consultant to Abbott Vascular (Abbott Park, Illinois), AstraZeneca (London, United Kingdom), Boston Scientific (Natick, Massachusetts), Covidien (Mansfield, Massachusetts), The Medicines Company (Parsippany, New Jersey), Janssen (Johnson and Johnson) (New Brunswick, New Jersey), Regado Biosciences (Basking Ridge, New Jersey), Maya Medical (Campbell, California), and Merck (Whitehouse Station, New Jersey) and has received research grant support from Bristol-Myers Squibb/Sanofi (Paris, France), The Medicines Company, and Lilly/Daiichi Sankyo (Tokyo, Japan). Dr. Naber is a speaker for Abbott Vascular. Cordis (Bridgewater Township, New Jersey), Biotronik (Berlin, Germany), Biosensors (Singapore), Medtronic (Minneapolis, Minnesota), Stentys (Paris, France), Daiichi Sankyo, The Medicines Company, Edwards Lifesciences (Irvine, California), Boston Scientific, and St. Jude Medical (Saint Paul, Minnesota); has received research support from Abbott Vascular, Biotronik, Direct Flow (Santa Rosa, California), St. Jude Medical, Sadra Medical (Los Gatos California), Stentys, and Icon (Dublin, Ireland); and is on the advisory board of Biotronik and Abbott Vascular. Dr. Margey is a proctor for Edwards Lifesciences. Dr. Moses is a consultant for Cordis and Boston Scientific. Dr. Erg lis is a consultant for and is on the speakers' bureaus of Medtronic, Boston Scientific, Cordis.(Johnson and Johnson), Biosensors, and Abbott Vascular and has received research contracts from Abbott Vascular and Boston Scientific. Dr. Tamburino has received honoraria from CeloNova (San Antonio, Texas), Medtronic, CardioKinetix (Menlo Park, California), and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this report to disclose. NR 21 TC 5 Z9 5 U1 0 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2014 VL 113 IS 12 BP 2007 EP 2012 DI 10.1016/j.amjcard.2014.03.044 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ4KE UT WOS:000337644300012 PM 24793677 ER PT J AU Schneider, PM Pellegrini, CN Wang, YF Fein, AS Reynolds, MR Curtis, JP Masoudi, FA Varosy, PD AF Schneider, Preston M. Pellegrini, Cara N. Wang, Yongfei Fein, Adam S. Reynolds, Matthew R. Curtis, Jeptha P. Masoudi, Frederick A. Varosy, Paul D. TI Prevalence of Guideline-Directed Medical Therapy Among Patients Receiving Cardiac Resynchronization Therapy Defibrillator Implantation in the National Cardiovascular Data Registry During the Years 2006 to 2008 SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CHRONIC HEART-FAILURE; RANDOMIZED-TRIAL; ASSOCIATION; MORTALITY; SURVIVAL; HOSPITALIZATIONS; ENALAPRIL; PERFORMANCE; CARVEDILOL; MORBIDITY AB Cardiac resynchronization therapy (CRT) reduces morbidity and mortality among selected patients with left ventricular systolic dysfunction and severe heart failure symptoms despite guideline-directed medical therapy (GDMT). Contemporaneous guidelines provided clear recommendations regarding selection of patients for CRT, including that all patients should first receive GDMT with beta blockers and renin-angiotensin axis antagonists. Prevalence of GDMT among real-world patients receiving CRT defibrillators (CRT-D) has not been well studied. We identified 45,392 patients in the National Cardiovascular Data Registry Implantable Cardioverter-Defibrillator Registry who underwent first CRT-D implantation for primary prevention of sudden death from January 2006 to June 2008. We calculated the proportion of patients with contemporaneous class I guideline indications for CRT-D, the proportion receiving GDMT for heart failure, and the proportion receiving GDMT who had class I guideline indications for CRT-D. Among patients without contraindications, 87% were prescribed beta blockers, 78% an angiotensin-converting enzyme inhibitor or an angiotensin II receptor inhibitor, and 70% both a beta blocker and an angiotensin-converting enzyme or angiotensin II receptor inhibitor at discharge. Finally, 50% of patients met class I guideline indications and were prescribed GDMT at discharge; 9% neither met class I indications nor were prescribed GDMT at discharge. The major limitation of this study is the lack of dosage information in the Implantable Cardioverter-Defibrillator Registry and lack of prescribing information at times other than discharge. In conclusion, many patients receiving CRT-D are not receiving GDMT at discharge. Ensuring that all patients receiving CRT-D are also receiving GDMT appears to be a quality improvement target. (C) 2014 Elsevier Inc. All rights reserved. C1 [Schneider, Preston M.; Masoudi, Frederick A.; Varosy, Paul D.] Univ Colorado, Div Cardiol, Aurora, CO 80045 USA. [Pellegrini, Cara N.] Univ Calif San Francisco, Dept Med, Cardiac Electrophysiol Sect, Sect Cardiol,San Francisco Vet Adm Med Ctr, San Francisco, CA 94143 USA. [Pellegrini, Cara N.] Univ Calif San Francisco, Dept Med, Div Cardiol, Sect Cardiol,San Francisco Vet Adm Med Ctr, San Francisco, CA 94143 USA. [Wang, Yongfei; Curtis, Jeptha P.] Yale Univ, Sch Med, New Haven, CT USA. [Fein, Adam S.; Reynolds, Matthew R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Masoudi, Frederick A.; Varosy, Paul D.] Colorado Cardiovasc Outcomes Res CCOR Grp, Denver, CO USA. [Masoudi, Frederick A.] Kaiser Permanente Colorado Inst Hlth Res, Denver, CO USA. [Masoudi, Frederick A.] Denver Hlth Med Ctr, Denver, CO USA. [Varosy, Paul D.] Vet Adm Eastern Colorado Healthcare Syst, Div Cardiol, Denver, CO USA. RP Schneider, PM (reprint author), Univ Colorado, Div Cardiol, Anschutz Med Campus, Aurora, CO 80045 USA. EM Preston.Schneider@ucdenver.edu FU NCATS NIH HHS [UL1 TR001082]; NHLBI NIH HHS [T32 HL007822] NR 27 TC 4 Z9 4 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 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2014 VL 113 IS 12 BP 2052 EP 2056 DI 10.1016/j.amjcard.2014.03.049 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ4KE UT WOS:000337644300019 PM 24793671 ER PT J AU Wilker, EH Ljungman, PL Rice, MB Kloog, I Schwartz, J Gold, DR Koutrakis, P Vita, JA Mitchell, GF Vasan, RS Benjamin, EJ Hamburg, NM Mittleman, MA AF Wilker, Elissa H. Ljungman, Petter L. Rice, Mary B. Kloog, Itai Schwartz, Joel Gold, Diane R. Koutrakis, Petros Vita, Joseph A. Mitchell, Gary F. Vasan, Ramachandran S. Benjamin, Emelia J. Hamburg, Naomi M. Mittleman, Murray A. TI Relation of Long-Term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR EVENTS; ENDOTHELIAL FUNCTION; VASCULAR REACTIVITY; HEALTHY-ADULTS; HEART; VASOCONSTRICTION; INHALATION; RESPONSES; DESIGN AB Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may, in part, explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function has not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow-mediated dilation%, and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 [53%] women, mean age 49 +/- 14 years). Spatially resolved average PM2.5 was associated with lower flow-mediated dilation% and hyperemic flow velocity. An inter-quartile range difference in PM2.5 (1.99 mu g/m(3)) was associated with -0.16% (95% confidence interval [CI] -0.27%, -0.05%) lower flow-mediated dilation% and -0.72 (95% CI -1.38, -0.06) cm/s lower hyperemic flow velocity%. Residential proximity to a major roadway was negatively associated with flow-mediated dilation%. Compared with living 400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% CI -0.58%, -0.06%), but results for hyperemic flow velocity had wide confidence intervals -0.68 cm/s (95% CI -2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wilker, Elissa H.; Ljungman, Petter L.; Rice, Mary B.; Mittleman, Murray A.] Beth Israel Deaconess Med Ctr, Dept Med, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Wilker, Elissa H.; Schwartz, Joel; Gold, Diane R.; Koutrakis, Petros; Mittleman, Murray A.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Ljungman, Petter L.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Rice, Mary B.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Kloog, Itai] Ben Gurion Univ Negev, Dept Geog & Environm Dev, IL-84105 Beer Sheva, Israel. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] NHLBI, Framingham, MA USA. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. RP Wilker, EH (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. EM ewilker@bidmc.harvard.edu RI Ljungman, Petter/C-6371-2014; OI Ljungman, Petter/0000-0002-7815-2632; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI [N01HC 25195, 1R01HL60040, 1R01HL70100]; USEPA [RD834798]; NIEHS [ES009825, ES022243, ES023352, ES000002]; Swedish Council for Working Life and Social Research; Marie Curie International Postdoctoral Fellowship Programme; Swedish Heart-Lung Foundation; Swedish Society of Cardiology; Swedish Society for Medical Research FX This work was supported by the NHLBI (N01HC 25195, 1R01HL60040, 1R01HL70100), the USEPA (RD834798), and NIEHS (ES009825, ES022243, ES023352, and ES000002), Swedish Council for Working Life and Social Research, Marie Curie International Postdoctoral Fellowship Programme, the Swedish Heart-Lung Foundation, the Swedish Society of Cardiology, and the Swedish Society for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the EPA. Further, the NTH and USEPA do not endorse the purchase of any commercial products or services mentioned in the publication. NR 25 TC 17 Z9 18 U1 0 U2 6 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2014 VL 113 IS 12 BP 2057 EP 2063 DI 10.1016/j.amjcard.2014.03.048 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ4KE UT WOS:000337644300020 PM 24793676 ER PT J AU Keane, FK Chen, MH Zhang, DJ Loffredo, MJ Kantoff, PW Renshaw, AA D'Amico, AV AF Keane, Florence K. Chen, Ming-Hui Zhang, Danjie Loffredo, Marian J. Kantoff, Philip W. Renshaw, Andrew A. D'Amico, Anthony V. TI The Likelihood of Death From Prostate Cancer in Men With Favorable or Unfavorable Intermediate-Risk Disease SO CANCER LA English DT Article DE prostate cancer; radiation therapy; hormonal therapy; prostate-cancer specific mortality ID BEAM RADIATION-THERAPY; ANDROGEN SUPPRESSION THERAPY; PREOPERATIVE PSA VELOCITY; NEEDLE-BIOPSY SPECIMENS; RADICAL PROSTATECTOMY; RANDOMIZED-TRIAL; COMPETING RISK; DEPRIVATION THERAPY; RADIOTHERAPY; MORTALITY AB BACKGROUND: Recently, men with intermediate-risk prostate cancer (PC) were classified into favorable and unfavorable categories; however, whether the risk of PC-specific mortality (PCSM) among men with high-risk PC versus unfavorable intermediate-risk PC is increased is unknown. METHODS: In a prospective, randomized trial conducted between 1995 and 2001, 206 men with intermediate-risk or high-risk PC were randomized to receive 70 Gy with or without 6 months of androgen-suppression therapy (AST). The subgroup of 197 patients with information available on the percentage of positive biopsies formed the cohort. Fine and Gray regression analysis was used to assess whether men with high-risk PC versus unfavorable intermediate-risk PC had an increased risk of PCSM. RESULTS: After a median follow-up of 14.3 years, there were 127 deaths (64.5%), including 22 deaths (17.3%) from PC. There were no PC deaths in the favorable intermediate-risk group. There was an increase in the risk of PCSM among men with high-risk PC versus unfavorable intermediate-risk PC, but the difference was not significant (adjusted hazard ratio, 1.59; 95% confidence interval, 0.66-3.83; P = .30) after adjusting for age, randomized treatment arm, and comorbidity. CONCLUSIONS: The lack of PC deaths among men with favorable intermediate-risk PC suggests that adding AST may not reduce their risk of PCSM; whereas many men with unfavorable intermediate-risk PC are at risk for harboring occult PC with Gleason scores from 8 to 10 and, if proven, would benefit from long-term AST. Multiparametric magnetic resonance imaging and targeted biopsy of suspicious lesions should be considered to identify PC with Gleason scores from 8 to 10 in these men. (C) 2014 American Cancer Society. C1 [Keane, Florence K.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kantoff, Philip W.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Renshaw, Andrew A.] Baptist Hosp Miami, Dept Pathol, Miami, FL USA. RP Keane, FK (reprint author), Brigham & Womens Hosp, ASB1 L2,75 Francis St, Boston, MA 02115 USA. EM fkeane@partners.org NR 41 TC 18 Z9 18 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2014 VL 120 IS 12 BP 1787 EP 1793 DI 10.1002/cncr.28609 PG 7 WC Oncology SC Oncology GA AJ2VR UT WOS:000337522900008 PM 24604289 ER PT J AU Cella, D Davis, MP Negrier, S Figlin, RA Michaelson, MD Bushmakin, AG Cappelleri, JC Sandin, R Korytowsky, B Charbonneau, C Matczak, E Motzer, RJ AF Cella, David Davis, Mellar P. Negrier, Sylvie Figlin, Robert A. Michaelson, M. Dror Bushmakin, Andrew G. Cappelleri, Joseph C. Sandin, Rickard Korytowsky, Beata Charbonneau, Claudie Matczak, Ewa Motzer, Robert J. TI Characterizing Fatigue Associated With Sunitinib and Its Impact on Health-Related Quality of Life in Patients With Metastatic Renal Cell Carcinoma SO CANCER LA English DT Article DE sunitinib; metastatic renal cell carcinoma; fatigue; health-related quality of life; phase 3 ID CANCER CLINICAL-TRIALS; INTERFERON-ALPHA; TARGETED THERAPIES; FUNCTIONAL ASSESSMENT; REPORTED OUTCOMES; TOXICITY; RELIABILITY; STRATEGIES; SCALE AB BACKGROUND: Using phase 3 trial data for sunitinib versus interferon (IFN)-alpha in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL). METHODS: Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-alpha at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade. RESULTS: M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-alpha for the same CTCAE fatigue grade. CONCLUSIONS: Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience. (C) 2014 American Cancer Society. C1 [Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Davis, Mellar P.] Cleveland Clin, Cleveland, OH 44106 USA. [Negrier, Sylvie] Ctr Leon Berard, F-69373 Lyon, France. [Figlin, Robert A.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Michaelson, M. Dror] Massachusetts Gen Hosp, Genitourinary Canc Ctr, Boston, MA 02114 USA. [Bushmakin, Andrew G.; Cappelleri, Joseph C.] Pfizer Inc, Stat, Groton, CT 06340 USA. [Sandin, Rickard] Pfizer Oncol, Global Hlth Econ & Outcomes Res, Sollentuna, Sweden. [Korytowsky, Beata] Pfizer Oncol, Global Hlth Econ Outcomes Res, New York, NY USA. [Charbonneau, Claudie] Pfizer Inc,Paris, Specialty Care BU, Global Outcomes Res, Paris, France. [Matczak, Ewa] Pfizer Oncol, New York, NY USA. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Cella, D (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, 633 N St Clair St,19th Fl, Chicago, IL 60611 USA. EM d-cella@northwestern.edu OI Michaelson, Dror/0000-0001-9249-6338 FU Pfizer Inc.; Pfizer FX This study was sponsored by Pfizer Inc. Medical writing support was provided by Andy Gannon at Acumed (New York, NY) with funding from Pfizer. NR 36 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2014 VL 120 IS 12 BP 1871 EP 1880 DI 10.1002/cncr.28660 PG 10 WC Oncology SC Oncology GA AJ2VR UT WOS:000337522900018 PM 24634003 ER PT J AU Sarkissian, T Timmons, A Arya, R Abdelwahid, E White, K AF Sarkissian, Tatevik Timmons, Allison Arya, Richa Abdelwahid, Eltyeb White, Kristin TI Detecting apoptosis in Drosophila tissues and cells SO METHODS LA English DT Article DE Drosophila; Apoptosis; TUNEL; Caspase ID IN-SITU; CASPASE ACTIVITY; ACRIDINE ORANGE; GENETIC-CONTROL; DEATH; OOGENESIS; OVARY; DCP-1; DNA; MELANOGASTER AB In this chapter we discuss methods that can be used to study apoptotic cell death in the Drosophila embryo, ovary, as well as in cultured cell lines. These methods assay various aspects of the cell death process, from mitochondrial changes to caspase activation and DNA cleavage. The assays are useful for examining apoptosis in normal development and in response to developmental perturbations and external stresses. These techniques include Acridine Orange staining, TUNEL, cleaved caspase staining, caspase activity assays and assays for mitochondrial fission and permeabilization. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sarkissian, Tatevik; Arya, Richa; Abdelwahid, Eltyeb; White, Kristin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, CBRC, Boston, MA 02129 USA. [Timmons, Allison] Boston Univ, Dept Biol, Boston, MA 02215 USA. RP White, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, CBRC, Boston, MA 02129 USA. EM kristin.white@cbrc2.mgh.harvard.edu OI Lord, Allison/0000-0002-8412-315X FU MGH Fund; [R01GM55568] FX This work was funded in part by R01GM55568 (K.W.) and an MGH Fund for Medical Discovery fellowship (R.A.). NR 43 TC 10 Z9 10 U1 2 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JUN 15 PY 2014 VL 68 IS 1 BP 89 EP 96 DI 10.1016/j.ymeth.2014.02.033 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ3FG UT WOS:000337551300010 PM 24613678 ER PT J AU Pauty, J Rodrigue, A Couturier, A Buisson, R Masson, JY AF Pauty, Joris Rodrigue, Amelie Couturier, Anthony Buisson, Remi Masson, Jean-Yves TI Exploring the roles of PALB2 at the crossroads of DNA repair and cancer SO BIOCHEMICAL JOURNAL LA English DT Review DE double-strand break repair; Fanconi's anaemia; genome integrity; partner and localizer of BRCA2 (PALB2) ID FANCONI-ANEMIA PATHWAY; HOMOLOGY-DIRECTED REPAIR; DOUBLE-STRAND BREAKS; SUSCEPTIBILITY GENE; PANCREATIC-CANCER; RAD51 FILAMENT; BRCA2-INTERACTING PROTEIN; SYNTHETICALLY LETHAL; EMBRYONIC LETHALITY; IONIZING-RADIATION AB PALB2 [partner and localizer of BRCA2 (breast cancer early-onset 1)] has emerged as a key player in the maintenance of genome integrity. Biallelic mutations in PALB2 cause FA (Fanconi's anaemia) subtype FA-N, a devastating inherited disorder marked by developmental abnormalities, bone marrow failure and childhood cancer susceptibility, whereas monoallelic mutations predispose to breast, ovarian and pancreatic cancer. The tumour suppressor role of PALB2 has been intimately linked to its ability to promote HR (homologous recombination)mediated repair of DNA double-strand breaks. Because PALB2 lies at the crossroads between FA, HR and cancer susceptibility, understanding its function has become the primary focus of several studies. The present review discusses a current synthesis of the contribution of PALB2 to these pathways. We also provide a molecular description of FA- or cancer-associated PALB2 mutations. C1 [Pauty, Joris; Rodrigue, Amelie; Couturier, Anthony; Masson, Jean-Yves] CHU Quebec Res Ctr, Genome Stabil Lab, Quebec City, PQ G1R 2J6, Canada. [Pauty, Joris; Rodrigue, Amelie; Couturier, Anthony; Masson, Jean-Yves] Univ Laval, Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ G1V 0A6, Canada. [Buisson, Remi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA. RP Masson, JY (reprint author), CHU Quebec Res Ctr, Genome Stabil Lab, HDQ Pavil,9 McMahon, Quebec City, PQ G1R 2J6, Canada. EM Jean-Yves.Masson@fmed.ulaval.ca OI Couturier, Anthony/0000-0002-1512-9558 FU CIHR (Canadian Institutes of Health Research) FX This work was supported by the CIHR (Canadian Institutes of Health Research) (to J.-Y.M.). NR 113 TC 13 Z9 13 U1 2 U2 7 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUN 15 PY 2014 VL 460 BP 331 EP 342 DI 10.1042/BJ20140208 PN 3 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ0JD UT WOS:000337335900002 PM 24870022 ER PT J AU Siddiqi, OK Ghebremichael, M Dang, X Atadzhanov, M Kaonga, P Khoury, MN Koralnik, IJ AF Siddiqi, Omar K. Ghebremichael, Musie Dang, Xin Atadzhanov, Masharip Kaonga, Patrick Khoury, Michael N. Koralnik, Igor J. TI Molecular Diagnosis of Central Nervous System Opportunistic Infections in HIV-Infected Zambian Adults SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; Zambia; cerebrospinal fluid; PCR; opportunistic infections ID EPSTEIN-BARR-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; FOCAL BRAIN-LESIONS; REAL-TIME PCR; CEREBROSPINAL-FLUID; TOXOPLASMA-GONDII; MENINGITIS; COUNTRIES; AIDS AB Background. Knowledge of central nervous system (CNS) opportunistic infections (OIs) among people living with human immunodeficiency virus (HIV) in sub-Saharan Africa is limited. Methods.aEuro integral We analyzed 1 cerebrospinal fluid (CSF) sample from each of 331 HIV-infected adults with symptoms suggestive of CNS OI at a tertiary care center in Zambia. We used pathogen-specific primers to detect DNA from JC virus (JCV), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV) types 1 and 2, Mycobacterium tuberculosis, and Toxoplasma gondii via real-time polymerase chain reaction (PCR). Results.aEuro integral The patients' median CD4(+) T-cell count was 89 cells/A mu L (interquartile range, 38-191 cells/A mu L). Of 331 CSF samples, 189 (57.1%) had at least 1 pathogen. PCR detected DNA from EBV in 91 (27.5%) patients, M. tuberculosis in 48 (14.5%), JCV in 20 (6.0%), CMV in 20 (6.0%), VZV in 13 (3.9%), HSV-1 in 5 (1.5%), and HSV-2 and T. gondii in none. Fungal and bacteriological studies showed Cryptococcus in 64 (19.5%) patients, pneumococcus in 8 (2.4%), and meningococcus in 2 (0.6%). Multiple pathogens were found in 68 of 189 (36.0%) samples. One hundred seventeen of 331 (35.3%) inpatients died during their hospitalization. Men were older than women (median, 37 vs 34 years; P = .01), more recently diagnosed with HIV (median, 30 vs 63 days; P = .03), and tended to have a higher mortality rate (40.2% vs 30.2%; P = .07). Conclusions.aEuro integral CNS OIs are frequent, potentially treatable complications of AIDS in Zambia. Multiple pathogens often coexist in CSF. EBV is the most prevalent CNS organism in isolation and in coinfection. Whether it is associated with CNS disease or a marker of inflammation requires further investigation. More comprehensive testing for CNS pathogens could improve treatment and patient outcomes in Zambia. C1 [Siddiqi, Omar K.; Dang, Xin; Khoury, Michael N.; Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Div Neurovirol, Boston, MA 02215 USA. [Siddiqi, Omar K.; Atadzhanov, Masharip; Kaonga, Patrick] Univ Zambia, Sch Med, Dept Internal Med, Lusaka, Zambia. [Ghebremichael, Musie] Harvard Univ, Sch Med, Boston, MA USA. [Ghebremichael, Musie] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. RP Siddiqi, OK (reprint author), Beth Israel Deaconess Med Ctr, E-CLS-1005,330 Brookline Ave, Boston, MA 02215 USA. EM osiddiqi@bidmc.harvard.edu FU National Institutes of Health [P30A1060354, R24TW007988, R01NS047029, NS074995, K24NS060950] FX Financial support. This work was supported by the National Institutes of Health (grant numbers P30A1060354 and R24TW007988 to O.K.S. and R01NS047029, NS074995, and K24NS060950 to I.J.K.). NR 31 TC 14 Z9 14 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2014 VL 58 IS 12 BP 1771 EP 1777 DI 10.1093/cid/ciu191 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AI7AO UT WOS:000337031700021 PM 24668125 ER PT J AU Muir, AM Ren, YS Butz, DH Davis, NA Blank, RD Birk, DE Lee, SJ Rowe, D Feng, JQ Greenspan, DS AF Muir, Alison M. Ren, Yinshi Butz, Delana Hopkins Davis, Nicholas A. Blank, Robert D. Birk, David E. Lee, Se-Jin Rowe, David Feng, Jian Q. Greenspan, Daniel S. TI Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID BONE MORPHOGENETIC PROTEIN-1; PROCOLLAGEN-C-PROTEINASE; MAMMALIAN TOLLOID-LIKE; DENTIN MATRIX PROTEIN-1; LATENT MYOSTATIN; TGF-BETA; IN-VIVO; METALLOPROTEINASES; WNT; ACTIVATION AB Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1(-/-) and Tll1(-/-) lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures-defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI. C1 [Muir, Alison M.; Butz, Delana Hopkins; Davis, Nicholas A.; Greenspan, Daniel S.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Madison, WI 53792 USA. [Muir, Alison M.] Univ Wisconsin, Genet Lab, Madison, WI 53792 USA. [Ren, Yinshi; Feng, Jian Q.] Baylor Coll Dent, Texas A&M Hlth Sci Ctr, Dept Biomed Sci, Dallas, TX 75246 USA. [Blank, Robert D.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Blank, Robert D.] Univ Wisconsin, Sch Med & Publ Hlth, Div Endocrinol Diabet & Metab, Dept Med, Madison, WI 53792 USA. [Birk, David E.] Univ S Florida, Morsani Coll Med, Dept Pharmacol & Physiol, Tampa, FL USA. [Lee, Se-Jin] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Rowe, David] Univ Connecticut, Sch Dent Med, Dept Reconstruct Sci Biomat & Skeletal Dev, Farmington, CT 06032 USA. RP Greenspan, DS (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Room K4-430,Box 4672,600 Highland Ave, Madison, WI 53792 USA. EM dsgreens@wisc.edu RI Birk, David/I-4072-2012; OI Birk, David/0000-0002-4865-9088; Blank, Robert Daniel/0000-0003-2950-1944; Greenspan, Daniel/0000-0001-8096-7446 FU National Institutes of Health [AR60636, AR59685, AR54753, AR44745, DE018486, AR53815, AR47746] FX This work was supported by grants AR60636 and AR59685 (to S.-J.L.), AR54753 (to R. D. B.), AR44745 (to D. E. B.), DE018486 (to J.F.), and AR53815 and AR47746 (to D. S. G.) from the National Institutes of Health. NR 67 TC 13 Z9 14 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2014 VL 23 IS 12 BP 3085 EP 3101 DI 10.1093/hmg/ddu013 PG 17 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AI7CJ UT WOS:000337038600002 PM 24419319 ER PT J AU Morris, DW Cormican, P Kenny, EM O'Dushlaine, CT Perreault, LPL Giannoulatou, E Tropea, D Maher, BS Wormley, B Kelleher, E Fahey, C Molinos, I Bellini, S Pirinen, M Strange, A Freeman, C Thiselton, DL Elves, RL Regan, R Ennis, S Dinan, TG McDonald, C Murphy, KC O'Callaghan, E Waddington, JL Walsh, D O'Donovan, M Grozeva, D Craddock, N Stone, J Scolnick, E Purcell, S Sklar, P Coe, B Eichler, EE Ophoff, R Buizer, J Szatkiewicz, J Hultman, C Sullivan, P Gurling, H Mcquillin, A St Clair, D Rees, E Kirov, G Walters, J Blackwood, D Johnstone, M Donohoe, G O'Neill, FA Kendler, KS Gill, M Riley, BP Spencer, CCA Corvin, A AF Morris, Derek W. Cormican, Paul Kenny, Elaine M. O'Dushlaine, Colm T. Perreault, Louis-Philippe Lemieux Giannoulatou, Eleni Tropea, Daniela Maher, Brion S. Wormley, Brandon Kelleher, Eric Fahey, Ciara Molinos, Ines Bellini, Stefania Pirinen, Matti Strange, Amy Freeman, Colin Thiselton, Dawn L. Elves, Rachel L. Regan, Regina Ennis, Sean Dinan, Timothy G. McDonald, Colm Murphy, Kieran C. O'Callaghan, Eadbhard Waddington, John L. Walsh, Dermot O'Donovan, Michael Grozeva, Detelina Craddock, Nick Stone, Jennifer Scolnick, Ed Purcell, Shaun Sklar, Pamela Coe, Bradley Eichler, Evan E. Ophoff, Roel Buizer, Jacobine Szatkiewicz, Jin Hultman, Christina Sullivan, Patrick Gurling, Hugh Mcquillin, Andrew St Clair, David Rees, Elliott Kirov, George Walters, James Blackwood, Douglas Johnstone, Mandy Donohoe, Gary O'Neill, Francis A. Kendler, Kenneth S. Gill, Michael Riley, Brien P. Spencer, Chris C. A. Corvin, Aiden CA Int Schizophrenia Consortium SGENE Consortium Wellcome Trust Case Control Consor TI An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COPY NUMBER VARIATION; BIPOLAR-DISORDER; COMMON VARIANTS; SCHIZOPHRENIA; POPULATION; RARE; DELETIONS; CONTRIBUTES; MECHANISMS AB Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (> 100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 x 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, az]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem similar to 149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 x 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity. C1 [Morris, Derek W.; Kenny, Elaine M.; O'Dushlaine, Colm T.; Maher, Brion S.; Kelleher, Eric; Fahey, Ciara; Molinos, Ines; Bellini, Stefania; Donohoe, Gary; Gill, Michael; Corvin, Aiden] Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland. [Morris, Derek W.; Kenny, Elaine M.; O'Dushlaine, Colm T.; Maher, Brion S.; Kelleher, Eric; Fahey, Ciara; Molinos, Ines; Bellini, Stefania; Donohoe, Gary; Gill, Michael; Corvin, Aiden] Univ Dublin Trinity Coll, Neuropsychiatr Genet Res Grp, Inst Mol Med, Dublin 2, Ireland. [Cormican, Paul; Giannoulatou, Eleni; Tropea, Daniela; Pirinen, Matti; Strange, Amy; Freeman, Colin; Spencer, Chris C. A.; Wellcome Trust Case Control Consor] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Perreault, Louis-Philippe Lemieux; Stone, Jennifer; Scolnick, Ed; Purcell, Shaun; Sklar, Pamela] Massachusetts Gen Hosp, Broad Inst, Boston, MA 02142 USA. [Perreault, Louis-Philippe Lemieux; Stone, Jennifer; Scolnick, Ed; Purcell, Shaun; Sklar, Pamela] Massachusetts Gen Hosp, Broad Inst, Boston, MA 02142 USA. [Perreault, Louis-Philippe Lemieux; Stone, Jennifer; Scolnick, Ed; Purcell, Shaun; Sklar, Pamela] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02142 USA. [Giannoulatou, Eleni] Univ Montreal, Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Wormley, Brandon; Thiselton, Dawn L.; Elves, Rachel L.; Kendler, Kenneth S.; Riley, Brien P.] Virginia Commonwealth Univ, Dept Psychiat, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. [Wormley, Brandon; Thiselton, Dawn L.; Elves, Rachel L.; Kendler, Kenneth S.; Riley, Brien P.] Virginia Commonwealth Univ, Dept Human Genet, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. [Regan, Regina; Ennis, Sean] Univ Coll Dublin, Sch Med & Med Sci, Dublin 2, Ireland. [Dinan, Timothy G.] Natl Univ Ireland Univ Coll Cork, Dept Psychiat, Cork, Ireland. [McDonald, Colm] Natl Univ Ireland, Dept Psychiat, Galway, Ireland. [Murphy, Kieran C.] Beaumont Hosp, Dept Psychiat, RCSI Educ & Res Ctr, Dublin 9, Ireland. [O'Callaghan, Eadbhard] Dun Laoghaire Co, DETECT Early Intervent Psychosis Serv, Dublin, Ireland. [Waddington, John L.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Walsh, Dermot] Hlth Res Board, Dublin 2, Ireland. [O'Donovan, Michael; Grozeva, Detelina; Craddock, Nick; Rees, Elliott; Kirov, George; Walters, James] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF4 4XN, S Glam, Wales. [O'Donovan, Michael; Grozeva, Detelina; Craddock, Nick; Rees, Elliott; Kirov, George; Walters, James] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF4 4XN, S Glam, Wales. [Purcell, Shaun; Sklar, Pamela] Mt Sinai Hosp, New York, NY 10029 USA. [Coe, Bradley; Eichler, Evan E.] Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Ophoff, Roel] Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Buizer, Jacobine] Univ Utrecht, Rudolf Magnus Inst, NL-3584 CG Utrecht, Netherlands. [Szatkiewicz, Jin; Sullivan, Patrick] Univ N Carolina, Chapel Hill, NC 27599 USA. [Hultman, Christina] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Gurling, Hugh; Mcquillin, Andrew] UCL, Mental Hlth Sci Unit, Mol Psychiat Lab, London WC1E 6BT, England. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Blackwood, Douglas; Johnstone, Mandy] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. [O'Neill, Francis A.] Queens Univ, Dept Psychiat, Belfast BT7 1NN, Antrim, North Ireland. RP Corvin, A (reprint author), Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland. EM acorvin@tcd.ie RI McDonald, Colm/C-1430-2009; Coe, Bradley/A-2878-2009; McQuillin, Andrew/C-1623-2008; OI Pirinen, Matti/0000-0002-1664-1350; Dinan, Timothy/0000-0002-2316-7220; Walters, James/0000-0002-6980-4053; McQuillin, Andrew/0000-0003-1567-2240; Donohoe, Gary/0000-0003-3037-7426; Tropea, Daniela/0000-0001-9730-6636; Johnstone, Mandy/0000-0002-8398-0862; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Morris, Derek/0000-0002-3413-570X; Gill, Michael/0000-0003-0206-5337; Murphy, Kieran/0000-0003-2930-4465; Giannoulatou, Eleni/0000-0002-7084-6736 FU Wellcome Trust Case Control Consortium [085475/B/08/Z, 085475/Z/08/Z]; Wellcome Trust [072894/Z/03/Z, 090532/Z/09/Z, 075491/Z/04/B, 068545/Z/02]; NIMH [MH 41953, MH083094]; Science Foundation Ireland [08/IN.1/B1916]; Medical Research Council [G0000934]; Wellcome Trust Career Development Fellowship [097364/Z/11/Z] FX Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 54 TC 7 Z9 7 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2014 VL 23 IS 12 BP 3316 EP 3326 DI 10.1093/hmg/ddu025 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AI7CJ UT WOS:000337038600022 PM 24474471 ER PT J AU Zhang, YS Zhu, YB Gupta, A Huang, YY Murray, CK Vrahas, MS Sherwood, ME Baer, DG Hamblin, MR Dai, TH AF Zhang, Yunsong Zhu, Yingbo Gupta, Asheesh Huang, Yingying Murray, Clinton K. Vrahas, Mark S. Sherwood, Margaret E. Baer, David G. Hamblin, Michael R. Dai, Tianhong TI Antimicrobial Blue Light Therapy for Multidrug-Resistant Acinetobacter baumannii Infection in a Mouse Burn Model: Implications for Prophylaxis and Treatment of Combat-related Wound Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Blue light; Acinetobacter baumannii; burn; infection; multidrug resistance; mouse model ID MRSA IN-VITRO; STAPHYLOCOCCUS-AUREUS; PHOTODYNAMIC THERAPY; VISIBLE-LIGHT; BACTERIA; INACTIVATION; AFGHANISTAN; PORPHYRINS; 405-NM; MICE AB In this study, we investigated the utility of antimicrobial blue light therapy for multidrug-resistant Acinetobacter baumannii infection in a mouse burn model. A bioluminescent clinical isolate of multidrug-resistant A. baumannii was obtained. The susceptibility of A. baumannii to blue light (415 nm)-inactivation was compared in vitro to that of human keratinocytes. Repeated cycles of sublethal inactivation of bacterial by blue light were performed to investigate the potential resistance development of A. baumannii to blue light. A mouse model of third degree burn infected with A. baumannii was developed. A single exposure of blue light was initiated 30 minutes after bacterial inoculation to inactivate A. baumannii in mouse burns. It was found that the multidrug-resistant A. baumannii strain was significantly more susceptible than keratinocytes to blue light inactivation. Transmission electron microscopy revealed blue light-induced ultrastructural damage in A. baumannii cells. Fluorescence spectroscopy suggested that endogenous porphyrins exist in A. baumannii cells. Blue light at an exposure of 55.8 J/cm(2) significantly reduced the bacterial burden in mouse burns. No resistance development to blue light inactivation was observed in A. baumannii after 10 cycles of sublethal inactivation of bacteria. No significant DNA damage was detected in mouse skin by means of a skin TUNEL assay after a blue light exposure of 195 J/cm(2). C1 [Zhang, Yunsong; Zhu, Yingbo; Gupta, Asheesh; Huang, Yingying; Sherwood, Margaret E.; Hamblin, Michael R.; Dai, Tianhong] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Vrahas, Mark S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Zhang, Yunsong; Gupta, Asheesh; Huang, Yingying; Hamblin, Michael R.; Dai, Tianhong] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Murray, Clinton K.] Brooke Army Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Baer, David G.] US Army Inst Surg Res, Ft Sam Houston, TX USA. [Zhang, Yunsong] Jinan Univ, Dept Burn & Plast Surg, Guangzhou Red Cross Hosp, Guangzhou, Guangdong, Peoples R China. [Zhu, Yingbo] Tongji Univ, Sch Med, Shanghai 200092, Peoples R China. [Gupta, Asheesh] Def Inst Physiol & Allied Sci, Delhi, India. RP Dai, TH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR 404B,55 Fruit St, Boston, MA 02114 USA. EM tdai@mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU Center for Integration of Medicine and Innovative Technology (CIMIT) under a US Army Medical Research Acquisition Activity [13-1033]; COTA/Smith and Nephew [2012-16]; Airlift Research Foundation [109421]; National Institutes of Health [RO1AI050875] FX This work was supported by the Center for Integration of Medicine and Innovative Technology (CIMIT) under a US Army Medical Research Acquisition Activity cooperative agreement (CIMIT no. 13-1033 to T. D.), COTA/Smith and Nephew (grant 2012-16 to T. D.), the Airlift Research Foundation (Extremity Trauma Research Grant 109421 to T. D.), and the National Institutes of Health (grant RO1AI050875 to M. R. H.). NR 34 TC 18 Z9 19 U1 0 U2 31 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2014 VL 209 IS 12 BP 1963 EP 1971 DI 10.1093/infdis/jit842 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AI7JB UT WOS:000337063100015 PM 24381206 ER PT J AU Haggarty, SJ Perlis, RH AF Haggarty, Stephen J. Perlis, Roy H. TI Translation: Screening for Novel Therapeutics With Disease-Relevant Cell Types Derived from Human Stem Cell Models SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Disease-relevant cell type; high-throughput screening; induced pluripotent stem cells; neural progenitors; neuropharmacology; neuroplasticity; phenotypic assays; reprogramming ID NEURAL PROGENITOR CELLS; ADULT HUMAN FIBROBLASTS; HUMAN SOMATIC-CELLS; FRAGILE-X-SYNDROME; IN-VITRO; RETT-SYNDROME; SMALL-MOLECULE; DEFINED FACTORS; NS CELLS; HUMAN ES AB The advent of somatic cell reprogramming technologies-which enables the generation of patient-specific, induced pluripotent stem cell and other trans-differentiated human neuronal cell models-provides new means of gaining insight into the molecular mechanisms and neural substrates of psychiatric disorders. By allowing a more precise understanding of genotype-phenotype relationship in disease-relevant human cell types, the use of reprogramming technologies in tandem with emerging genome engineering approaches provides a previously "missing link" between basic research and translational efforts. In this review, we summarize advances in applying human pluripotent stem cell and reprogramming technologies to generate specific neural subtypes with a focus on the use of these in vitro systems for the discovery of small molecule-probes and novel therapeutics. Examples are given where human cell models of psychiatric disorders have begun to reveal new mechanistic insight into pathophysiology and simultaneously have provided the foundation for developing disease-relevant, phenotypic assays suitable for both functional genomic and chemical screens. A number of areas for future research are discussed, including the need to develop robust methodology for the reproducible, large-scale production of disease-relevant neural cell types in formats compatible with high-throughput screening modalities, including high-content imaging, multidimensional, signature-based screening, and in vitro network with multielectrode arrays. Limitations, including the challenges in recapitulating neurocircuits and non-cell autonomous phenotypes are discussed. Although these technologies are still in active development, we conclude that, as our understanding of how to efficiently generate and probe the plasticity of patient-specific stem models improves, their utility is likely to advance rapidly. C1 [Haggarty, Stephen J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Chem Neurobiol Lab, Boston, MA 02114 USA. [Haggarty, Stephen J.; Perlis, Roy H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Haggarty, Stephen J.; Perlis, Roy H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Haggarty, Stephen J.; Perlis, Roy H.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haggarty, Stephen J.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Haggarty, SJ (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, 185 Cambridge St, Boston, MA 02114 USA. EM haggarty@chgr.mgh.harvard.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU FRAXA Research Foundation; Harvard Stem Cell Institute Seed Grant; Marigold Foundation; Stanley Medical Research Institute; Tau Consortium; Pitt-Hopkins Research Foundation; National Institute of Mental Health [R33MH087896, R01MH091115, R01MH095088, R21MH093958]; National Institute of Aging [RF1AG042978] FX Members of the Haggarty and Perlis laboratories and the Massachusetts General Hospital Center for Experimental Drugs and Diagnostics are thanked for their continued dedication to advancing patient-specific induced pluripotent stem cell models of psychiatric disorders and spirited discussions. Research in the Haggarty and Perlis laboratories has been supported in part by the FRAXA Research Foundation, Harvard Stem Cell Institute Seed Grant, Marigold Foundation, Stanley Medical Research Institute, Tau Consortium, Pitt-Hopkins Research Foundation, National Institute of Mental Health (R33MH087896; R01MH091115; R01MH095088; R21MH093958), and National Institute of Aging (RF1AG042978). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. NR 95 TC 7 Z9 7 U1 1 U2 13 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 JUN 15 PY 2014 VL 75 IS 12 BP 952 EP 960 DI 10.1016/j.biopsych.2013.05.028 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AH8DV UT WOS:000336365200008 PM 23876186 ER PT J AU Agostoni, P Swenson, ER Fumagalli, R Salvioni, E Cattadori, G Farina, S Bussotti, M Tamplenizza, M Lombardi, C Bonacina, D Brioschi, M Caravita, S Modesti, P Revera, M Giuliano, A Meriggi, P Faini, A Bilo, G Banfi, C Parati, G AF Agostoni, Piergiuseppe Swenson, Erik R. Fumagalli, Roberto Salvioni, Elisabetta Cattadori, Gaia Farina, Stefania Bussotti, Maurizio Tamplenizza, Margherita Lombardi, Carolina Bonacina, Daniele Brioschi, Maura Caravita, Sergio Modesti, Pietro Revera, Miriam Giuliano, Andrea Meriggi, Paolo Faini, Andrea Bilo, Grzegorz Banfi, Cristina Parati, Gianfranco TI Acute high-altitude exposure reduces lung diffusion: Data from the HIGHCARE Alps Project (vol 188, pg 223, 2013) SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Correction C1 [Agostoni, Piergiuseppe; Salvioni, Elisabetta; Cattadori, Gaia; Farina, Stefania; Brioschi, Maura; Banfi, Cristina] IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy. [Swenson, Erik R.] Univ Washington, VA Med Ctr, Dept Med, Div Pulm Crit Care & Med, Seattle, WA 98108 USA. [Agostoni, Piergiuseppe] Dept Clin Sci & Community Hlth, I-20138 Milan, Italy. [Swenson, Erik R.] Univ Washington, VA Med Ctr, VA Puget Sound Hlth Care Syst, Div Pulm & Crit Care & Med,Dept Med, Seattle, WA 98108 USA. [Fumagalli, Roberto; Bonacina, Daniele] Univ Milano Bicocca, Dipartimento Med Sperimentale, Osped S Gerardo Monza, Unita Operat Anestesia & Rianimaz 1, Milan, Italy. [Bussotti, Maurizio] IRCCS, Fdn S Maugeri, I-20138 Milan, Italy. [Tamplenizza, Margherita] Univ Milan, CIMAINA, Milan, Italy. [Lombardi, Carolina; Caravita, Sergio; Revera, Miriam; Giuliano, Andrea; Faini, Andrea; Bilo, Grzegorz; Parati, Gianfranco] S Luca Hosp, Ist Auxol Italian, Dept Cardiol, I-20149 Milan, Italy. [Revera, Miriam; Parati, Gianfranco] Univ Milano Bicocca, Dept Clin Med & Prevent, I-20149 Milan, Italy. [Modesti, Pietro] Univ Florence, Dipartimento Area Crit Med Chirurg, I-50134 Florence, Italy. [Modesti, Pietro] IRCCS Ctr Santa Maria Ulivi Pozzolat, Fdn Don C Gnocchi, Florence, Italy. [Meriggi, Paolo] Fdn Don Carlo Gnocchi, Polo Tecnol Biomed Technol Dept, I-20148 Milan, Italy. RP Agostoni, P (reprint author), Ctr Cardiol Monzino, Via Parea 4, I-20138 Milan, Italy. EM piergiuseppe.agostoni@unimi.it RI Modesti, Pietro Amedeo/B-2638-2012; Bilo, Grzegorz/J-8694-2016; Parati, Gianfranco/K-7151-2016 OI Modesti, Pietro Amedeo/0000-0002-9511-2173; Bilo, Grzegorz/0000-0002-5104-9176; Parati, Gianfranco/0000-0001-9402-7439 NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 EI 1878-1519 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD JUN 15 PY 2014 VL 197 BP 53 EP 53 DI 10.1016/j.resp.2014.03.008 PG 1 WC Physiology; Respiratory System SC Physiology; Respiratory System GA AH8AW UT WOS:000336357500008 ER PT J AU Wason, JMS Trippa, L AF Wason, James M. S. Trippa, Lorenzo TI A comparison of Bayesian adaptive randomization and multi-stage designs for multi-arm clinical trials SO STATISTICS IN MEDICINE LA English DT Article DE adaptive randomization; group-sequential designs; multi-arm trials; multiple testing ID PERSONALIZED MEDICINE; CANCER; ONCOLOGY; OUTCOMES; THERAPY; AGENTS; RULE AB When several experimental treatments are available for testing, multi-arm trials provide gains in efficiency over separate trials. Including interim analyses allows the investigator to effectively use the data gathered during the trial. Bayesian adaptive randomization (AR) and multi-arm multi-stage (MAMS) designs are two distinct methods that use patient outcomes to improve the efficiency and ethics of the trial. AR allocates a greater proportion of future patients to treatments that have performed well; MAMS designs use pre-specified stopping boundaries to determine whether experimental treatments should be dropped. There is little consensus on which method is more suitable for clinical trials, and so in this paper, we compare the two under several simulation scenarios and in the context of a real multi-arm phase II breast cancer trial. We compare the methods in terms of their efficiency and ethical properties. We also consider the practical problem of a delay between recruitment of patients and assessment of their treatment response. Both methods are more efficient and ethical than a multi-arm trial without interim analyses. Delay between recruitment and response assessment attenuates this efficiency gain. We also consider futility stopping rules for response adaptive trials that add efficiency when all treatments are ineffective. Our comparisons show that AR is more efficient than MAMS designs when there is an effective experimental treatment, whereas if none of the experimental treatments is effective, then MAMS designs slightly outperform AR. (c) 2014 The Authors Statistics in Medicine Published by John Wiley & Sons, Ltd. C1 [Wason, James M. S.] Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England. [Trippa, Lorenzo] Dana Farber, Dept Biostat & Computat Biol, Boston, MA USA. [Trippa, Lorenzo] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Wason, JMS (reprint author), Inst Publ Hlth, MRC Biostat Unit, Robinson Way, Cambridge CB2 0SR, England. EM james.wason@mrc-bsu.cam.ac.uk FU MRC [G0800860, MR/J004979/1] FX This work is sponsored by MRC (grant numbers G0800860 and MR/J004979/1). We thank the reviewers for useful comments that helped improve the paper. NR 42 TC 10 Z9 10 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2014 VL 33 IS 13 BP 2206 EP 2221 DI 10.1002/sim.6086 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AG9XH UT WOS:000335772800004 PM 24421053 ER PT J AU Inouye, SK Westendorp, RGJ Saczynski, JS Kimchi, EY Cleinman, AA AF Inouye, Sharon K. Westendorp, Rudi G. J. Saczynski, Jane S. Kimchi, Eyal Y. Cleinman, Alycia A. TI Delirium in elderly people Reply SO LANCET LA English DT Letter C1 [Inouye, Sharon K.] Hebrew SeniorLife, Inst Aging Res, Aging Brain Ctr, Boston, MA 02131 USA. [Westendorp, Rudi G. J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA USA. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA USA. [Kimchi, Eyal Y.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cleinman, Alycia A.] Univ Mississippi, Med Ctr, Div Geriatr, Jackson, MS 39216 USA. RP Inouye, SK (reprint author), Hebrew SeniorLife, Inst Aging Res, Aging Brain Ctr, Boston, MA 02131 USA. EM sharoninouye@hsl.harvard.edu NR 3 TC 2 Z9 2 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 14 PY 2014 VL 383 IS 9934 BP 2045 EP 2045 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AI9VZ UT WOS:000337292400020 PM 24931690 ER PT J AU Wills, AM Hubbard, J Macklin, EA Glass, J Tandan, R Simpson, EP Brooks, B Gelinas, D Mitsumoto, H Mozaffar, T Hanes, GP Ladha, SS Heiman-Patterson, T Katz, J Lou, JS Mahoney, K Grasso, D Lawson, R Yu, H Cudkowicz, M AF Wills, Anne-Marie Hubbard, Jane Macklin, Eric A. Glass, Jonathan Tandan, Rup Simpson, Ericka P. Brooks, Benjamin Gelinas, Deborah Mitsumoto, Hiroshi Mozaffar, Tahseen Hanes, Gregory P. Ladha, Shafeeq S. Heiman-Patterson, Terry Katz, Jonathan Lou, Jau-Shin Mahoney, Katy Grasso, Daniela Lawson, Robert Yu, Hong Cudkowicz, Merit CA MDA Clinical Res Network TI Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial SO LANCET LA English DT Article ID BODY-MASS INDEX; ALS PATIENTS; ENERGY-EXPENDITURE; SURVIVAL; DYSLIPIDEMIA; MANAGEMENT; PREDICTOR; NEUROLOGY; BENEFIT; DEATH AB Background Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. Methods In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983. Findings Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. Interpretation Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. C1 [Wills, Anne-Marie; Mahoney, Katy; Grasso, Daniela; Lawson, Robert; Yu, Hong; Cudkowicz, Merit] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wills, Anne-Marie; Mahoney, Katy; Grasso, Daniela; Lawson, Robert; Yu, Hong; Cudkowicz, Merit] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA. [Hubbard, Jane] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Harvard Catalyst Massachusetts Gen Hosp,Clin Res, Boston, MA 02114 USA. [Macklin, Eric A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Glass, Jonathan] Emory Univ, Sch Med, Atlanta, GA USA. [Tandan, Rup] Univ Vermont, Burlington, VT USA. [Simpson, Ericka P.] Methodist Neurol Inst, Houston, TX USA. [Brooks, Benjamin] Neuromuscular ALS MDA Ctr, Med Ctr, Charlotte, NC USA. [Gelinas, Deborah] St Marys Hlth Care, Grand Rapids, MI USA. [Mitsumoto, Hiroshi] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Mozaffar, Tahseen] Univ Calif Irvine, Irvine, CA USA. [Hanes, Gregory P.] Sarasota Mem Hosp, Sarasota, FL USA. [Ladha, Shafeeq S.] St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ USA. [Heiman-Patterson, Terry] Drexel Univ, Philadelphia, PA 19104 USA. [Katz, Jonathan] Univ Calif San Francisco, Calif Pacific Med Ctr, San Francisco, CA 94143 USA. [Lou, Jau-Shin] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Wills, AM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM awills@partners.org RI Ladha, Shafeeq/A-4948-2010; OI Ladha, Shafeeq/0000-0003-1955-4292; Macklin, Eric/0000-0003-1618-3502 FU Muscular Dystrophy Association; National Center for Research Resources; National Institutes of Health; Harvard NeuroDiscovery Center FX Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center. NR 31 TC 45 Z9 46 U1 3 U2 21 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 14 PY 2014 VL 383 IS 9934 BP 2065 EP 2072 DI 10.1016/S0140-6736(14)60222-1 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AI9VZ UT WOS:000337292400026 PM 24582471 ER PT J AU Jang, JY Kim, SJ Cho, EK Jeong, SW Park, EJ Lee, WC Lee, SH Kim, SG Kim, YS Kim, HS Kim, BS Lin, WY Chung, RT AF Jang, Jae Young Kim, Seong-Jun Cho, Eun Kyung Jeong, Soung Won Park, Eui Ju Lee, Woong Cheul Lee, Sae Hwan Kim, Sang Gyune Kim, Young Seok Kim, Hong Soo Kim, Boo Sung Lin, Wenyu Chung, Raymond T. TI TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications SO PLOS ONE LA English DT Article ID VIRAL-HEPATITIS; DEATH RECEPTORS; LIVER-INJURY; POLY(ADP-RIBOSE) POLYMERASE; HUMAN HEPATOCYTES; LIGAND; ACTIVATION; CLEAVAGE; MITOCHONDRIA; MODULATION AB Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection. C1 [Jang, Jae Young; Cho, Eun Kyung; Jeong, Soung Won; Park, Eui Ju; Lee, Woong Cheul; Kim, Boo Sung] Soonchunhyang Univ, Inst Digest Res, Ctr Digest Dis, Dept Internal Med,Coll Med, Seoul, South Korea. [Lee, Sae Hwan; Kim, Hong Soo] Soonchunhyang Univ, Dept Internal Med, Coll Med, Cheonan, South Korea. [Kim, Sang Gyune; Kim, Young Seok] Soonchunhyang Univ, Dept Internal Med, Coll Med, Puchon, South Korea. [Kim, Seong-Jun] Univ Calif San Diego, Dept Med, Div Infect Dis, La Jolla, CA 92093 USA. [Lin, Wenyu; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02138 USA. RP Chung, RT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02138 USA. EM rtchung@partners.org FU National Research Foundation of Korea (NRF) Grant - Korean Government (MOE) [NRF-2011-0010229]; NIH [AI069939] FX This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MOE) (No. Grant Number: NRF-2011-0010229) and NIH AI069939 (R.T.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 5 Z9 5 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2014 VL 9 IS 6 AR e98171 DI 10.1371/journal.pone.0098171 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2VQ UT WOS:000338278100013 PM 24927176 ER PT J AU Singhal, V Lawson, EA Ackerman, KE Fazeli, PK Clarke, H Lee, H Eddy, K Marengi, DA Derrico, NP Bouxsein, ML Misra, M AF Singhal, Vibha Lawson, Elizabeth A. Ackerman, Kathryn E. Fazeli, Pouneh K. Clarke, Hannah Lee, Hang Eddy, Kamryn Marengi, Dean A. Derrico, Nicholas P. Bouxsein, Mary L. Misra, Madhusmita TI Irisin Levels Are Lower in Young Amenorrheic Athletes Compared with Eumenorrheic Athletes and Non-Athletes and Are Associated with Bone Density and Strength Estimates SO PLOS ONE LA English DT Article ID GROWTH-FACTOR 21; BROWN ADIPOSE-TISSUE; ANOREXIA-NERVOSA; MINERAL DENSITY; EXERCISE; HUMANS; OBESITY; WOMEN; SERUM; FGF21 AB Irisin and FGF21 are novel hormones implicated in the "browning'' of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14-21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes. C1 [Singhal, Vibha; Lawson, Elizabeth A.; Ackerman, Kathryn E.; Fazeli, Pouneh K.; Clarke, Hannah; Eddy, Kamryn; Marengi, Dean A.; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Singhal, Vibha; Lawson, Elizabeth A.; Ackerman, Kathryn E.; Fazeli, Pouneh K.; Clarke, Hannah; Lee, Hang; Eddy, Kamryn; Marengi, Dean A.; Derrico, Nicholas P.; Bouxsein, Mary L.; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. [Singhal, Vibha; Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. [Ackerman, Kathryn E.] Boston Childrens Hosp, Div Sports Med, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Eddy, Kamryn] Massachusetts Gen Hosp, Harris Ctr, Boston, MA 02114 USA. [Derrico, Nicholas P.; Bouxsein, Mary L.] Massachusetts Gen Hosp, Div Endocrine, Boston, MA 02114 USA. [Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Boston, MA 02215 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM mmisra@partners.org FU NIH [UL1 RR025758, R01 HD060827, K23 MH092560, K24HD071843]; Massachusetts General Hospital Claflin Distinguished Scholar Award FX This study was funded by NIH Grants UL1 RR025758, R01 HD060827, K23 MH092560; K24HD071843; and Massachusetts General Hospital Claflin Distinguished Scholar Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 13 Z9 13 U1 2 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2014 VL 9 IS 6 AR e100218 DI 10.1371/journal.pone.0100218 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2VQ UT WOS:000338278100121 PM 24926783 ER PT J AU Chen, G Zhang, DC Fuchs, TA Manwani, D Wagner, DD Frenette, PS AF Chen, Grace Zhang, Dachuan Fuchs, Tobias A. Manwani, Deepa Wagner, Denisa D. Frenette, Paul S. TI Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease SO BLOOD LA English DT Article ID ACUTE CHEST SYNDROME; ACUTE LUNG INJURY; DNA TRAPS; ADHERENT LEUKOCYTES; OXIDATIVE STRESS; MICE; HEMOGLOBIN; ACTIVATION; THROMBOSIS; ADHESION AB Sickle cell disease (SCD) is characterized by recurring episodes of vascular occlusion in which neutrophil activation plays a major role. The disease is associated with chronic hemolysis with elevated cell-free hemoglobin and heme. The ensuing depletion of heme scavenger proteins leads to nonspecific heme uptake and heme-catalyzed generation of reactive oxygen species. Here, we have identified a novel role for heme in the induction of neutrophil extracellular trap (NET) formation in SCD. NETs are decondensed chromatin decorated by granular enzymes and are released by activated neutrophils. In humanized SCD mice, we have detected NETs in the lungs and soluble NET components in plasma. The presence of NETs was associated with hypothermia and death of these mice, which could be prevented and delayed, respectively, by dismantling NETs with DNase I treatment. We have identified heme as the plasma factor that stimulates neutrophils to release NETs in vitro and in vivo. Increasing or decreasing plasma heme concentrations can induce or prevent, respectively, in vivo NET formation, indicating that heme plays a crucial role in stimulating NET release in SCD. Our results thus suggest that NETs significantly contribute to SCD pathogenesis and can serve as a therapeutic target for treating SCD. C1 [Chen, Grace; Zhang, Dachuan; Frenette, Paul S.] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA. [Fuchs, Tobias A.; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Fuchs, Tobias A.; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA USA. [Manwani, Deepa] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [Wagner, Denisa D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. RP Frenette, PS (reprint author), Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Price Ctr, 1301 Morris Pk Ave,Room 101B, Bronx, NY 10461 USA. EM paul.frenette@einstein.yu.edu FU National Institutes of Health [R01 HL069438, HL097700, R01 HL102101] FX This work was supported by the National Institutes of Health (grants R01 HL069438 and HL097700) (P. S. F.) and (grant R01 HL102101) (D.D.W.). NR 48 TC 46 Z9 49 U1 0 U2 9 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 12 PY 2014 VL 123 IS 24 BP 3818 EP 3827 DI 10.1182/blood-2013-10-529982 PG 10 WC Hematology SC Hematology GA AQ2LI UT WOS:000342617200026 PM 24620350 ER PT J AU Layfield, LJ Pitman, MB Demay, RM Shidham, VB AF Layfield, Lester James Pitman, Martha Bishop DeMay, Richard M. Shidham, Vinod B. TI Pancreaticobiliary tract cytology: Journey toward "Bethesda" style guidelines from the Papanicolaou Society of Cytopathology SO CYTOJOURNAL LA English DT Editorial Material ID NEEDLE-ASPIRATION BIOPSY; OF-CYTOPATHOLOGY; FOLLOW-UP; SPECIMENS; LESIONS; RECOMMENDATIONS; CLASSIFICATION; NOMENCLATURE; DIAGNOSIS; BILIARY C1 [Layfield, Lester James] Univ Missouri, Dept Pathol, Columbia, MO 65201 USA. [Layfield, Lester James] Univ Missouri, Dept Anat Sci, Columbia, MO USA. [Pitman, Martha Bishop] Harvard Univ, Sch Med, Boston, MA USA. [Pitman, Martha Bishop] Massachusetts Gen Hosp, Boston, MA 02114 USA. [DeMay, Richard M.] Univ Chicago, Chicago, IL 60637 USA. [Shidham, Vinod B.] Wayne State Univ, Sch Med, DMC, Detroit, MI 48202 USA. [Shidham, Vinod B.] Karmanos Canc Ctr, Detroit, MI USA. RP Shidham, VB (reprint author), Wayne State Univ, Sch Med, DMC, Detroit, MI 48202 USA. EM layfieldl@health.missouri.edu; mpitman@partners.org; rdemay@uchicago.edu; vshidham@med.wayne.edu NR 24 TC 5 Z9 5 U1 2 U2 3 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0974-5963 EI 1742-6413 J9 CYTOJOURNAL JI CytoJournal PD JUN 12 PY 2014 VL 11 AR 18 DI 10.4103/1742-6413.134441 PG 3 WC Pathology SC Pathology GA AO3QL UT WOS:000341248600004 PM 25071860 ER PT J AU Escott-Price, V Bellenguez, C Wang, LS Choi, SH Harold, D Jones, L Holmans, P Gerrish, A Vedernikov, A Richards, A DeStefano, AL Lambert, JC Ibrahim-Verbaas, CA Naj, AC Sims, R Jun, G Bis, JC Beecham, GW Grenier-Boley, B Russo, G Thornton-Wells, TA Denning, N Smith, AV Chouraki, V Thomas, C Ikram, MA Zelenika, D Vardarajan, BN Kamatani, Y Lin, CF Schmidt, H Kunkle, B Dunstan, ML Vronskaya, M Johnson, AD Ruiz, A Bihoreau, MT Reitz, C Pasquier, F Hollingworth, P Hanon, O Fitzpatrick, AL Buxbaum, JD Campion, D Crane, PK Baldwin, C Becker, T Gudnason, V Cruchaga, C Craig, D Amin, N Berr, C Lopez, OL De Jager, PL Deramecourt, V Johnston, JA Evans, D Lovestone, S Letenneur, L Hernandez, I Rubinsztein, DC Eiriksdottir, G Sleegers, K Goate, AM Fievet, N Huentelman, MJ Gill, M Brown, K Kamboh, MI Keller, L Barberger-Gateau, P McGuinness, B Larson, EB Myers, AJ Dufouil, C Todd, S Wallon, D Love, S Rogaeva, E Gallacher, J St George-Hyslop, P Clarimon, J Lleo, A Bayer, A Tsuang, DW Yu, L Tsolaki, M Bossu, P Spalletta, G Proitsi, P Collinge, J Sorbi, S Garcia, FS Fox, NC Hardy, J Naranjo, MCD Bosco, P Clarke, R Brayne, C Galimberti, D Scarpini, E Bonuccelli, U Mancuso, M Siciliano, G Moebus, S Mecocci, P Del Zompo, M Maier, W Hampel, H Pilotto, A Frank-Garcia, A Panza, F Solfrizzi, V Caffarra, P Nacmias, B Perry, W Mayhaus, M Lannfelt, L Hakonarson, H Pichler, S Carrasquillo, MM Ingelsson, M Beekly, D Alvarez, V Zou, FG Valladares, O Younkin, SG Coto, E Hamilton-Nelson, KL Gu, W Razquin, C Pastor, P Mateo, I Owen, MJ Faber, KM Jonsson, PV Combarros, O O'Donovan, MC Cantwell, LB Soininen, H Blacker, D Mead, S Mosley, TH Bennett, DA Harris, TB Fratiglioni, L Holmes, C de Bruijn, RFAG Passmore, P Montine, TJ Bettens, K Rotter, JI Brice, A Morgan, K Foroud, TM Kukull, WA Hannequin, D Powell, JF Nalls, MA Ritchie, K Lunetta, KL Kauwe, JSK Boerwinkle, E Riemenschneider, M Boada, M Hiltunen, M Martin, ER Schmidt, R Rujescu, D Dartigues, JF Mayeux, R Tzourio, C Hofman, A Nothen, MM Graff, C Psaty, BM Haines, JL Lathrop, M Pericak-Vance, MA Launer, LJ Van Broeckhoven, C Farrer, LA van Duijn, CM Ramirez, A Seshadri, S Schellenberg, GD Amouyel, P Williams, J AF Escott-Price, Valentina Bellenguez, Celine Wang, Li-San Choi, Seung-Hoan Harold, Denise Jones, Lesley Holmans, Peter Gerrish, Amy Vedernikov, Alexey Richards, Alexander DeStefano, Anita L. Lambert, Jean-Charles Ibrahim-Verbaas, Carla A. Naj, Adam C. Sims, Rebecca Jun, Gyungah Bis, Joshua C. Beecham, Gary W. Grenier-Boley, Benjamin Russo, Giancarlo Thornton-Wells, Tricia A. Denning, Nicola Smith, Albert V. Chouraki, Vincent Thomas, Charlene Ikram, M. Arfan Zelenika, Diana Vardarajan, Badri N. Kamatani, Yoichiro Lin, Chiao-Feng Schmidt, Helena Kunkle, Brian Dunstan, Melanie L. Vronskaya, Maria Johnson, Andrew D. Ruiz, Agustin Bihoreau, Marie-Therese Reitz, Christiane Pasquier, Florence Hollingworth, Paul Hanon, Olivier Fitzpatrick, Annette L. Buxbaum, Joseph D. Campion, Dominique Crane, Paul K. Baldwin, Clinton Becker, Tim Gudnason, Vilmundur Cruchaga, Carlos Craig, David Amin, Najaf Berr, Claudine Lopez, Oscar L. De Jager, Philip L. Deramecourt, Vincent Johnston, Janet A. Evans, Denis Lovestone, Simon Letenneur, Luc Hernandez, Isabel Rubinsztein, David C. Eiriksdottir, Gudny Sleegers, Kristel Goate, Alison M. Fievet, Nathalie Huentelman, Matthew J. Gill, Michael Brown, Kristelle Kamboh, M. Ilyas Keller, Lina Barberger-Gateau, Pascale McGuinness, Bernadette Larson, Eric B. Myers, Amanda J. Dufouil, Carole Todd, Stephen Wallon, David Love, Seth Rogaeva, Ekaterina Gallacher, John St George-Hyslop, Peter Clarimon, Jordi Lleo, Alberto Bayer, Anthony Tsuang, Debby W. Yu, Lei Tsolaki, Magda Bossu, Paola Spalletta, Gianfranco Proitsi, Petra Collinge, John Sorbi, Sandro Garcia, Florentino Sanchez Fox, Nick C. Hardy, John Deniz Naranjo, Maria Candida Bosco, Paolo Clarke, Robert Brayne, Carol Galimberti, Daniela Scarpini, Elio Bonuccelli, Ubaldo Mancuso, Michelangelo Siciliano, Gabriele Moebus, Susanne Mecocci, Patrizia Del Zompo, Maria Maier, Wolfgang Hampel, Harald Pilotto, Alberto Frank-Garcia, Ana Panza, Francesco Solfrizzi, Vincenzo Caffarra, Paolo Nacmias, Benedetta Perry, William Mayhaus, Manuel Lannfelt, Lars Hakonarson, Hakon Pichler, Sabrina Carrasquillo, Minerva M. Ingelsson, Martin Beekly, Duane Alvarez, Victoria Zou, Fanggeng Valladares, Otto Younkin, Steven G. Coto, Eliecer Hamilton-Nelson, Kara L. Gu, Wei Razquin, Cristina Pastor, Pau Mateo, Ignacio Owen, Michael J. Faber, Kelley M. Jonsson, Palmi V. Combarros, Onofre O'Donovan, Michael C. Cantwell, Laura B. Soininen, Hilkka Blacker, Deborah Mead, Simon Mosley, Thomas H., Jr. Bennett, David A. Harris, Tamara B. Fratiglioni, Laura Holmes, Clive de Bruijn, Renee F. A. G. Passmore, Peter Montine, Thomas J. Bettens, Karolien Rotter, Jerome I. Brice, Alexis Morgan, Kevin Foroud, Tatiana M. Kukull, Walter A. Hannequin, Didier Powell, John F. Nalls, Michael A. Ritchie, Karen Lunetta, Kathryn L. Kauwe, John S. K. Boerwinkle, Eric Riemenschneider, Matthias Boada, Merce Hiltunen, Mikko Martin, Eden R. Schmidt, Reinhold Rujescu, Dan Dartigues, Jean-Francois Mayeux, Richard Tzourio, Christophe Hofman, Albert Noethen, Markus M. Graff, Caroline Psaty, Bruce M. Haines, Jonathan L. Lathrop, Mark Pericak-Vance, Margaret A. Launer, Lenore J. Van Broeckhoven, Christine Farrer, Lindsay A. van Duijn, Cornelia M. Ramirez, Alfredo Seshadri, Sudha Schellenberg, Gerard D. Amouyel, Philippe Williams, Julie CA United Kingdom Brain Expression TI Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease SO PLOS ONE LA English DT Article ID GENOME SCAN METAANALYSIS; IDENTIFIES VARIANTS; BIPOLAR DISORDER; COMMON VARIANTS; COMPLEX TRAITS; LEIGH-SYNDROME; ASSOCIATION; EXPRESSION; TP53INP1; CANCER AB Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. C1 [Escott-Price, Valentina; Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; Sims, Rebecca; Denning, Nicola; Thomas, Charlene; Dunstan, Melanie L.; Vronskaya, Maria; Hollingworth, Paul; Owen, Michael J.; O'Donovan, Michael C.; Williams, Julie] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Bellenguez, Celine; Lambert, Jean-Charles; Grenier-Boley, Benjamin; Chouraki, Vincent; Fievet, Nathalie; Amouyel, Philippe] INSERM, U744, F-59045 Lille, France. [Bellenguez, Celine; Lambert, Jean-Charles; Grenier-Boley, Benjamin; Chouraki, Vincent; Pasquier, Florence; Deramecourt, Vincent; Amouyel, Philippe] Univ Lille 2, Lille, France. [Bellenguez, Celine; Lambert, Jean-Charles; Grenier-Boley, Benjamin; Chouraki, Vincent; Fievet, Nathalie; Amouyel, Philippe] Inst Pasteur, F-59019 Lille, France. [Wang, Li-San; Lin, Chiao-Feng; Valladares, Otto; Cantwell, Laura B.; Schellenberg, Gerard D.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Choi, Seung-Hoan; DeStefano, Anita L.; Jun, Gyungah; Lunetta, Kathryn L.; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ibrahim-Verbaas, Carla A.] Erasmus MC Univ Med Ctr, Dept Epidemiol & Neurol, Rotterdam, Netherlands. [Naj, Adam C.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Naj, Adam C.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Jun, Gyungah; Vardarajan, Badri N.; Baldwin, Clinton; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Jun, Gyungah; Lathrop, Mark; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Bis, Joshua C.; Fitzpatrick, Annette L.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Beecham, Gary W.; Kunkle, Brian; Perry, William; Hamilton-Nelson, Kara L.; Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Beecham, Gary W.; Perry, William; Pericak-Vance, Margaret A.] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA. [Russo, Giancarlo] ETH Univ Zurich, Funct Genom Ctr Zurich, Zurich, Switzerland. [Thornton-Wells, Tricia A.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Smith, Albert V.; Gudnason, Vilmundur; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Smith, Albert V.; Gudnason, Vilmundur; Eiriksdottir, Gudny] Iceland Heart Assoc, Kopavogur, Iceland. [Chouraki, Vincent; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Ikram, M. Arfan; Hofman, Albert] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan; Hofman, Albert] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Ikram, M. Arfan; Hofman, Albert] Erasmus MC Univ Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Ikram, M. Arfan; Hofman, Albert; van Duijn, Cornelia M.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Zelenika, Diana; Bihoreau, Marie-Therese] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France. [Kamatani, Yoichiro; Lathrop, Mark] Fdn Jean Dausset CEPH, Paris, France. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [Zelenika, Diana; United Kingdom Brain Expression] UCL Inst Neurol, Dept Mol Neurosci, Reta Lila Weston Res Labs, London, England. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA USA. [Ruiz, Agustin; Hernandez, Isabel; Boada, Merce] Fundacio ACE, Memory Clin, Inst Catala Neurociencies Aplicades, Barcelona, Spain. [Vardarajan, Badri N.; Reitz, Christiane; Mayeux, Richard] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Vardarajan, Badri N.; Reitz, Christiane; Mayeux, Richard] Columbia Univ, Dept Neurol, Gertrude H Sergievsky Ctr, New York, NY USA. [Pasquier, Florence; Deramecourt, Vincent; Amouyel, Philippe] CHRU Lille, CNR MAJ, F-59037 Lille, France. [Hanon, Olivier] Univ Paris 05, Sorbonne Paris 5, Broca Hosp, Dept Geriatr, Paris, France. [Fitzpatrick, Annette L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Fitzpatrick, Annette L.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genet, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genom Sci, New York, NY USA. [Campion, Dominique; Wallon, David; Hannequin, Didier] Rouen Univ Hosp, CNR MAJ, INSERM, U1079, F-76031 Rouen, France. [Crane, Paul K.; Larson, Eric B.] Univ Washington, Dept Med, Seattle, WA USA. [Becker, Tim] Univ Bonn, German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Becker, Tim] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany. [Cruchaga, Carlos; Goate, Alison M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Cruchaga, Carlos; Goate, Alison M.] Washington Univ, Sch Med, Hope Ctr Program Prot Aggregat & Neurodegenerat, St Louis, MO USA. [Craig, David; Johnston, Janet A.; McGuinness, Bernadette; Todd, Stephen; Passmore, Peter] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Publ Hlth, Ageing Grp, Belfast, Antrim, North Ireland. [Amin, Najaf; van Duijn, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Berr, Claudine; Ritchie, Karen] Hop Colombiere, Fac Med, INSERM, U1061, Montpellier, France. [Lopez, Oscar L.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol & Psychiat, Inst Neurosci, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA USA. [De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Boston, MA USA. [Evans, Denis] Rush Univ, Med Ctr, Dept Internal Med, Rush Inst Hlth Aging, Chicago, IL 60612 USA. [Lovestone, Simon; Barberger-Gateau, Pascale; Proitsi, Petra; Powell, John F.] Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England. [Letenneur, Luc; Dufouil, Carole; Dartigues, Jean-Francois] Victor Segalen Univ, INSERM, U897, F-33076 Bordeaux, France. [Rubinsztein, David C.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Sleegers, Kristel; Bettens, Karolien; Van Broeckhoven, Christine] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium. [Sleegers, Kristel; Bettens, Karolien; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium. [Huentelman, Matthew J.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. [Gill, Michael] Univ Dublin Trinity Coll, Discipline Psychiat, Dublin 2, Ireland. [Brown, Kristelle; Morgan, Kevin] Univ Nottingham, Queens Med Ctr, Inst Genet, Nottingham NG7 2RD, England. [Kamboh, M. Ilyas] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Kamboh, M. Ilyas] Univ Pittsburgh, Alzheimers Dis Res Ctr, Pittsburgh, PA USA. [Keller, Lina] Karolinska Inst, Dept Neurobiol, Care Sci & Soc, Aging Reasearch Ctr, Stockholm, Sweden. [Keller, Lina; Fratiglioni, Laura] Stockholm Univ, S-10691 Stockholm, Sweden. [Larson, Eric B.] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA. [Myers, Amanda J.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Love, Seth] Univ Bristol, Inst Clin Neurosci, Sch Clin Sci, Frenchay Hosp, Bristol, Avon, England. [Rogaeva, Ekaterina; St George-Hyslop, Peter] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [Gallacher, John; Bayer, Anthony] Cardiff Univ, Neuadd Meirionnydd, Univ Wales Hosp, Inst Primary Care & Publ Hlth, Cardiff CF10 3AX, S Glam, Wales. [St George-Hyslop, Peter] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [St George-Hyslop, Peter] Univ Cambridge, Dept Clin Neurosci, Cambridge, England. [Clarimon, Jordi; Lleo, Alberto] Univ Autonoma Barcelona, St Pau Hosp, IIB St Pau, Dept Neurol, E-08193 Barcelona, Spain. [Clarimon, Jordi; Lleo, Alberto] Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Barcelona, Spain. [Tsuang, Debby W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Tsolaki, Magda] Aristotle Univ Thessaloniki, Dept Neurol 3, GR-54006 Thessaloniki, Greece. [Bossu, Paola; Spalletta, Gianfranco] Fdn Santa Lucia, Rome, Italy. [Collinge, John; Mead, Simon] UCL Inst Neurol, Dept Neurodegenerat Dis, MRC Prion Unit, London, England. [Sorbi, Sandro; Nacmias, Benedetta] Univ Florence, NEUROFARBA Dept Neurosci Psychol Drug Res & Child, Florence, Italy. [Sorbi, Sandro; Nacmias, Benedetta] Univ Florence, Ctr Ric Trasferimento & Alta Formaz DENOTHE, Florence, Italy. [Garcia, Florentino Sanchez; Deniz Naranjo, Maria Candida] Hosp Univ Dr Negrin, Dept Immunol, Las Palmas Gran Canaria, Spain. [Fox, Nick C.] UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, England. [Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. [Bosco, Paolo] IRCCS Assoc Oasi Maria SS, Troina, Italy. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, OHAP, Oxford, England. [Brayne, Carol] Univ Cambridge, Inst Publ Hlth, CFAS, Cambridge, England. [Galimberti, Daniela; Scarpini, Elio] Univ Milan, Fdn Ca Granda, IRCCS Osped Policlin, Milan, Italy. [Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele] Univ Pisa, Neurol Clin, Pisa, Italy. [Moebus, Susanne] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Mecocci, Patrizia] Univ Perugia, Dept Clin & Expt Med, Sect Gerontol & Geriatr, I-06100 Perugia, Italy. [Del Zompo, Maria] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy. [Maier, Wolfgang] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Maier, Wolfgang; Noethen, Markus M.] German Ctr Neurodegenerat Dis DZNE Bonn, Bonn, Germany. [Hampel, Harald] Goethe Univ Frankfurt, Dept Psychiat, D-60054 Frankfurt, Germany. [Hampel, Harald; Rujescu, Dan] Univ Munich, Dept Psychiat, D-80539 Munich, Germany. [Pilotto, Alberto] IRCCS Casa Sollievo Sofferenza, Gerontol & Geriatr Res Lab, San Giovanni Rotondo, Italy. [Frank-Garcia, Ana] Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid, Spain. [Frank-Garcia, Ana] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Frank-Garcia, Ana] Hosp la Paz IdIPaz, Inst Invest Sanitaria, Madrid, Spain. [Panza, Francesco; Solfrizzi, Vincenzo] Univ Bari, Ctr Aging Brain, Dept Geriatr, Bari, Italy. [Caffarra, Paolo] Univ Parma, Dept Neurosci, I-43100 Parma, Italy. [Caffarra, Paolo] Ctr Cognit Disorders AUSL, Parma, Italy. [Mayhaus, Manuel; Pichler, Sabrina] Univ Hosp, Dept Psychiat, Saarland, Germany. [Lannfelt, Lars; Ingelsson, Martin] Uppsala Univ, Dept Publ Health Geriatr, Uppsala, Sweden. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Carrasquillo, Minerva M.; Zou, Fanggeng; Younkin, Steven G.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Beekly, Duane] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA. [Alvarez, Victoria; Coto, Eliecer] Genet Mol Huca Oviedo, Oviedo, Spain. [Gu, Wei; Riemenschneider, Matthias] Univ Hosp, Dept Psychiat, Saarland, Germany. [Razquin, Cristina; Pastor, Pau] Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, E-31080 Pamplona, Spain. [Pastor, Pau] Inst Salud Carlos III, Ctr Invest Biome Red Enfermedades Neurodegenerat, CIBERNED, Madrid, Spain. [Mateo, Ignacio; Combarros, Onofre] Univ Cantabria, Marques de Valdecilla Univ Hosp, Neurol Serv, E-39005 Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] Univ Cantabria, Marques de Valdecilla Univ Hosp, CIBERNED, E-39005 Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] IFIMAV, Santander, Spain. [Faber, Kelley M.; Foroud, Tatiana M.] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. [Jonsson, Palmi V.] Landspitali Univ Hosp, Reykjavik, Iceland. [Soininen, Hilkka; Hiltunen, Mikko] Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland. [Soininen, Hilkka; Hiltunen, Mikko] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Geriatr Med, Jackson, MS 39216 USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Harris, Tamara B.; Launer, Lenore J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Fratiglioni, Laura] Karolinska Inst, Care Sci & Soc, Dept Neurobiol, Aging Res Ctr, Stockholm, Sweden. [Fratiglioni, Laura; Graff, Caroline] Karolinska Univ Hosp Huddinge, Genet Unit, Dept Geriatr Med, Stockholm, Sweden. [Holmes, Clive] Univ Southampton, Sch Med, Div Clin Neurosci, Southampton, Hants, England. [de Bruijn, Renee F. A. G.] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands. [de Bruijn, Renee F. A. G.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Brice, Alexis] Univ Paris 06, INSERM UMR S975 CNRS UMR 7225, Ctr Rech, Inst Cerveau & Moelle Epiniere CRICM,Hop Salpetri, Paris, France. [Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Paris, France. [Kukull, Walter A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Ritchie, Karen] Univ London Imperial Coll Sci Technol & Med, London, England. [Kauwe, John S. K.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77030 USA. [Boada, Merce] Univ Autonoma Barcelona VHIR UAB, Inst Recerca, Hosp Univ Vall d Hebron, Barcelona, Spain. [Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Dartigues, Jean-Francois] CHU Bordeaux, Ctr Memoire Ressources & Rech Bordeaux, Bordeaux, France. [Tzourio, Christophe] Victor Segalen Univ, INSERM, U708, Bordeaux, France. [Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Inst Human Genet, Bonn, Germany. [Graff, Caroline] Karolinska Inst, Dept Neurobiol, Care Sci & Soc, KIADRC, Stockholm, Sweden. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Haines, Jonathan L.] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN 37235 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Lathrop, Mark] McGill Univ, Montreal, PQ, Canada. [Lathrop, Mark] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Ramirez, Alfredo] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Ramirez, Alfredo] Univ Bonn, Inst Human Genet, Bonn, Germany. [Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Amouyel, Philippe] CHRU Lille, F-59037 Lille, France. RP Schellenberg, GD (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM gerardsc@mail.med.upenn.edu; philippe.amouyel@pasteur-lille.fr; WilliamsJ@cf.ac.uk RI Lambert, jean-charles/A-9553-2014; Smith, Albert/K-5150-2015; Ritchie, Karen/G-3571-2013; Caffarra, Paolo/K-6567-2016; Bonuccelli, Ubaldo/K-8681-2016; berr, Claudine/D-5238-2014; Johnson, Andrew/G-6520-2013; Tsuang, Debby/L-7234-2016; graff, caroline/A-2545-2009; Hardy, John/C-2451-2009; Pastor, Pau/C-9834-2009; Tzourio, christophe/B-4015-2009; Fox, Nick/B-1319-2009; Powell, John/G-4412-2011; lambert, jean-charles/F-8787-2013; Holmans, Peter/F-4518-2015; Frank Garcia, Ana/I-5159-2015; Gudnason, Vilmundur/K-6885-2015; Bosso, Paola/E-4832-2014; Kamatani, Yoichiro/N-5513-2015 OI Harold, Denise/0000-0001-5195-0143; Buxbaum, Joseph/0000-0001-8898-8313; Panza, Francesco/0000-0002-7220-0656; Nothen, Markus/0000-0002-8770-2464; Todd, Stephen/0000-0002-2312-9195; Clarimon, Jordi/0000-0002-6824-6942; Bayer, Antony/0000-0002-7514-248X; Gill, Michael/0000-0003-0206-5337; Escott-Price, Valentina/0000-0003-1784-5483; mancuso, michelangelo/0000-0003-2738-8562; Seshadri, Sudha/0000-0001-6135-2622; galimberti, daniela/0000-0002-9284-5953; O'Donovan, Michael/0000-0001-7073-2379; Denning, Nicola/0000-0001-8467-7382; Kukull, Walter/0000-0001-8761-9014; Cruchaga, Carlos/0000-0002-0276-2899; sorbi, sandro/0000-0002-0380-6670; Kamboh, M. Ilyas/0000-0002-3453-1438; scarpini, elio/0000-0002-6395-2119; Lambert, jean-charles/0000-0003-0829-7817; Smith, Albert/0000-0003-1942-5845; Caffarra, Paolo/0000-0003-2246-5223; Bonuccelli, Ubaldo/0000-0001-6218-6312; berr, Claudine/0000-0001-5254-7655; Tsuang, Debby/0000-0002-4716-1894; Crane, Paul/0000-0003-4278-7465; NACMIAS, Benedetta/0000-0001-9338-9040; Chouraki, Vincent/0000-0002-4698-1794; Farrer, Lindsay/0000-0001-5533-4225; Pastor, Pau/0000-0002-7493-8777; Tzourio, christophe/0000-0002-6517-2984; Fox, Nick/0000-0002-6660-657X; Powell, John/0000-0001-6124-439X; Holmans, Peter/0000-0003-0870-9412; Frank Garcia, Ana/0000-0003-3858-9116; Gudnason, Vilmundur/0000-0001-5696-0084; Bosso, Paola/0000-0002-1432-0078; FU French National Foundation; Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary; LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease); LABEX GENMED grant (Medical Genomics); IGAP; National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Genotypage; The Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise, de Securite Sanitaire des Produits de Sante; ANR; Eisai; Belgian Science Policy Office Interuniversity Attraction Poles program; Foundation Alzheimer Research (SAO-FRA); Flemish Government initiated Methusalem Excellence Program; Research Foundation Flanders (FWO); University of Antwerp Research Fund, Belgium; Health Research Council of the Academy of Finland; Kuopio University Hospital [5772708]; Nordic Centre of Excellence in Neurodegeneration; Cassa di Risparmio di Pistoia e Pescia [2012]; Cassa di Risparmio di Firenze [2012]; Stichting MS Research; Brain Net Europe; Hersenstichting Nederland Breinbrekend Werk; International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek; Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona; ADNI; Abbott; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation; Genentech; GE Healthcare; Glaxo-SmithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co; Medpace, Inc; Merck and Co., Inc.; Novartis AG; Pfizer Inc; F. Hoffman-La Roche; Schering-Plough; Synarc, Inc.; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Dana Foundation; National Institute of Biomedical Imaging and Bioengineering; NIA [U01 AG024904, RC2 AG036535, K01 AG030514]; ADNI (National Institutes of Health) [U01 AG024904]; National Institute on Aging; The Canadian Institutes of Health Research; NIH [K01 AG030514, P30 AG010129]; Alzheimer Association (LAF) [IIRG-08-89720]; Alzheimer Association (MP-V) [IIRG-05-14147]; United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program; Wellcome Trust; Howard Hughes Medical Institute; Canadian Institute of Health; LABEX; CNG; EADI; Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche; [RF-2010-2319722] FX The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Genotypage, and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Genotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Sante et de la Recherche Medicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise, de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM << Cohortes et collections de donnees biologiques >> programme. Lille Genopole received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation.; The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 27 Z9 28 U1 3 U2 36 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2014 VL 9 IS 6 AR e94661 DI 10.1371/journal.pone.0094661 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8TP UT WOS:000338701300002 PM 24922517 ER PT J AU Liu, J Lee, GY Lawitts, JA Toner, M Biggers, JD AF Liu, Jie Lee, Gloria Y. Lawitts, Joel A. Toner, Mehmet Biggers, John D. TI Live Pups from Evaporatively Dried Mouse Sperm Stored at Ambient Temperature for up to 2 Years SO PLOS ONE LA English DT Article ID ZYGOTIC TRANSITION; SPERMATOZOA; INJECTION; OOCYTES; STORAGE; MICE AB The purpose of this study is to develop a mouse sperm preservation method based on evaporative drying. Mouse sperm were evaporatively dried and stored at 4 degrees C and ambient temperature for 3 months to 2 years. Upon rehydration, a single sperm was injected into a mature oocyte to develop into a blastocyst after culture or a live birth after embryo transfer to a recipient female. For the samples stored at 4 degrees C for 3, 6, 12, 18, and 24 months, the blastocyst formation rate was 61.5%, 49.1%, 31.5%, 32.2%, and 41.4%, respectively. The blastocyst rate for those stored at ambient temperature (similar to 22 degrees C) for 3, 6, 12, and 18 months was 57.8%, 36.2%, 33.6%, and 34.4%, respectively. Fifteen, eight and three live pups were produced from sperm stored at room temperature for 12, 18, and 24 months, respectively. This is the first report of live offspring produced from dried mouse sperm stored at ambient temperature for up to 2 years. Based on these results, we suggest that evaporative drying is a potentially useful method for the routine preservation of mouse sperm. C1 [Liu, Jie; Lee, Gloria Y.; Toner, Mehmet; Biggers, John D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. [Liu, Jie; Lee, Gloria Y.; Toner, Mehmet; Biggers, John D.] Shriners Hosp Children, Boston, MA USA. [Lawitts, Joel A.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Biggers, John D.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Liu, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. EM jliu22@mgh.harvard.edu FU National Institutes of Health and the National Center for Research Resources [R24 RR018934] FX This work was supported by the National Institutes of Health and the National Center for Research Resources (grant number R24 RR018934). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 2 Z9 2 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2014 VL 9 IS 6 AR e99809 DI 10.1371/journal.pone.0099809 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8TP UT WOS:000338701300095 PM 24924588 ER PT J AU Zhou, YX Yu, F Duong, T AF Zhou, Yongxia Yu, Fang Duong, Timothy TI Multiparametric MRI Characterization and Prediction in Autism Spectrum Disorder Using Graph Theory and Machine Learning SO PLOS ONE LA English DT Article ID INFERIOR FRONTAL GYRUS; FUNCTIONAL CONNECTIVITY; CORTICAL THICKNESS; FEATURE-SELECTION; BRAIN; CHILDREN; CORTEX; AGE; FLUCTUATIONS; PERFORMANCE AB This study employed graph theory and machine learning analysis of multiparametric MRI data to improve characterization and prediction in autism spectrum disorders (ASD). Data from 127 children with ASD (13.5 +/- 6.0 years) and 153 age- and gender-matched typically developing children (14.5 +/- 5.7 years) were selected from the multi-center Functional Connectome Project. Regional gray matter volume and cortical thickness increased, whereas white matter volume decreased in ASD compared to controls. Small-world network analysis of quantitative MRI data demonstrated decreased global efficiency based on gray matter cortical thickness but not with functional connectivity MRI (fcMRI) or volumetry. An integrative model of 22 quantitative imaging features was used for classification and prediction of phenotypic features that included the autism diagnostic observation schedule, the revised autism diagnostic interview, and intelligence quotient scores. Among the 22 imaging features, four (caudate volume, caudate-cortical functional connectivity and inferior frontal gyrus functional connectivity) were found to be highly informative, markedly improving classification and prediction accuracy when compared with the single imaging features. This approach could potentially serve as a biomarker in prognosis, diagnosis, and monitoring disease progression. C1 [Zhou, Yongxia] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Yu, Fang; Duong, Timothy] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, South Texas Vet Hlth Care Syst, Dept Vet Affairs,Dept Ophthalmol, San Antonio, TX 78229 USA. RP Duong, T (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, South Texas Vet Hlth Care Syst, Dept Vet Affairs,Dept Ophthalmol, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu OI Zhou, Yongxia (Sharon)/0000-0002-4931-2318 FU NINDS NIH HHS [R01 NS039135] NR 56 TC 13 Z9 13 U1 4 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2014 VL 9 IS 6 AR e90405 DI 10.1371/journal.pone.0090405 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8TP UT WOS:000338701300001 PM 24922325 ER PT J AU Chirinos, JA Gurubhagavatula, I Teff, K Rader, DJ Wadden, TA Townsend, R Foster, GD Maislin, G Saif, H Broderick, P Chittams, J Hanlon, AL Pack, AI AF Chirinos, Julio A. Gurubhagavatula, Indira Teff, Karen Rader, Daniel J. Wadden, Thomas A. Townsend, Raymond Foster, Gary D. Maislin, Greg Saif, Hassam Broderick, Preston Chittams, Jesse Hanlon, Alexandra L. Pack, Allan I. TI CPAP, Weight Loss, or Both for Obstructive Sleep Apnea SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSITIVE AIRWAY PRESSURE; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; HYPERTENSIVE PATIENTS; INSULIN SENSITIVITY; METABOLIC SYNDROME; LOW-CARBOHYDRATE; BLOOD-PRESSURE; SEVERE OBESITY; RISK-FACTORS AB BACKGROUND Obesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear. METHODS We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure. RESULTS Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone. CONCLUSIONS In adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone. C1 [Chirinos, Julio A.; Gurubhagavatula, Indira] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Chirinos, Julio A.; Gurubhagavatula, Indira; Rader, Daniel J.; Wadden, Thomas A.; Townsend, Raymond; Maislin, Greg; Saif, Hassam; Broderick, Preston; Pack, Allan I.] Univ Penn, Perelman Sch Med, Hosp Univ Penn, Philadelphia, PA 19104 USA. [Teff, Karen] Monell Chem Senses Ctr, Philadelphia, PA USA. [Foster, Gary D.] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Chittams, Jesse; Hanlon, Alexandra L.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. RP Chirinos, JA (reprint author), Univ Penn, Div Cardiol, Rm 8B111,Univ & Woodland Aves, Philadelphia, PA 19104 USA. EM julio.chirinos@uphs.upenn.edu FU National Heart, Lung, and Blood Institute [HL-R01080076, P01 HL094307]; Novo Nordisk; Nutrisystem; Orexigen; Boehringer Ingelheim; Weight Watchers; ConAgra Foods; Tate and Lyle; UnitedHealth Group FX Supported by grants from the National Heart, Lung, and Blood Institute (HL-R01080076, to Dr. Chirinos; and P01 HL094307, to Dr. Pack).; Dr. Wadden reports receiving fees for serving on advisory boards for Novo Nordisk, Nutrisystem, and Orexigen, consulting fees from Boehringer Ingelheim, and grant support from Weight Watchers, Novo Nordisk, and Nutrisystem. Dr. Foster reports receiving fees for serving on advisory boards for ConAgra Foods, Tate and Lyle, and UnitedHealth Group and reports being an employee of Weight Watchers. No other potential conflict of interest relevant to this article was reported. NR 42 TC 91 Z9 91 U1 3 U2 24 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 12 PY 2014 VL 370 IS 24 BP 2265 EP 2275 DI 10.1056/NEJMoa1306187 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AI7BB UT WOS:000337033700006 PM 24918371 ER PT J AU Burgin, S Stone, JH Shenoy-Bhangle, AS McGuone, D AF Burgin, Susan Stone, John H. Shenoy-Bhangle, Anuradha S. McGuone, Declan TI Case 18-2014: A 32-Year-Old Man with a Rash, Myalgia, and Weakness Dermatomyositis. Malignant atrophic papulosis (Degos's disease), involving the skin and gastrointestinal tract. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMPLEMENT C1 [Burgin, Susan] Beth Israel Deaconess Med Ctr, Dept Dermatol, Boston, MA 02215 USA. [Stone, John H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Shenoy-Bhangle, Anuradha S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [McGuone, Declan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Burgin, Susan] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Stone, John H.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shenoy-Bhangle, Anuradha S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [McGuone, Declan] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Burgin, S (reprint author), Beth Israel Deaconess Med Ctr, Dept Dermatol, Boston, MA 02215 USA. NR 18 TC 6 Z9 6 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 12 PY 2014 VL 370 IS 24 BP 2327 EP 2337 DI 10.1056/NEJMcpc1304161 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AI7BB UT WOS:000337033700013 PM 24918376 ER PT J AU Gonzalez-Castillo, J Handwerker, DA Robinson, ME Hoy, CW Buchanan, LC Saad, ZS Bandettini, PA AF Gonzalez-Castillo, Javier Handwerker, Daniel A. Robinson, Meghan E. Hoy, Colin Weir Buchanan, Laura C. Saad, Ziad S. Bandettini, Peter A. TI The spatial structure of resting state connectivity stability on the scale of minutes SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE fMRI; connectivity dynamics; stability; rest; sliding window analysis ID SPONTANEOUS BRAIN ACTIVITY; DEFAULT MODE NETWORK; INTRINSIC FUNCTIONAL CONNECTIVITY; FMRI CONNECTIVITY; CORPUS-CALLOSUM; MRI; ARCHITECTURE; CORTEX; ORGANIZATION; CONNECTOME AB Resting state functional M RI (rsfMRI) connectivity patterns are not temporally stable, but fluctuate in time at scales shorter than most common rest scan durations (5-10 min). Consequently, connectivity patterns for two different portions of the same scan can differ drastically. To better characterize this temporal variability and understand how it is spatially distributed across the brain, we scanned subjects continuously for 60 min, at a temporal resolution of 1 s, while they rested inside the scanner. We then computed connectivity matrices between functionally-defined regions of interest for non-overlapping 1 min windows, and classified connections according to their strength, polarity, and variability. We found that the most stable connections correspond primarily to inter-hemispheric connections between left/right homologous ROls. However, only 32% of all within-network connections were classified as most stable. This shows that resting state networks have some long-term stability, but confirms the flexible configuration of these networks, particularly those related to higher order cognitive functions. The most variable connections correspond primarily to inter-hemispheric, across-network connections between non-homologous regions in occipital and frontal cortex. Finally we found a series of connections with negative average correlation, but further analyses revealed that such average negative correlations may be related to the removal of CSF signals during pre-processing. Using the same dataset, we also evaluated how similarity of within-subject whole-brain connectivity matrices changes as a function of window duration (used here as a proxy for scan duration). Our results suggest scanning for a minimum of 10 min to optimize within-subject reproducibility of connectivity patterns across the entire brain, rather than a few predefined networks. C1 [Gonzalez-Castillo, Javier; Handwerker, Daniel A.; Robinson, Meghan E.; Hoy, Colin Weir; Buchanan, Laura C.; Bandettini, Peter A.] NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. [Robinson, Meghan E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorder TRACTS, Boston, MA USA. [Saad, Ziad S.] NIMH, Sci & Stat Comput Core, NIH, Bethesda, MD 20892 USA. RP Gonzalez-Castillo, J (reprint author), NIMH, Sect Funct Imaging Methods, NIH, Building 10,Room 1D80,10 Ctr Dr, Bethesda, MD 20892 USA. EM javier.gonzalez-castillo@nih.gov OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU NIMHIRP FX This research was possible thanks to the support of the NIMHIRP. Portions of this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf. nih.gov). Also, we would like to acknowledge Dr. Gang Chen from the Statistical and Scientific Computing Core for his valuable input. NR 57 TC 21 Z9 21 U1 0 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JUN 11 PY 2014 VL 8 AR 138 DI 10.3389/fnins.2014.00138 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AW8CM UT WOS:000346488200001 PM 24999315 ER PT J AU Leng, J Ho, HP Buzon, MJ Pereyra, F Walker, BD Yu, XG Chang, EJ Lichterfeld, M AF Leng, Jin Ho, Hsin-Pin Buzon, Maria J. Pereyra, Florencia Walker, Bruce D. Yu, Xu G. Chang, Emmanuel J. Lichterfeld, Mathias TI A Cell-Intrinsic Inhibitor of HIV-1 Reverse Transcription in CD4(+) T Cells from Elite Controllers SO CELL HOST & MICROBE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PHOSPHORYLATION; REPLICATION; INFECTION; RESTRICTION; KINASE; TAT; MACROPHAGES; EXPRESSION; BINDING AB HIV-1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication, but cell-intrinsic mechanisms that can block HIV-1 reverse transcription in a clinically significant way are poorly defined. We find that effective HIV-1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin-dependent kinase (CDK) 2 at a highly conserved Threonine residue. CDK2-dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness. Interestingly, p21, a cell-intrinsic CDK inhibitor that is upregulated in CD4(+) T cells from "elite controllers,'' potently inhibited CDK2-dependent phosphorylation of HIV-1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription. These data suggest that p21 can indirectly block HIV-1 reverse transcription by inhibiting host cofactors supporting HIV-1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV-1 replication. C1 [Leng, Jin; Buzon, Maria J.; Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Leng, Jin; Buzon, Maria J.; Pereyra, Florencia; Walker, Bruce D.; Yu, Xu G.; Lichterfeld, Mathias] MGH MIT & Harvard, Ragon Inst, Cambridge, MA 02139 USA. [Ho, Hsin-Pin; Chang, Emmanuel J.] CUNY York Coll, Dept Chem, New York, NY 11451 USA. [Ho, Hsin-Pin; Chang, Emmanuel J.] CUNY, Grad Ctr, New York, NY 11451 USA. [Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Lichterfeld, M (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM mlichterfeld@harvard.mgh.edu RI Buzon, Maria J/G-8286-2015 OI Buzon, Maria J/0000-0003-4427-9413 FU National Institutes of Health [AI093203, AI098487, AI089339, AI078799, AI098484, SC2GM086343]; Doris Duke Charitable Foundation [2009034]; American Foundation for AIDS Research [108302-51-RGRL] FX M. L. is supported by the National Institutes of Health (AI093203 and AI098487), Clinical Scientist Development Award from the Doris Duke Charitable Foundation (grant 2009034), and American Foundation for AIDS Research (grant 108302-51-RGRL). X.G.Y. (AI089339, AI078799, and AI098484) and E.J.C. (SC2GM086343) are supported by the National Institutes of Health. The authors would like to acknowledge Pratikkumar Rathod, Abbas Nazir, and Shantelle Walker for technical assistance and Xiu Sheng Liang for graphic design. Sample collection from elite controllers was supported by the Bill and Melinda Gates Foundation, Mark and Lisa Schwartz Foundation, Ragon Institute of MGH, MIT, and Harvard, and International HIV Controller Consortium. NR 39 TC 9 Z9 9 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 11 PY 2014 VL 15 IS 6 BP 717 EP 728 DI 10.1016/j.chom.2014.05.011 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AM6BA UT WOS:000339944300010 PM 24922574 ER PT J AU Estrada, K Aukrust, I Bjorkhaug, L Burtt, NP Mercader, JM Garcia-Ortiz, H Huerta-Chagoya, A Moreno-Macias, H Walford, G Flannick, J Williams, AL Gomez-Vazquez, MJ Fernandez-Lopez, JC Martinez-Hernandez, A Centeno-Cruz, F Mendoza-Caamal, E Revilla-Monsalve, C Islas-Andrade, S Cordova, EJ Soberon, X Gonzalez-Villalpando, ME Henderson, E Wilkens, LR Le Marchand, L Arellano-Campos, O Ordonez-Sanchez, ML Rodriguez-Torres, M Rodriguez-Guillen, R Riba, L Najmi, LA Jacobs, SBR Fennell, T Gabriel, S Fontanillas, P Hanis, CL Lehman, DM Jenkinson, CP Abboud, HE Bell, GI Cortes, ML Boehnke, M Gonzalez-Villalpando, C Orozco, L Haiman, CA Tusie-Luna, T Aguilar-Salinas, CA Altshuler, D Njolstad, PR Florez, JC MacArthur, DG AF Estrada, Karol Aukrust, Ingvild Bjorkhaug, Lise Burtt, Noel P. Mercader, Josep M. Garcia-Ortiz, Humberto Huerta-Chagoya, Alicia Moreno-Macias, Hortensia Walford, Geoffrey Flannick, Jason Williams, Amy L. Gomez-Vazquez, Maria J. Fernandez-Lopez, Juan C. Martinez-Hernandez, Angelica Centeno-Cruz, Federico Mendoza-Caamal, Elvia Revilla-Monsalve, Cristina Islas-Andrade, Sergio Cordova, Emilio J. Soberon, Xavier Gonzalez-Villalpando, Maria E. Henderson, E. Wilkens, Lynne R. Le Marchand, Loic Arellano-Campos, Olimpia Ordonez-Sanchez, Maria L. Rodriguez-Torres, Maribel Rodriguez-Guillen, Rosario Riba, Laura Najmi, Laeya A. Jacobs, Suzanne B. R. Fennell, Timothy Gabriel, Stacey Fontanillas, Pierre Hanis, Craig L. Lehman, Donna M. Jenkinson, Christopher P. Abboud, Hanna E. Bell, Graeme I. Cortes, Maria L. Boehnke, Michael Gonzalez-Villalpando, Clicerio Orozco, Lorena Haiman, Christopher A. Tusie-Luna, Teresa Aguilar-Salinas, Carlos A. Altshuler, David Njolstad, Pal R. Florez, Jose C. MacArthur, Daniel G. CA SIGMA Type 2 Diabet Consortium TI Association of a Low-Frequency Variant in HNF1A With Type 2 Diabetes in a Latino Population SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; MEXICAN-AMERICANS; YOUNG MODY; RARE VARIANTS; ONSET; MUTATIONS; MELLITUS; PREVALENCE; COMMON; HNF-1-ALPHA AB IMPORTANCE Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14 276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% Cl, 2.83-10.61; P = 4.4 x 10(-7)) in hepatocyte nuclear factor 1-a (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% Cl, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required. C1 [Estrada, Karol; Burtt, Noel P.; Mercader, Josep M.; Flannick, Jason; Williams, Amy L.; Jacobs, Suzanne B. R.; Fontanillas, Pierre; Altshuler, David; Florez, Jose C.; MacArthur, Daniel G.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Estrada, Karol] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Estrada, Karol; Walford, Geoffrey; Altshuler, David; Florez, Jose C.; MacArthur, Daniel G.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Aukrust, Ingvild; Bjorkhaug, Lise; Najmi, Laeya A.; Njolstad, Pal R.] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway. [Bjorkhaug, Lise; Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Aukrust, Ingvild] Univ Bergen, Dept Biomed, Bergen, Norway. [Mercader, Josep M.; Walford, Geoffrey; Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Mercader, Josep M.; Walford, Geoffrey; Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Mercader, Josep M.] Barcelona Supercomp Ctr, Joint BSC CRG IRB Res Program Computat Biol, Barcelona, Spain. [Garcia-Ortiz, Humberto; Fernandez-Lopez, Juan C.; Martinez-Hernandez, Angelica; Centeno-Cruz, Federico; Mendoza-Caamal, Elvia; Cordova, Emilio J.; Soberon, Xavier; Orozco, Lorena] Inst Nacl Med Genom, Mexico City, DF, Mexico. [Huerta-Chagoya, Alicia; Riba, Laura; Tusie-Luna, Teresa] UNAM INCMNSZ, UNAM Unidad Biol Mol & Med Genom, Inst Invest Biomed, Mexico City, DF, Mexico. [Moreno-Macias, Hortensia] Univ Autonoma Metropolitana, Mexico City, DF, Mexico. [Gonzalez-Villalpando, Maria E.; Gonzalez-Villalpando, Clicerio] Inst Nacl Salud Publ, Ctr Estudios Diabet, Unidad Invest Diabet & Riesgo Cardiovasc, Ctr Invest Salud Poblac, Mexico City, DF, Mexico. [Flannick, Jason; Altshuler, David] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA. [Williams, Amy L.] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Henderson, E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Gomez-Vazquez, Maria J.; Arellano-Campos, Olimpia; Ordonez-Sanchez, Maria L.; Rodriguez-Torres, Maribel; Rodriguez-Guillen, Rosario; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos A.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Secc 16, Mexico City, DF, Mexico. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Altshuler, David] MIT, Dept Biol, Cambridge, MA 02139 USA. [Revilla-Monsalve, Cristina; Islas-Andrade, Sergio] Inst Mexicano Seguro Social, CMN SXXI, Unidad Invest Med Enfermedades Metab, Mexico City, DF, Mexico. [Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Najmi, Laeya A.] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Fennell, Timothy; Gabriel, Stacey; Cortes, Maria L.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Hanis, Craig L.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Lehman, Donna M.; Jenkinson, Christopher P.; Abboud, Hanna E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Bell, Graeme I.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Bell, Graeme I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Diabet Unit, Boston, MA 02114 USA. EM jcflorez@partners.org RI Fernandez, Juan Carlos/C-4976-2013; OI Fernandez, Juan Carlos/0000-0003-3680-4193; Mercader, Josep M/0000-0001-8494-3660; Gundersen, Lise Bjorkhaug/0000-0002-9695-4559 FU Carlos Slim Health Institute in Mexico; Consejo Nacional de Ciencia y Tecnologia [138826, 128877, CONACT-SALUD 2009-01-115250, 86867]; Direccion General de Asuntos del Personal Academic, UNAM [IT 214711]; Instituto Carlos Slim de la Salud, A.C.; National Institutes of Health (NIH) [R01HL24799]; Consejo Nacional de Ciencia y Tenologia [2092, M9303, F677-M9407, 251M, 2005-C01-14502, SALUD 2010-2-151165]; NIH [CA164973, CA054281, CA063464, R01 CA55069, R35 CA53890, R01 CA80205, R01 CA144034, U01DK085526, U01DK085501]; National Medical Research Council of Singapore; Veterans Administration Epidemiologic grant; University of Bergen; Research Council of Norway; KG Jebsen Foundation; Helse Vest; European Research Council; Instituto Carlos III, Spain; Netherlands Organization for Scientific Research [825.12.023]; [R01 DK042273]; [R01 DK047482]; [R01DK053889]; [R01 DK057295]; [P01 HL045522] FX The work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Health Institute in Mexico. The UNAM/INCMNSZ Diabetes Study was supported by Consejo Nacional de Ciencia y Tecnologia grants 138826, 128877, CONACT-SALUD 2009-01-115250, and a grant from Direccion General de Asuntos del Personal Academic, UNAM, IT 214711. The Diabetes in Mexico Study was supported by Consejo Nacional de Ciencia y Tecnologia grant 86867 and by Instituto Carlos Slim de la Salud, A.C. The Mexico City Diabetes Study was supported by National Institutes of Health (NIH) grant R01HL24799 and by the Consejo Nacional de Ciencia y Tenologia grants 2092, M9303, F677-M9407, 251M, and 2005-C01-14502, SALUD 2010-2-151165. The Multiethnic Cohort was supported by NIH grants CA164973, CA054281, and CA063464. The Singapore Chinese Health Study was funded by the National Medical Research Council of Singapore under its individual research grant scheme and by NIH grants R01 CA55069, R35 CA53890, R01 CA80205, and R01 CA144034. The Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) project was supported by NIH grants U01DK085526 and U01DK085501. The San Antonio Mexican American Family Studies (SAMAFS) were supported by R01 DK042273, R01 DK047482, R01DK053889, R01 DK057295, P01 HL045522, and a Veterans Administration Epidemiologic grant (R.A.D). The University of Bergen, Research Council of Norway, KG Jebsen Foundation, Helse Vest, and European Research Council funded the Norwegian team. Dr Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III, Spain. Dr Estrada was supported by The Netherlands Organization for Scientific Research under the Rubicon fellowship 825.12.023. NR 51 TC 38 Z9 38 U1 2 U2 16 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 11 PY 2014 VL 311 IS 22 BP 2305 EP 2314 DI 10.1001/jama.2014.6511 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AI6HL UT WOS:000336972600022 ER PT J AU Hiddingh, L Raktoe, RS Jeuken, J Hulleman, E Noske, DP Kaspers, GJL Vandertop, WP Wesseling, P Wurdinger, T AF Hiddingh, Lotte Raktoe, Rajiv S. Jeuken, Judith Hulleman, Esther Noske, David P. Kaspers, Gertjan J. L. Vandertop, W. Peter Wesseling, Pieter Wurdinger, Thomas TI Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis SO SCIENTIFIC REPORTS LA English DT Article ID O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; LYMPHOBLASTIC-LEUKEMIA; ADJUVANT TEMOZOLOMIDE; EXPRESSION DATA; PHF6 MUTATIONS; MSH6 MUTATIONS; GLIOMA-CELLS; GENE; APOPTOSIS; MICRORNA AB Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma. C1 [Hiddingh, Lotte; Noske, David P.; Vandertop, W. Peter; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Dept Neurosurg, Amsterdam, Netherlands. [Hiddingh, Lotte; Hulleman, Esther; Kaspers, Gertjan J. L.] Vrije Univ Amsterdam Med Ctr, Dept Pediat Oncol, Amsterdam, Netherlands. [Wesseling, Pieter] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Hiddingh, Lotte; Raktoe, Rajiv S.; Hulleman, Esther; Noske, David P.; Wesseling, Pieter; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp, Amsterdam, Netherlands. [Jeuken, Judith] PAMM, Dept Pathol, Eindhoven, Netherlands. [Wesseling, Pieter] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands. [Wurdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wurdinger, Thomas] Harvard Univ, Sch Med, Boston, MA USA. RP Wurdinger, T (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Neurosurg, Amsterdam, Netherlands. EM t.wurdinger@vumc.nl RI Wesseling, P./H-8114-2014 OI Wesseling, P./0000-0001-5453-5201 FU Stichting STOPhersentumoren.nl; KiKa; NWO FX This work was funded by Stichting STOPhersentumoren.nl (TW, JJ), KiKa (TW), and NWO (TW). NR 53 TC 9 Z9 10 U1 0 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 11 PY 2014 VL 4 AR 5260 DI 10.1038/srep05260 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI6XC UT WOS:000337019300013 PM 24919120 ER PT J AU Paganoni, S Quinn, C Salajegheh, MK AF Paganoni, Sabrina Quinn, Colin Salajegheh, Mohammad Kian TI Clinical Reasoning: A 20-year-old woman with rapidly progressive weakness SO NEUROLOGY LA English DT Editorial Material ID ACUTE INTERMITTENT PORPHYRIA C1 [Paganoni, Sabrina] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. [Quinn, Colin] Univ Massachusetts, Dept Neurol, Boston, MA 02125 USA. [Salajegheh, Mohammad Kian] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Salajegheh, MK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. EM msalajegheh@partners.org FU NIAMS NIH HHS [R03AR063297]; NICHD NIH HHS [K12 HD001097, 2K12HD001097-16] NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 10 PY 2014 VL 82 IS 23 BP E200 EP E204 DI 10.1212/WNL.0000000000000499 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA AQ5CA UT WOS:000342819500001 PM 24960830 ER PT J AU Drye, LT Spragg, D Devanand, DP Frangakis, C Marano, C Meinert, CL Mintzer, JE Munro, CA Pelton, G Pollock, BG Porsteinsson, AP Rabins, PV Rosenberg, PB Schneider, LS Shade, DM Weintraub, D Yesavage, J Lyketsos, CG AF Drye, Lea T. Spragg, David Devanand, D. P. Frangakis, Constantine Marano, Christopher Meinert, Curtis L. Mintzer, Jacobo E. Munro, Cynthia A. Pelton, Gregory Pollock, Bruce G. Porsteinsson, Anton P. Rabins, Peter V. Rosenberg, Paul B. Schneider, Lon S. Shade, David M. Weintraub, Daniel Yesavage, Jerome Lyketsos, Constantine G. CA CitAD Res Grp TI Changes in QTc Interval in the Citalopram for Agitation in Alzheimer's Disease (CitAD) Randomized Trial SO PLOS ONE LA English DT Article ID ANTIDEPRESSANT USE; HEALTHY-SUBJECTS; CLINICAL-TRIAL; MORTALITY; POPULATION; AGE; DISPERSION; PEOPLE; GENDER; IMPACT AB Background: A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group. Methods: CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1:1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began. Results: Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase >= 30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death. Conclusion: Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation. C1 [Drye, Lea T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Drye, Lea T.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Clin Trials, Baltimore, MD USA. [Spragg, David] Johns Hopkins Univ Hosp, Electrophysiol Lab, Baltimore, MD 21287 USA. [Spragg, David; Rosenberg, Paul B.] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. [Devanand, D. P.] Columbia Univ, Coll Phys & Surg, Div Geriatr Psychiat, New York, NY USA. [Frangakis, Constantine] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Marano, Christopher] Johns Hopkins Univ, Sch Med, Div Geriatr Psychiat & Neuropsychiat, Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. [Meinert, Curtis L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Meinert, Curtis L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Mintzer, Jacobo E.] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Clin Biotechnol Res Inst, Roper St Francis Healthcare,Dept Hlth Studies, Charleston, SC 29425 USA. [Munro, Cynthia A.] Johns Hopkins Bayview & Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Munro, Cynthia A.] Johns Hopkins Bayview & Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. [Pelton, Gregory] Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, Div Geriatr Psychiat, New York, NY USA. [Pollock, Bruce G.] Univ Toronto, Campbell Family Mental Hlth Res Inst, Div Geriatr Psychiat, Toronto, ON, Canada. [Pollock, Bruce G.] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Porsteinsson, Anton P.] Univ Rochester, Sch Med & Dent, Alzheimers Dis Care Res & Educ Program AD CARE, Rochester, NY USA. [Rabins, Peter V.; Rosenberg, Paul B.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Rabins, Peter V.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [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 Gerontol, Los Angeles, CA 90033 USA. [Shade, David M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Pulm Med, Baltimore, MD USA. [Shade, David M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Shade, David M.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Clin Trials, Baltimore, MD USA. [Weintraub, Daniel] Univ Penn, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Mental Illness Res Educ & Clin Ctr,Dept Psychiat, Perelman Sch Med,Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Mental Illness Res Educ & Clin Ctr,Dept Neurol, Perelman Sch Med,Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Yesavage, Jerome] Stanford Univ, Mental Illness Res Educ & Clin Ctr, Vet Affairs Palo Alto Hlth Care Syst, Aging Clin Res Ctr,Dept Psychiat,Sch Med, Palo Alto, CA 94304 USA. [Yesavage, Jerome] Stanford Univ, Sch Med, Dept Behav Sci, Palo Alto, CA 94304 USA. [Lyketsos, Constantine G.] Johns Hopkins Bayview & Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Memory & Alzheimers Treatment Ctr, Baltimore, MD USA. RP Drye, LT (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM ldrye@jhsph.edu FU National Institute on Aging; National Institute of Mental Health [R01AG031348] FX Grant funding: National Institute on Aging and National Institute of Mental Health, R01AG031348. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 12 Z9 12 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 10 PY 2014 VL 9 IS 6 AR e98426 DI 10.1371/journal.pone.0098426 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9SD UT WOS:000340947700020 PM 24914549 ER PT J AU Goodson, JM Kantarci, A Hartman, ML Denis, GV Stephens, D Hasturk, H Yaskell, T Vargas, J Wang, XS Cugini, M Barake, R Alsmadi, O Al-Mutawa, S Ariga, J Soparkar, P Behbehani, J Behbehani, K Welty, F AF Goodson, J. Max Kantarci, Alpdogan Hartman, Mor-Li Denis, Gerald V. Stephens, Danielle Hasturk, Hatice Yaskell, Tina Vargas, Jorel Wang, Xiaoshan Cugini, Maryann Barake, Roula Alsmadi, Osama Al-Mutawa, Sabiha Ariga, Jitendra Soparkar, Pramod Behbehani, Jawad Behbehani, Kazem Welty, Francine TI Metabolic Disease Risk in Children by Salivary Biomarker Analysis SO PLOS ONE LA English DT Article ID REACTIVE PROTEIN-LEVELS; PLASMA-INSULIN; CHRONIC PERIODONTITIS; NONDIABETIC SUBJECTS; DIABETIC-PATIENTS; WHOLE SALIVA; INFLAMMATION; OBESITY; GLUCOSE; ADOLESCENTS AB Objective: The study of obesity-related metabolic syndrome or Type 2 diabetes (T2D) in children is particularly difficult because of fear of needles. We tested a non-invasive approach to study inflammatory parameters in an at-risk population of children to provide proof-of-principle for future investigations of vulnerable subjects. Design and Methods: We evaluated metabolic differences in 744, 11-year old children selected from underweight, normal healthy weight, overweight and obese categories by analyzing fasting saliva samples for 20 biomarkers. Saliva supernatants were obtained following centrifugation and used for analyses. Results: Salivary C-reactive protein (CRP) was 6 times higher, salivary insulin and leptin were 3 times higher, and adiponectin was 30% lower in obese children compared to healthy normal weight children (all P<0.0001). Categorical analysis suggested that there might be three types of obesity in children. Distinctly inflammatory characteristics appeared in 76% of obese children while in 13%, salivary insulin was high but not associated with inflammatory mediators. The remaining 11% of obese children had high insulin and reduced adiponectin. Forty percent of the non-obese children were found in groups which, based on biomarker characteristics, may be at risk for becoming obese. Conclusions: Significantly altered levels of salivary biomarkers in obese children from a high-risk population, suggest the potential for developing non-invasive screening procedures to identify T2D-vulnerable individuals and a means to test preventative strategies. C1 [Goodson, J. Max; Kantarci, Alpdogan; Hartman, Mor-Li; Stephens, Danielle; Hasturk, Hatice; Yaskell, Tina; Vargas, Jorel; Wang, Xiaoshan; Cugini, Maryann; Soparkar, Pramod] Forsyth Res Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Denis, Gerald V.] Boston Univ, Sch Med, Canc Res Ctr, Boston, MA 02118 USA. [Barake, Roula; Alsmadi, Osama; Behbehani, Kazem] Dasman Diabet Inst, Kuwait, Kuwait. [Al-Mutawa, Sabiha; Ariga, Jitendra] Minist Hlth, Kuwait, Kuwait. [Behbehani, Jawad] Kuwait Univ, Fac Dent, Kuwait, Kuwait. [Welty, Francine] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. RP Goodson, JM (reprint author), Forsyth Res Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. EM mgoodson@forsyth.org OI Denis, Gerald/0000-0001-9886-0401 FU Dasman Diabetes Institute in Kuwait FX This project was funded by a grant from the Dasman Diabetes Institute in Kuwait. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 17 Z9 18 U1 0 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 10 PY 2014 VL 9 IS 6 AR e98799 DI 10.1371/journal.pone.0098799 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9SD UT WOS:000340947700033 PM 24915044 ER PT J AU Shin, B Oh, H Park, SM Han, HE Ye, M Song, WK Park, WJ AF Shin, Baehyun Oh, Hyejin Park, Sang Min Han, Hye-Eun Ye, Michael Song, Woo Keun Park, Woo Jin TI Intracellular Cleavage of Amyloid beta by a Viral Protease NIa Prevents Amyloid beta-Mediated Cytotoxicity SO PLOS ONE LA English DT Article ID NEPRILYSIN GENE-TRANSFER; APP TRANSGENIC MICE; ALZHEIMERS-DISEASE; A-BETA; PLAQUE-FORMATION; SYNAPTIC PLASTICITY; PREMATURE DEATH; MOUSE MODEL; PEPTIDE; OLIGOMERS AB Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid beta (A beta) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral A beta levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known A beta-cleaving protease, on oligomeric A beta-induced cell death were evaluated. NIa cleaved monomeric and oligomeric A beta at a similar rate, whereas NEP only cleaved monomeric A beta. Oligomeric A beta-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled A beta localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Ab and thus preventing mitochondrial deposition of A beta. C1 [Shin, Baehyun; Park, Sang Min; Han, Hye-Eun; Ye, Michael; Park, Woo Jin] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju, South Korea. [Oh, Hyejin; Song, Woo Keun] Gwangju Inst Sci & Technol, Sch Life Sci, Bio Imaging & Cell Dynam Res Ctr, Kwangju, South Korea. [Shin, Baehyun; Oh, Hyejin] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Park, WJ (reprint author), Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju, South Korea. EM woojinpark@me.com FU National Research Foundation of Korea [2009-0085747]; Global Research Laboratory Program - Korean Government (MEST) [M6-0605-00-0001]; Systems Biology Infrastructure Establishment Grant by GIST FX This work was supported by a grant from the National Research Foundation of Korea (2009-0085747) and by the Global Research Laboratory Program (M6-0605-00-0001) funded by the Korean Government (MEST) and by a grant from the Systems Biology Infrastructure Establishment Grant provided by GIST. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 2 Z9 2 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 10 PY 2014 VL 9 IS 6 AR e98650 DI 10.1371/journal.pone.0098650 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9SD UT WOS:000340947700028 PM 24915567 ER PT J AU Culley, DJ Snayd, M Baxter, MG Xie, ZC Lee, IH Rudolph, J Inouye, SK Marcantonio, ER Crosby, G AF Culley, Deborah J. Snayd, Mary Baxter, Mark G. Xie, Zhongcong Lee, In Ho Rudolph, James Inouye, Sharon K. Marcantonio, Edward R. Crosby, Gregory TI Systemic inflammation impairs attention and cognitive flexibility but not associative learning in aged rats: possible implications for delirium SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE aging neuroscience; rats; inflammation; frontal cortex; lipopolysaccharides; CCL2; set-shifting ID POSTOPERATIVE DELIRIUM; EXECUTIVE FUNCTION; PREFRONTAL CORTEX; WORKING-MEMORY; INTERLEUKIN-6; HUMANS; HIPPOCAMPUS; DYSFUNCTION; DISRUPTION; DEPRESSION AB Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 mu g/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1-3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNF alpha and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma INF alpha and CCL2 acutely but this resolved within 24-48 h. INF alpha in the frontal cortex did not change whereas CCL2 increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical INFot and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further. C1 [Culley, Deborah J.; Snayd, Mary; Crosby, Gregory] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. [Baxter, Mark G.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02115 USA. [Lee, In Ho] Kwandong Univ, Coll Med, Cheil Gen Hosp, Dept Anesthesiol, Seoul, South Korea. [Rudolph, James] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Inouye, Sharon K.; Marcantonio, Edward R.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Internal Med, Boston, MA 02115 USA. RP Culley, DJ (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol, 75 Francis St, Boston, MA 02115 USA. EM dculley@zeus.bwh.harvard.edu FU NIH [R01 GM088817] FX This study was supported by NIH R01 GM088817. NR 42 TC 9 Z9 10 U1 2 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUN 10 PY 2014 VL 6 AR 107 DI 10.3389/fnagi.2014.00107 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AM0SE UT WOS:000339556200001 PM 24959140 ER PT J AU Escudier, B Michaelson, MD Motzer, RJ Hutson, TE Clark, JI Lim, HY Porfiri, E Zalewski, P Kannourakis, G Staehler, M Tarazi, J Rosbrook, B Cisar, L Hariharan, S Kim, S Rini, BI AF Escudier, B. Michaelson, M. D. Motzer, R. J. Hutson, T. E. Clark, J. I. Lim, H. Y. Porfiri, E. Zalewski, P. Kannourakis, G. Staehler, M. Tarazi, J. Rosbrook, B. Cisar, L. Hariharan, S. Kim, S. Rini, B. I. TI Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial SO BRITISH JOURNAL OF CANCER LA English DT Article ID TARGETED THERAPY; TUMOR BURDEN; GUIDELINES; SURVIVAL; AXIS AB Background: In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines. Methods: In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs >= median), and tumour burden (baseline sum of the longest diameter < vs >= median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated. Results: Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy. Conclusions: AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC. C1 [Escudier, B.] Inst Gustave Roussy, Dept Med Oncol, F-94805 Villejuif, France. [Michaelson, M. D.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Hutson, T. E.] Baylor Sammons Texas Oncol Phys Assoc, Sammons Canc Ctr, Dallas, TX 75246 USA. [Clark, J. I.] Loyola Univ, Chicago Cardinal Bemardin Canc Ctr, Dept Med, Maywood, IL 60153 USA. [Lim, H. Y.] Sungkyunkwan Univ, Samsung Med Ctr, Dept Internal Med, Seoul 135710, South Korea. [Porfiri, E.] Queen Elizabeth Hosp, Birmingham B15 2WB, W Midlands, England. [Zalewski, P.] Durham Reg Canc Ctr, Oshawa, ON L1G 2B9, Canada. [Kannourakis, G.] Fiona Elsey Canc Res Inst, Ballarat, Vic 3355, Australia. [Kannourakis, G.] Ballarat Oncol & Haematol Serv, Ballarat, Vic 3355, Australia. [Staehler, M.] Univ Munich, D-80539 Munich, Germany. [Tarazi, J.; Rosbrook, B.; Kim, S.] Pfizer Oncol, San Diego, CA 92121 USA. [Cisar, L.; Hariharan, S.] Pfizer Oncol, New York, NY 10017 USA. [Rini, B. I.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44195 USA. RP Escudier, B (reprint author), Inst Gustave Roussy, Dept Med Oncol, F-94805 Villejuif, France. EM escudier@igr.fr OI Michaelson, Dror/0000-0001-9249-6338 FU Pfizer Inc FX This study was sponsored by Pfizer Inc. We thank Glen I Andrews, MS, of Pfizer Inc for review of the manuscript. Medical writing support was provided by Joanna Bloom, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc. NR 21 TC 36 Z9 36 U1 0 U2 7 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 10 PY 2014 VL 110 IS 12 BP 2821 EP 2828 DI 10.1038/bjc.2014.244 PG 8 WC Oncology SC Oncology GA AK1NG UT WOS:000338181200001 PM 24823696 ER PT J AU Yang, X Yang, P Shen, J Osaka, E Choy, E Cote, G Harmon, D Zhang, Z Mankin, H Hornicek, FJ Duan, Z AF Yang, X. Yang, P. Shen, J. Osaka, E. Choy, E. Cote, G. Harmon, D. Zhang, Z. Mankin, H. Hornicek, F. J. Duan, Z. TI Prevention of multidrug resistance (MDR) in osteosarcoma by NSC23925 SO BRITISH JOURNAL OF CANCER LA English DT Article DE drug resistance; NSC23925; osteosarcorna; Pgp; paclitaxel ID X-RECEPTOR AGONIST; ACUTE MYELOID-LEUKEMIA; CELL LUNG-CANCER; P-GLYCOPROTEIN; VALSPODAR PSC-833; OVARIAN-CANCER; PHASE-II; IN-VITRO; GROUP-B; PACLITAXEL AB Background: The major limitation to the success of chemotherapy in osteosarcoma is the development of multidrug resistance (MDR). Preventing the emergence of MDR during chemotherapy treatment has been a high priority of clinical and investigational oncology, but it remains an elusive goal. The NSC23925 has recently been identified as a novel and potent MDR reversal agent. However, whether NSC23925 can prevent the development of MDR in cancer is unknown. Therefore, this study aims to evaluate the effects of NSC23925 on prevention of the development of MDR in osteosarcoma. Methods: Human osteosarcoma cell lines U-2OS and Saos were exposed to increasing concentrations of paclitaxel alone or in combination with NSC23925 for 6 months. Cell sublines selected at different time points were evaluated for their drug sensitivity, drug transporter P-glycoprotein (Pgp) expression and activity. Results: We observed that tumour cells selected with increasing concentrations of paclitaxel alone developed MDR with resistance to paclitaxel and other Pgp substrates, whereas cells cultured with paclitaxel-NSC23925 did not develop MDR and cells remained sensitive to chemotherapeutic agents. Paclitaxel-resistant cells showed high expression and activity of the Pgp, whereas paclitaxel-NSC23925-treated cells did not express Pgp. No changes in IC50 and Pgp expression and activity were observed in cells grown with the NSC23925 alone. Conclusions: Our findings suggest that NSC23925 may prevent the development of MDR by specifically preventing the overexpression of Pgp. Given the significant incidence of MDR in osteosarcoma and the lack of effective agents for prevention of MDR, NSC23925 and derivatives hold the potential to improve the outcome of cancer patients with poor prognosis due to drug resistance. C1 [Yang, X.; Yang, P.; Shen, J.; Osaka, E.; Choy, E.; Cote, G.; Harmon, D.; Mankin, H.; Hornicek, F. J.; Duan, Z.] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [Yang, X.; Yang, P.; Shen, J.; Osaka, E.; Choy, E.; Cote, G.; Harmon, D.; Mankin, H.; Hornicek, F. J.; Duan, Z.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yang, X.; Zhang, Z.] Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynaecol, Zhengzhou 450052, Henan Province, Peoples R China. RP Duan, Z (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Gattegno fund; Wechsler fund; Kenneth Stanton Fund through a grant from the Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH); UOI; China Scholarship Council FX This work was supported in part by grants from the Gattegno and Wechsler funds. Support has also been provided by the Kenneth Stanton Fund. Dr Duan is supported, in part, through a grant from the Sarcoma Foundation of America (SFA) and a grant from the National Cancer Institute (NCI)/National Institutes of Health (NIH), UOI, CA 151452. Dr Yang is supported by scholarship from the China Scholarship Council. NR 43 TC 8 Z9 8 U1 0 U2 5 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 10 PY 2014 VL 110 IS 12 BP 2896 EP 2904 DI 10.1038/bjc.2014.254 PG 9 WC Oncology SC Oncology GA AK1NG UT WOS:000338181200010 PM 24853187 ER PT J AU Bocking, T Aguet, F Rapoport, I Banzhaf, M Yu, A Zeeh, JC Kirchhausen, T AF Boecking, Till Aguet, Francois Rapoport, Iris Banzhaf, Manuel Yu, Anan Zeeh, Jean Christophe Kirchhausen, Tom TI Key Interactions for Clathrin Coat Stability SO STRUCTURE LA English DT Article ID ADAPTER COMPLEX; ELECTRON CRYOMICROSCOPY; UNCOATING ATPASE; AUXILIN; VESICLES; MECHANISM; PROTEIN; AP2; DISSOCIATION; ORGANIZATION AB Clathrin-coated vesicles are major carriers of vesicular traffic in eukaryotic cells. This endocytic pathway relies on cycles of clathrin coat assembly and Hsc70-mediated disassembly. Here we identify histidine residues as major determinants of lattice assembly and stability. They are located at the invariant interface between the proximal and distal segments of clathrin heavy chains, in triskelions centered on two adjacent vertices of the coated-vesicle lattice. Mutation of these histidine residues to glutamine alters the pH dependence of coat stability. We then describe single-particle fluorescence imaging experiments in which we follow the effect of these histidine mutations on susceptibility to Hsc70-dependent uncoating. Coats destabilized by these mutations require fewer Hsc70 molecules to initiate disassembly, as predicted by a model in which Hsc70 traps conformational distortions during the auxilin- and Hsc70:ATP-mediated uncoating reaction. C1 [Boecking, Till; Aguet, Francois; Rapoport, Iris; Banzhaf, Manuel; Yu, Anan; Zeeh, Jean Christophe; Kirchhausen, Tom] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kirchhausen, Tom] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Rapoport, Iris; Banzhaf, Manuel; Yu, Anan; Zeeh, Jean Christophe; Kirchhausen, Tom] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Boecking, Till] Univ New S Wales, Ctr Vasc Res, Sydney, NSW 2052, Australia. RP Bocking, T (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM till.boecking@unsw.edu.au; kirchhausen@crystal.harvard.edu OI Banzhaf, Manuel/0000-0002-4682-1037; Bocking, Till/0000-0003-1165-3122 FU Human Frontier Science Program Organization; Swiss National Science Foundation; European Molecular Biology Organization; NIH [GM-36548, GM-075252]; Australian Research Council [FT100100411] FX We thank S. C. Harrison for input into the design of the mutants, discussions, and editorial help; E. Marino for maintaining the Imaging Resource; and members of our laboratories for discussions. T. B. was supported by a fellowship from the Human Frontier Science Program Organization. F. A. was supported by a fellowship from the Swiss National Science Foundation. M. B. was supported by a fellowship from the European Molecular Biology Organization. This work was supported by NIH grants GM-36548 and GM-075252 to T. K. and Australian Research Council grant FT100100411 to T.B. NR 36 TC 3 Z9 3 U1 2 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUN 10 PY 2014 VL 22 IS 6 BP 819 EP 829 DI 10.1016/j.str.2014.04.002 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AK1VP UT WOS:000338206200005 PM 24815030 ER PT J AU Kini, V Soufi, MK Deo, R Epstein, AE Bala, R Riley, M Groeneveld, PW Shalaby, A Dixit, S AF Kini, Vinay Soufi, Mohamad Khaled Deo, Rajat Epstein, Andrew E. Bala, Rupa Riley, Michael Groeneveld, Peter W. Shalaby, Alaa Dixit, Sanjay TI Appropriateness of Primary Prevention Implantable Cardioverter-Defibrillators at the Time of Generator Replacement Are Indications Still Met? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ICD generator replacement; implantable cardioverter-defibrillator; sudden cardiac death ID VENTRICULAR EJECTION FRACTION; CARDIAC RESYNCHRONIZATION THERAPY; HEART-FAILURE; MYOCARDIAL-INFARCTION; NONISCHEMIC CARDIOMYOPATHY; COST-EFFECTIVENESS; SURVIVAL; SHOCKS; DEATH; STRATIFICATION AB Objectives This study sought to determine how often patients with primary prevention implantable cardioverter-defibrillators (ICDs) meet guideline-derived indications at the time of generator replacement. Background Professional societies have developed guideline criteria for the appropriate implantation of an ICD for the primary prevention of sudden cardiac death. It is unknown whether patients continue to meet criteria when their devices need replacement for battery depletion. Methods We performed a retrospective chart review of patients undergoing replacement of primary prevention ICDs at 2 tertiary Veterans Affairs Medical Centers. Indications for continued ICD therapy at the time of generator replacement included a left ventricular ejection fraction (LVEF) <= 35% or receipt of appropriate device therapy. Results In our cohort of 231 patients, 59 (26%) no longer met guideline-driven indications for an ICD at the time of generator replacement. An additional 79 patients (34%) had not received any appropriate ICD therapies and had not undergone reassessment of their LVEF. Patients with an initial LVEF of 30% to 35% were less likely to meet indications for ICD therapy at the time of replacement ( odds ratio: 0.52; 95% confidence interval: 0.30 to 0.88; p = 0.01). Patients without ICD indications subsequently received appropriate ICD therapies at a significantly lower rate than patients with indications ( 2.8% vs. 10.7% annually, p < 0.001). If ICD generator explantations were performed instead of replacements in the patients without ICD indications, the cost savings would be $1.6 million. Conclusions Approximately 25% of patients who receive primary prevention ICDs may no longer meet guideline indications for ICD use at the time of generator replacement, and these patients receive subsequent ICD therapies at a significantly lower rate. (C) 2014 by the American College of Cardiology Foundation C1 [Kini, Vinay; Deo, Rajat; Epstein, Andrew E.; Bala, Rupa; Riley, Michael; Dixit, Sanjay] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Soufi, Mohamad Khaled; Shalaby, Alaa] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Epstein, Andrew E.; Groeneveld, Peter W.; Dixit, Sanjay] Philadelphia VA Med Ctr, Pittsburgh, PA USA. RP Dixit, S (reprint author), Hosp Univ Penn, 9 Founders Pavill,3400 Spruce St, Philadelphia, PA 19104 USA. EM Sanjay.dixit@uphs.upenn.edu FU National Institutes of Health [K23DK089118]; Boston Scientific; Medtronic; St. Jude Medical; Biotronik FX Dr. Epstein has received honoraria from Boston Scientific, Medtronic, and St. Jude Medical; and research grants from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical. Dr. Dixit has received a research grant from Medtronic. Dr. Deo has received support from grant number K23DK089118 from the National Institutes of Health. Drs. Epstein, Bala, Riley, Deo, and Dixit have received fellowship support from Boston Scientific, Medtronic, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 26 TC 33 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 10 PY 2014 VL 63 IS 22 BP 2388 EP 2394 DI 10.1016/j.jacc.2014.03.025 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ0PG UT WOS:000337356800010 PM 24727249 ER PT J AU Udell, JA Morrow, DA Jarolim, P Sloan, S Hoffman, EB O'Donnell, TF Vora, AN Omland, T Solomon, SD Pfeffer, MA Braunwald, E Sabatine, MS AF Udell, Jacob A. Morrow, David A. Jarolim, Petr Sloan, Sarah Hoffman, Elaine B. O'Donnell, Thomas F. Vora, Amit N. Omland, Torbjorn Solomon, Scott D. Pfeffer, Marc A. Braunwald, Eugene Sabatine, Marc S. TI Fibroblast Growth Factor-23, Cardiovascular Prognosis, and Benefit of Angiotensin-Converting Enzyme Inhibition in Stable Ischemic Heart Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angiotensin-converting enzyme inhibitors; biomarkers; coronary artery disease; fibroblast growth factor-23; kidney ID CHRONIC KIDNEY-DISEASE; CORONARY-ARTERY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; C-REACTIVE PROTEIN; PARATHYROID-HORMONE; HEALTHY-VOLUNTEERS; RISK PREDICTION; RENAL-FUNCTION; PEACE TRIAL; MORTALITY AB Objectives This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. Background FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. Methods FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. Results After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p= 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction=0.0039). This interaction was independent of and additive to stratification based on renal function. Conclusions Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558) (J Am Coll Cardiol 2014; 63: 2421-8) (C) 2014 by the American College of Cardiology Foundation C1 [Udell, Jacob A.] Univ Toronto, Womens Coll Hosp, Womens Coll Res Inst, Toronto, ON, Canada. [Udell, Jacob A.] Univ Toronto, Womens Coll Hosp, Dept Med, Div Cardiol, Toronto, ON, Canada. [Morrow, David A.; Sloan, Sarah; Hoffman, Elaine B.; Braunwald, Eugene; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, Boston, MA 02115 USA. [Morrow, David A.; Jarolim, Petr; Sloan, Sarah; Hoffman, Elaine B.; O'Donnell, Thomas F.; Solomon, Scott D.; Pfeffer, Marc A.; Braunwald, Eugene; Sabatine, Marc S.] Harvard Univ, Sch Med, Boston, MA USA. [Jarolim, Petr] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [O'Donnell, Thomas F.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Vora, Amit N.] Duke Clin Res Inst, Durham, NC USA. [Omland, Torbjorn] Univ Oslo, Akershus Univ Hosp, Div Med, Dept Cardiol, Oslo, Norway. [Omland, Torbjorn] Univ Oslo, Ctr Heart Failure Res, Oslo, Norway. [Omland, Torbjorn] Univ Oslo, KG Jebsen Cardiac Res Ctr, Oslo, Norway. [Solomon, Scott D.; Pfeffer, Marc A.] Brigham & Womens Hosp, Div Cardiovasc, Dept Med, Boston, MA 02115 USA. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM msabatine@partners.org FU National Heart, Lung, and Blood Institute(NHLBI) [N01HC65149]; Knoll Pharmaceutical; Abbott Laboratories; Postdoctoral Research Fellowship; Canadian Institutes for Health Research (CIHR; Ottawa, Canada); Canadian Foundation for Women's Health (Ottawa, Canada); National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL094390]; Amgen; AstraZeneca, Athera, Beckman Coulter, BG Medicine, Bristol-Myers Squibb, Buhlmann Laboratories; Daiichi Sankyo Co Ltd; Eli Lilly and Co; Esai; GlaxoSmithKline; Johnson Johnson; Merck and Co.; Nanosphere; Novartis Pharmaceuticals; Ortho-Clinical Diagnostics; Pfizer; Randox; Roche Diagnostics; Sanofi-Aventis; Siemens; Singulex; Abbott Diagnostics; BG Medicine; Eli Lilly; Gilead; Novartis; Critical Diagnostics; Genentech; Instrumentation Laboratory; Konica-Minolta; Servier; Siemens Healthcare FX The PEACE trial was sponsored by the National Heart, Lung, and Blood Institute (NHLBI; N01HC65149) with support from Knoll Pharmaceuticals and Abbott Laboratories, which also provided the study medication. Dr. Udell was supported in part by a Postdoctoral Research Fellowship from the Canadian Institutes for Health Research (CIHR; Ottawa, Canada) and Canadian Foundation for Women's Health (Ottawa, Canada). Dr. Sabatine was supported in part by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL094390. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Reagent for measurement of high-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide were provided by Roche Diagnostics; midregional pro-atrial natriuretic peptide, midregional proadrenomedullin, and C-terminal pro-endothelin-1 were provided by B. R. A. H. M. S. GmbH. Drs. Morrow, Hoffman, Braunwald, and Sabatine, and S. Sloan are members of the TIMI Study Group, which has received grant support from Amgen, AstraZeneca, Athera, Beckman Coulter, BG Medicine, Bristol-Myers Squibb, Buhlmann Laboratories, Daiichi Sankyo Co Ltd, Eli Lilly and Co, Esai, GlaxoSmithKline, Johnson & Johnson, Merck and Co., Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex. Dr. Morrow has received grant support from Abbott Diagnostics, Beckman-Coulter, Nanosphere, Ortho-Clinical Diagnostics, Randox, Singulex, Amgen, Astra-Zeneca, Bristol-Myers-Squibb, Daiichi Sankyo, Esai, GlaxoSmithKline, Pfizer, Sanofi-Aventis, and Takeda; grants and personal fees from BG Medicine, Eli Lilly, Gilead, Johnson & Johnson, Merck & Company, Novartis, and Roche Diagnostics; and personal fees from Critical Diagnostics, Genentech, Instrumentation Laboratory, Konica-Minolta, and Servier outside the submitted work. Dr. Omland has received grants, personal fees, and nonfinancial support from Roche Diagnostics during the conduct of the study; grants, personal fees, and nonfinancial support from Abbott Laboratories; personal fees from Siemens Healthcare; and grants and nonfinancial support from AstraZeneca outside the submitted work. Dr. Pfeffer has received grant support from Amgen, Celladon, Novartis, and Sanofi-Aventis; consulting fees from Aastrom, Amgen, Bristol-Myers Squibb, Cerenis, Concert, Genzyme, Hamilton Health Sciences, Keryx, Medtronic, Merck and Co, Novartis, Roche Diagnostics, Servier, Teva, the University of Oxford, and Xoma; and is listed as a co-inventor on patents awarded to Brigham and Women's Hospital regarding the use of inhibition of the renin-angiotensin system that are licensed to Boehringer Ingelheim and Novartis and are irrevocably transferred to charity. Dr. Braunwald has received grant support from Knoll Pharmaceuticals and Abbott Laboratories (as a supplement to the PEACE trial). Dr.; Sabatine has received grant support from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, BRAHMS GmbH, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Roche Diagnostics, Sanofi-Aventis, Takeda; and personal fees from Aegerion, Amgen, AstraZeneca/ Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Daiichi-Sankyo/Lilly, diaDexus, GlaxoSmithKline, Intarcia, Merck, Ortho-Clinical Diagnostics, Pfizer, Sanofi-Aventis, Vertex, and Zeus outside the submitted work. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. NR 44 TC 19 Z9 19 U1 0 U2 4 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 10 PY 2014 VL 63 IS 22 BP 2421 EP 2428 DI 10.1016/j.jacc.2014.03.026 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ0PG UT WOS:000337356800015 PM 24727254 ER PT J AU Farvid, MS Cho, E Chen, WY Eliassen, AH Willett, WC AF Farvid, Maryam S. Cho, Eunyoung Chen, Wendy Y. Eliassen, A. Heather Willett, Walter C. TI Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID PHASEOLUS-VULGARIS L.; TOTAL-ENERGY-INTAKE; FOOD-CONSUMPTION; FATTY-ACIDS; MEAT INTAKE; RISK; WOMEN; METAANALYSIS; NUTRITION; HEALTH AB Objective To investigate the association between dietary protein sources in early adulthood and risk of breast cancer. Design Prospective cohort study. Setting Health professionals in the United States. Participants 88 803 premenopausal women from the Nurses' Health Study II who completed a questionnaire on diet in 1991. Main outcome measure Incident cases of invasive breast carcinoma, identified through self report and confirmed by pathology report. Results We documented 2830 cases of breast cancer during 20 years of follow-up. Higher intake of total red meat was associated with an increased risk of breast cancer overall (relative risk 1.22, 95% confidence interval 1.06 to 1.40; P-trend=0.01, for highest fifth v lowest fifth of intake). However, higher intakes of poultry, fish, eggs, legumes, and nuts were not related to breast cancer overall. When the association was evaluated by menopausal status, higher intake of poultry was associated with a lower risk of breast cancer in postmenopausal women (0.73, 0.58 to 0.91; P-trend=0.02, for highest fifth v lowest fifth of intake) but not in premenopausal women (0.93, 0.78 to 1.11; P-trend=0.60, for highest fifth v lowest fifth of intake). In estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women (0.85, 0.73 to 0.98) and a 19% lower risk among premenopausal women (0.81, 0.66 to 0.99). Also, substituting one serving/day of poultry for one serving/day of red meat was associated with a 17% lower risk of breast cancer overall (0.83, 0.72 to 0.96) and a 24% lower risk of postmenopausal breast cancer (0.76, 0.59 to 0.99). Furthermore, substituting one serving/day of combined legumes, nuts, poultry, and fish for one serving/day of red meat was associated with a 14% lower risk of breast cancer overall (0.86, 0.78 to 0.94) and premenopausal breast cancer (0.86, 0.76 to 0.98). Conclusion Higher red meat intake in early adulthood may be a risk factor for breast cancer, and replacing red meat with a combination of legumes, poultry, nuts and fish may reduce the risk of breast cancer. C1 [Farvid, Maryam S.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Farvid, Maryam S.] Shahid Beheshti Univ Med Sci, Fac Nutr Sci & Food Technol, Dept Community Nutr, Tehran, Iran. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Cho, Eunyoung; Chen, Wendy Y.; Eliassen, A. Heather; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Cho, Eunyoung; Chen, Wendy Y.; Eliassen, A. Heather; Willett, Walter C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Eliassen, A. Heather; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Farvid, MS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM mfarvid@hsph.harvard.edu FU National Institutes of Health [R01CA050385] FX This study was supported by the National Institutes of Health grant (R01CA050385). The study sponsors were not involved in the study design and collection, analysis, and interpretation of data, or the writing of the article or the decision to submit it for publication. The authors were independent from study sponsors. NR 36 TC 25 Z9 25 U1 2 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUN 10 PY 2014 VL 348 AR g3437 DI 10.1136/bmj.g3437 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AJ1FH UT WOS:000337400800001 PM 24916719 ER PT J AU Zwicker, JI Rojan, A Campigotto, F Rehman, N Funches, R Connolly, G Webster, J Aggarwal, A Mobarek, D Faselis, C Neuberg, D Rickles, FR Wun, T Streiff, MB Khorana, AA AF Zwicker, Jeffrey I. Rojan, Adam Campigotto, Federico Rehman, Nadia Funches, Renee Connolly, Gregory Webster, Jonathan Aggarwal, Anita Mobarek, Dalia Faselis, Charles Neuberg, Donna Rickles, Frederick R. Wun, Ted Streiff, Michael B. Khorana, Alok A. TI Pattern of Frequent But Nontargeted Pharmacologic Thromboprophylaxis for Hospitalized Patients With Cancer at Academic Medical Centers: A Prospective, Cross-Sectional, Multicenter Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VENOUS THROMBOEMBOLISM PROPHYLAXIS; PLACEBO-CONTROLLED TRIAL; CLINICAL-PRACTICE; AMERICAN SOCIETY; RISK; PREVENTION; THROMBOSIS; GUIDELINE AB Purpose Hospitalized patients with cancer are considered to be at high risk for venous thromboembolism (VTE). Despite strong recommendations in numerous clinical practice guidelines, retrospective studies have shown that pharmacologic thromboprophylaxis is underutilized in hospitalized patients with cancer. Patients and Methods We conducted a prospective, cross-sectional study of hospitalized patients with cancer at five academic hospitals to determine prescription rates of thromboprophylaxis and factors influencing its use during hospitalization. Results A total of 775 patients with cancer were enrolled across five academic medical centers. Two hundred forty-seven patients (31.9%) had relative contraindications to pharmacologic prophylaxis. Accounting for contraindications to anticoagulation, the overall rate of pharmacologic thromboprophylaxis was 74.2% (95% CI, 70.4% to 78.0%; 392 of 528 patients). Among the patients with cancer without contraindications for anticoagulation, individuals hospitalized with nonhematologic malignancies were significantly more likely to receive pharmacologic thromboprophylaxis than those with hematologic malignancies (odds ratio [OR], 2.34; 95% CI, 1.43 to 3.82; P = .007). Patients with cancer admitted for cancer therapy were significantly less likely to receive pharmacologic thromboprophylaxis than those admitted for other reasons (OR, 0.37; 95% CI, 0.22 to 0.61; P < .001). Sixty-three percent of patients with cancer classified as low risk, as determined by the Padua Scoring System, received anticoagulant thromboprophylaxis. Among the 136 patients who did not receive anticoagulation, 58.8% were considered to be high risk by the Padua Scoring System. Conclusion We conclude that pharmacologic thromboprophylaxis is frequently administered to hospitalized patients with cancer but that nearly one third of patients are considered to have relative contraindications for prophylactic anticoagulation. Pharmacologic thromboprophylaxis in hospitalized patients with cancer is commonly prescribed without regard to the presence or absence of concomitant risk factors for VTE. C1 [Zwicker, Jeffrey I.; Rojan, Adam; Funches, Renee] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Zwicker, Jeffrey I.; Rojan, Adam; Funches, Renee] Harvard Univ, Sch Med, Boston, MA USA. [Campigotto, Federico; Neuberg, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rehman, Nadia; Wun, Ted] Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA. [Rehman, Nadia; Wun, Ted] VA Northern Calif Hlth Care Syst, Sacramento, CA USA. [Connolly, Gregory] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Webster, Jonathan; Streiff, Michael B.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Aggarwal, Anita; Mobarek, Dalia; Faselis, Charles; Rickles, Frederick R.] Vet Adm Med Ctr, Washington, DC 20422 USA. [Aggarwal, Anita; Mobarek, Dalia; Faselis, Charles; Rickles, Frederick R.] George Washington Univ, Washington, DC USA. [Khorana, Alok A.] Cleveland Clin Fdn, Taussig Canc Inst, Cleveland, OH 44195 USA. RP Zwicker, JI (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM jzwicker@bidmc.harvard.edu OI Zwicker, Jeffrey/0000-0001-5810-6893 FU National Institutes of Health [8UL1TR000170- 05]; Scott Hamilton CARES Initiative grant FX Computerized data collection was supported by the 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 No. 8UL1TR000170- 05, and by Harvard University and its affiliated academic health care centers. Research support was provided to A. A. K. by the Sondra and Stephen Hardis Chair in Oncology and the Scott Hamilton CARES Initiative grant. NR 21 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2014 VL 32 IS 17 BP 1792 EP 1796 DI 10.1200/JCO.2013.53.5336 PG 5 WC Oncology SC Oncology GA AI9GF UT WOS:000337239600011 PM 24799475 ER PT J AU Levy, R Ganjoo, KN Leonard, JP Vose, JM Flinn, IW Ambinder, RF Connors, JM Berinstein, NL Belch, AR Bartlett, NL Nichols, C Emmanouilides, CE Timmerman, JM Gregory, SA Link, BK Inwards, DJ Freedman, AS Matous, JV Robertson, MJ Kunkel, LA Ingolia, DE Gentles, AJ Liu, CL Tibshirani, R Alizadeh, AA Denney, DW AF Levy, Ronald Ganjoo, Kristen N. Leonard, John P. Vose, Julie M. Flinn, Ian W. Ambinder, Richard F. Connors, Joseph M. Berinstein, Neil L. Belch, Andrew R. Bartlett, Nancy L. Nichols, Craig Emmanouilides, Christos E. Timmerman, John M. Gregory, Stephanie A. Link, Brian K. Inwards, David J. Freedman, Arnold S. Matous, Jeffrey V. Robertson, Michael J. Kunkel, Lori A. Ingolia, Diane E. Gentles, Andrew J. Liu, Chih Long Tibshirani, Robert Alizadeh, Ash A. Denney, Dan W., Jr. TI Active Idiotypic Vaccination Versus Control Immunotherapy for Follicular Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID B-CELL LYMPHOMA; COLONY-STIMULATING FACTOR; METASTATIC BREAST-CANCER; NON-HODGKINS-LYMPHOMA; PHASE-III; CLINICAL-TRIAL; ANTIIDIOTYPE ANTIBODY; IMMUNE-RESPONSES; FREE SURVIVAL; SIALYL-TN AB Purpose Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. Patients and Methods Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n = 287 [44%]) were randomly assigned at a ratio of 2: 1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. Results At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n = 195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. Conclusion This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study. C1 [Levy, Ronald; Belch, Andrew R.; Liu, Chih Long; Tibshirani, Robert; Alizadeh, Ash A.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Emmanouilides, Christos E.; Timmerman, John M.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Kunkel, Lori A.; Ingolia, Diane E.; Denney, Dan W., Jr.] Genitope, Fremont, CA USA. [Ganjoo, Kristen N.; Robertson, Michael J.] Indiana Univ, Med Ctr, Indianapolis, IN USA. [Leonard, John P.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Vose, Julie M.] Univ Nebraska Med Ctr, Omaha, NE USA. [Flinn, Ian W.; Ambinder, Richard F.] Johns Hopkins Univ, Ctr Oncol, Baltimore, MD 21205 USA. [Connors, Joseph M.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Berinstein, Neil L.] Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. [Belch, Andrew R.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Bartlett, Nancy L.] Washington Univ, Sch Med, St Louis, MO USA. [Nichols, Craig] Oregon Hlth & Sci Univ, Portland, OR USA. [Gregory, Stephanie A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Link, Brian K.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Inwards, David J.] Mayo Clin, Rochester, MN USA. [Freedman, Arnold S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Matous, Jeffrey V.] Rocky Mt Canc Ctr, Denver, CO USA. RP Alizadeh, AA (reprint author), 265 Campus Dr,SIM1-G2120B, Stanford, CA 94305 USA. EM arasha@stanford.edu OI Alizadeh, Arash Ash/0000-0002-5153-5625 FU NCI NIH HHS [P30 CA086862, P30 CA124435] NR 36 TC 16 Z9 16 U1 0 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2014 VL 32 IS 17 BP 1797 EP U75 DI 10.1200/JCO.2012.43.9273 PG 8 WC Oncology SC Oncology GA AI9GF UT WOS:000337239600012 PM 24799467 ER PT J AU Bower, JE Bak, K Berger, A Breitbart, W Escalante, CP Ganz, PA Schnipper, HH Lacchetti, C Ligibel, JA Lyman, GH Ogaily, MS Pirl, WF Jacobsen, PB AF Bower, Julienne E. Bak, Kate Berger, Ann Breitbart, William Escalante, Carmelita P. Ganz, Patricia A. Schnipper, Hester Hill Lacchetti, Christina Ligibel, Jennifer A. Lyman, Gary H. Ogaily, Mohammed S. Pirl, William F. Jacobsen, Paul B. TI Screening, Assessment, and Management of Fatigue in Adult Survivors of Cancer: An American Society of Clinical Oncology Clinical Practice Guideline Adaptation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; BREAST-CANCER; PHYSICAL-ACTIVITY; EXERCISE; METAANALYSIS; THERAPY; CARE; INTERVENTIONS; INVENTORY AB Purpose This guideline presents screening, assessment, and treatment approaches for the management of adult cancer survivors who are experiencing symptoms of fatigue after completion of primary treatment. Methods A systematic search of clinical practice guideline databases, guideline developer Web sites, and published health literature identified the pan-Canadian guideline on screening, assessment, and care of cancer-related fatigue in adults with cancer, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines In Oncology (NCCN Guidelines) for Cancer-Related Fatigue and the NCCN Guidelines for Survivorship. These three guidelines were appraised and selected for adaptation. Results It is recommended that all patients with cancer be evaluated for the presence of fatigue after completion of primary treatment and be offered specific information and strategies for fatigue management. For those who report moderate to severe fatigue, comprehensive assessment should be conducted, and medical and treatable contributing factors should be addressed. In terms of treatment strategies, evidence indicates that physical activity interventions, psychosocial interventions, and mind-body interventions may reduce cancer-related fatigue in post-treatment patients. There is limited evidence for use of psychostimulants in the management of fatigue in patients who are disease free after active treatment. Conclusion Fatigue is prevalent in cancer survivors and often causes significant disruption in functioning and quality of life. Regular screening, assessment, and education and appropriate treatment of fatigue are important in managing this distressing symptom. Given the multiple factors contributing to post-treatment fatigue, interventions should be tailored to each patient's specific needs. In particular, a number of nonpharmacologic treatment approaches have demonstrated efficacy in cancer survivors. C1 [Bower, Julienne E.; Ganz, Patricia A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Bak, Kate; Lacchetti, Christina] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Berger, Ann] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Breitbart, William] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Escalante, Carmelita P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Schnipper, Hester Hill] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA USA. [Pirl, William F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyman, Gary H.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Lyman, Gary H.] Univ Washington, Seattle, WA 98195 USA. [Ogaily, Mohammed S.] Oakwood Ctr Hematol & Oncol, Brownstown, MI USA. [Jacobsen, Paul B.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. RP Bower, JE (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 63 TC 79 Z9 82 U1 3 U2 24 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2014 VL 32 IS 17 BP 1840 EP U127 DI 10.1200/JCO.2013.53.4495 PG 12 WC Oncology SC Oncology GA AI9GF UT WOS:000337239600018 PM 24733803 ER PT J AU Arora, N Wenzel, PL McKinney-Freeman, SL Ross, SJ Kim, PG Chou, SS Yoshimoto, M Yoder, MC Daley, GQ AF Arora, Natasha Wenzel, Pamela L. McKinney-Freeman, Shannon L. Ross, Samantha J. Kim, Peter G. Chou, Stephanie S. Yoshimoto, Momoko Yoder, Mervin C. Daley, George Q. TI Effect of Developmental Stage of HSC and Recipient on Transplant Outcomes SO DEVELOPMENTAL CELL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; UMBILICAL-CORD BLOOD; COLONY-FORMING CELLS; MURINE YOLK-SAC; LONG-TERM; IN-VIVO; AGM REGION; MOUSE EMBRYO; FETAL LIVER; AORTIC ENDOTHELIUM AB The first hematopoietic stem cells (HSCs) that engraft irradiated adult mice arise in the aorta-gonad-mesonephros (AGM) on embryonic day 11.5 (E11.5). However, at this stage, there is a discrepancy between the apparent frequency of HSCs depicted with imaging and their rarity when measured with limiting dilution transplant. We have attempted to reconcile this difference using neonatal recipients, which are more permissive for embryonic HSC engraftment. We found that embryonic HSCs from E9.5 and E10.5 preferentially engrafted neonates, whereas developmentally mature, definitive HSCs from E1 4.5 fetal liver or adult bone marrow (BM) more robustly engrafted adults. Neonatal engraftment was enhanced after treating adult BM-derived HSCs with interferon. Adult BM-derived HSCs preferentially homed to the liver in neonatal mice yet showed balanced homing to the liver and spleen in adults. These findings emphasize the functional differences between nascent and mature definitive HSCs. C1 [Arora, Natasha; Ross, Samantha J.; Kim, Peter G.; Chou, Stephanie S.; Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Stem Cell Transplantat Program, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Arora, Natasha; Ross, Samantha J.; Kim, Peter G.; Chou, Stephanie S.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Arora, Natasha; Ross, Samantha J.; Kim, Peter G.; Chou, Stephanie S.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Arora, Natasha; Ross, Samantha J.; Kim, Peter G.; Chou, Stephanie S.; Daley, George Q.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Wenzel, Pamela L.] Univ Texas Med Sch Houston, Dept Pediat Surg, Houston, TX 77030 USA. [McKinney-Freeman, Shannon L.] St Jude Childrens Res Hosp, Div Expt Hematol, Memphis, TN 38105 USA. [Yoshimoto, Momoko; Yoder, Mervin C.] Indiana Univ Sch Med, Dept Pediat, Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. RP Daley, GQ (reprint author), Childrens Hosp, Howard Hughes Med Inst, Stem Cell Transplantat Program, Div Pediat Hematol Oncol, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Yoshimoto, Momoko/N-4238-2014 OI Yoshimoto, Momoko/0000-0002-7272-6682 FU US National Institute of Diabetes and Digestive and Kidney Diseases [R24-DK092760]; National Heart, Lung, Blood Institute Progenitor Cell Biology Consortium [UO1-HL100001]; Alex's Lemonade Stand; Harvard Stem Cell Institute; Doris Duke Medical Foundation FX The authors thank the Dana-Farber Cancer Institute flow cytometry core for assistance and F. Fahey, A. Packard, J. Dearling, and E. Snay for assistance with small animal imaging. G.Q.D. is supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (R24-DK092760) and the National Heart, Lung, Blood Institute Progenitor Cell Biology Consortium (UO1-HL100001), Alex's Lemonade Stand, Harvard Stem Cell Institute, and the Doris Duke Medical Foundation. G.Q.D. is an associate member of the Broad Institute and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. NR 47 TC 14 Z9 14 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JUN 9 PY 2014 VL 29 IS 5 BP 621 EP 628 DI 10.1016/j.devcel.2014.04.013 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AJ4KI UT WOS:000337644700013 PM 24914562 ER PT J AU Broering, TJ Alavattam, KG Sadreyev, RI Ichijima, Y Kato, Y Hasegawa, K Camerini-Otero, RD Lee, JT Andreassen, PR Namekawa, SH AF Broering, Tyler J. Alavattam, Kris G. Sadreyev, Ruslan I. Ichijima, Yosuke Kato, Yasuko Hasegawa, Kazuteru Camerini-Otero, R. Daniel Lee, Jeannie T. Andreassen, Paul R. Namekawa, Satoshi H. TI BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID ORDER CHROMATIN-STRUCTURE; DOUBLE-STRAND BREAKS; SEX-CHROMOSOMES; HOMOLOGOUS RECOMBINATION; MEIOTIC CHROMOSOMES; GENOME INTEGRITY; TUMOR SUPPRESSION; PROPHASE ARREST; MOUSE MEIOSIS; GERM-CELLS AB During meiosis, DNA damage response (DDR) proteins induce transcriptional silencing of unsynapsed chromatin, including the constitutively unsynapsed XY chromosomes in males. DDR proteins are also implicated in double strand break repair during meiotic recombination. Here, we address the function of the breast cancer susceptibility gene Brca1 in meiotic silencing and recombination in mice. Unlike in somatic cells, in which homologous recombination defects of Brca1 mutants are rescued by 53bp1 deletion, the absence of 53BP1 did not rescue the meiotic failure seen in Brca1 mutant males. Further, BRCA1 promotes amplification and spreading of DDR components, including AIR and TOPBP1, along XY chromosome axes and promotes establishment of pericentric heterochromatin on the X chromosome. We propose that BRCA1-dependent establishment of X-pericentric heterochromatin is critical for XY body morphogenesis and subsequent meiotic progression. In contrast, BRCA1 plays a relatively minor role in meiotic recombination, and female Brca1 mutants are fertile. We infer that the major meiotic role of BRCA1 is to promote the dramatic chromatin changes required for formation and function of the XY body. C1 [Broering, Tyler J.; Alavattam, Kris G.; Ichijima, Yosuke; Kato, Yasuko; Hasegawa, Kazuteru; Namekawa, Satoshi H.] Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Div Reprod Sci, Cincinnati, OH 45229 USA. [Broering, Tyler J.; Alavattam, Kris G.; Ichijima, Yosuke; Kato, Yasuko; Hasegawa, Kazuteru; Namekawa, Satoshi H.] Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Div Dev Biol, Cincinnati, OH 45229 USA. [Andreassen, Paul R.] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Broering, Tyler J.; Alavattam, Kris G.; Ichijima, Yosuke; Kato, Yasuko; Hasegawa, Kazuteru; Andreassen, Paul R.; Namekawa, Satoshi H.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. [Sadreyev, Ruslan I.; Lee, Jeannie T.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. [Sadreyev, Ruslan I.; Lee, Jeannie T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Camerini-Otero, R. Daniel] Natl Inst Diabet & Digest & Kidney Dis, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Namekawa, SH (reprint author), Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Div Reprod Sci, Cincinnati, OH 45229 USA. EM satoshi.namekawa@cchmc.org FU Developmental Fund Trustee Grant at Cincinnati Children's Hospital Medical Center; Basil O'Connor Starter Scholar Award from the March of Dimes Foundation; National Cancer Institute (National Institutes of Health) Intramural Research Program; National Institutes of Health [HL085587, GM098605] FX This work was supported by the Developmental Fund and Trustee Grant at Cincinnati Children's Hospital Medical Center to S.H. Namekawa, the Basil O'Connor Starter Scholar Award from the March of Dimes Foundation to S.H. Namekawa, the National Cancer Institute (National Institutes of Health) Intramural Research Program to R.D. Camerini-Otero, and National Institutes of Health grants HL085587 to P.R. Andreassen and GM098605 to S.H. Namekawa. NR 74 TC 11 Z9 12 U1 1 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUN 9 PY 2014 VL 205 IS 5 BP 663 EP 675 DI 10.1083/jcb.201311050 PG 13 WC Cell Biology SC Cell Biology GA AI8XR UT WOS:000337210800007 PM 24914237 ER PT J AU Hutchinson, JN Raj, T Fagerness, J Stahl, E Viloria, FT Gimelbrant, A Seddon, J Daly, M Chess, A Plenge, R AF Hutchinson, John N. Raj, Towfique Fagerness, Jes Stahl, Eli Viloria, Fernando T. Gimelbrant, Alexander Seddon, Johanna Daly, Mark Chess, Andrew Plenge, Robert TI Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; DNA METHYLATION; SUSCEPTIBILITY LOCI; COMMON VARIANTS; METAANALYSIS; EXPRESSION; RISK; TWIN; AGE; POLYMORPHISM AB We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results. C1 [Hutchinson, John N.; Stahl, Eli; Plenge, Robert] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Hutchinson, John N.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Raj, Towfique; Viloria, Fernando T.] Broad Inst, Cambridge, MA USA. [Raj, Towfique] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Fagerness, Jes; Daly, Mark] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Gimelbrant, Alexander] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Gimelbrant, Alexander] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Seddon, Johanna] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Seddon, Johanna] Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. [Chess, Andrew] Mt Sinai Sch Med, Friedman Brain Inst, Dept Genet & Genom Sci, Fishberg Dept Neurosci,Dept Dev & Regenerat Biol, New York, NY USA. RP Hutchinson, JN (reprint author), Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. EM jhutchin@hsph.harvard.edu FU NIH [R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648]; Burroughs Wellcome Fund; National Institutes of Health, Bethesda, MD [R01-EY11309]; Massachusetts Lions Eye Research Fund, Inc.; Research to Prevent Blindness, Inc., New York, NY; American Macular Degeneration Foundation, Northampton, MA; [RC2-GM093080] FX RMP was supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. The PhenoGenetic Project of Brigham and Women's Hospital was supported by RC2-GM093080. JS was supported in part by Grants R01-EY11309 from the National Institutes of Health, Bethesda, MD; Massachusetts Lions Eye Research Fund, Inc.; Unrestricted grant from Research to Prevent Blindness, Inc., New York, NY; the American Macular Degeneration Foundation, Northampton, MA; donations to the Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 11 Z9 11 U1 0 U2 11 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 9 PY 2014 VL 9 IS 6 AR e98464 DI 10.1371/journal.pone.0098464 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI8LF UT WOS:000337165600006 PM 24911414 ER PT J AU Jin, JO Zhang, W Du, JY Wong, KW Oda, T Yu, Q AF Jin, Jun-O Zhang, Wei Du, Jiang-Yuan Wong, Ka-Wing Oda, Tatsuya Yu, Qing TI Fucoidan Can Function as an Adjuvant In Vivo to Enhance Dendritic Cell Maturation and Function and Promote Antigen-Specific T Cell Immune Responses SO PLOS ONE LA English DT Article ID A SCAVENGER RECEPTOR; LANGERHANS CELLS; VIRUS-INFECTION; CANCER; CTL; MACROPHAGES; CYTOTOXICITY; STIMULATION; VACCINES AB Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, including promoting antigen uptake and enhancing anti-viral and anti-tumor effects. However, the effect of fucoidan in vivo, especially its adjuvant effect on in vivo anti-tumor immune responses, was not fully investigated. In this study, we investigated the effect of fucoidan on the function of spleen dendritic cells (DCs) and its adjuvant effect in vivo. Systemic administration of fucoidan induced up-regulation of CD40, CD80 and CD86 expression and production of IL-6, IL-12 and TNF-alpha in spleen cDCs. Fucoidan also promoted the generation of IFN-gamma-producing Th1 and Tc1 cells in an IL-12-dependent manner. When used as an adjuvant in vivo with ovalbumin (OVA) antigen, fucoidan promoted OVA-specific antibody production and primed IFN-gamma production in OVA-specific T cells. Moreover, fucoidan enhanced OVA-induced up-regulation of MHC class I and II on spleen cDCs and strongly prompted the proliferation of OVA-specific CD4 and CD8 T cells. Finally, OVA immunization with fucoidan as adjuvant protected mice from the challenge with B16-OVA tumor cells. Taken together, these results suggest that fucoidan can function as an adjuvant to induce Th1 immune response and CTL activation, which may be useful in tumor vaccine development. C1 [Jin, Jun-O; Zhang, Wei; Du, Jiang-Yuan; Wong, Ka-Wing] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai Med Coll, Shanghai 200433, Peoples R China. [Oda, Tatsuya] Nagasaki Univ, Grad Sch Sci & Technol, Nagasaki 852, Japan. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai Med Coll, Shanghai 200433, Peoples R China. EM Junojin1@gmail.com FU Shanghai Public Health Clinical Center in Fudan University [RCJJP17]; NIH [R01 DE023838] FX This study was supported by grants from the Shanghai Public Health Clinical Center in Fudan University (RCJJP17) and NIH grant R01 DE023838. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 16 Z9 17 U1 4 U2 24 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 9 PY 2014 VL 9 IS 6 AR e99396 DI 10.1371/journal.pone.0099396 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI8LF UT WOS:000337165600080 PM 24911024 ER PT J AU Huang, DL Abrass, IB Young, BA AF Huang, Deborah L. Abrass, Itamar B. Young, Bessie A. TI Medication safety and chronic kidney disease in older adults prescribed metformin: a cross-sectional analysis SO BMC NEPHROLOGY LA English DT Article DE Aged; Chronic kidney disease; Diabetes mellitus; Drug prescriptions; Medication safety; Metformin; Renal insufficiency ID GLOMERULAR-FILTRATION-RATE; EVALUATION PROGRAM KEEP; ELDERLY-PATIENTS; RENAL-FUNCTION; CREATININE CLEARANCE; SERUM CREATININE; LACTIC-ACIDOSIS; UNITED-STATES; PREVALENCE; EQUATIONS AB Background: Medication safety in patients with chronic kidney disease (CKD) is a growing concern. This is particularly relevant in older adults due to underlying CKD. Metformin use is contraindicated in patients with abnormal kidney function; however, many patients are potentially prescribed metformin inappropriately. We evaluated the prevalence of CKD among older adults prescribed metformin for type 2 diabetes mellitus using available equations to estimate kidney function and examined demographic characteristics of patients who were potentially inappropriately prescribed metformin. Methods: We conducted a cross-sectional analysis of older adults aged >= 65 years prescribed metformin from March 2008-March 2009 at an urban tertiary-care facility in Seattle, Washington, USA. CKD was defined using National Kidney Foundation-Kidney Disease Outcomes Quality Initiative criteria. Creatinine clearance was calculated using the Cockcroft-Gault equation; estimated glomerular filtration rate was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) and CKD-Epidemiology (EPI) Collaboration equations. Regression analyses were used to determine the associations between demographic characteristics and prevalent CKD. Results: Among 356 subjects (median age 69 years, 52.5% female, 39.4% non-Hispanic black), prevalence of stage 3 or greater CKD calculated by any of the equations was 31.4%. The Cockcroft-Gault equation identified more subjects as having CKD (23.7%) than the abbreviated MDRD (21.1%) or CKD-EPI (21.7%) equations (P < 0.001). Older age (OR = 1.13, 95% CI 1.08-1.19) and female sex (OR = 2.51, 95% CI 1.44-4.38) were associated with increased odds of potentially inappropriate metformin prescription due to CKD; non-Hispanic black race was associated with decreased odds of potentially inappropriate metformin prescription due to CKD (OR = 0.41, 95% CI 0.23-0.71). Conclusions: CKD is common in older adults prescribed metformin for type 2 diabetes, raising concern for potentially inappropriate medication use. No single equation to estimate kidney function may accurately identify CKD in this population. Medication safety deserves greater consideration among elderly patients due to the widespread prevalence of CKD. C1 [Huang, Deborah L.] Univ Washington, Div Gen Internal Med, Seattle, WA 98105 USA. [Abrass, Itamar B.] Univ Washington, Div Gerontol & Geriatr Med, Seattle, WA 98105 USA. [Young, Bessie A.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Innovat Vet Centered & Va, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Young, Bessie A.] Univ Washington, Kidney Res Inst, Div Nephrol, Seattle, WA 98105 USA. RP Huang, DL (reprint author), Univ Washington, Div Gen Internal Med, Box 354765,4245 Roosevelt Way NE, Seattle, WA 98105 USA. EM huangdx@uw.edu FU John A. Hartford Foundation Center of Excellence in Geriatric Medicine and Training Grant; NIH [NIDDK R01DK079745-01]; Department of Veterans Affairs, VA Puget Sound Health Care System, Seattle, Washington, USA FX DLH: This work was supported by a John A. Hartford Foundation Center of Excellence in Geriatric Medicine and Training Grant. BAY is supported by the Department of Veterans Affairs, VA Puget Sound Health Care System, Seattle, Washington, USA, and NIH grant NIDDK R01DK079745-01. The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review, or approval of the manuscript. NR 28 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUN 7 PY 2014 VL 15 AR 86 DI 10.1186/1471-2369-15-86 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AJ0EQ UT WOS:000337322800001 PM 24906409 ER PT J AU Sun, QQ Gao, XP Wang, HB Ko, DSC Li, XC AF Sun, Qiquan Gao, Xinpu Wang, Haibo Ko, Dicken Shiu-Chung Li, Xian Chang TI A new era for organ transplantation in China SO LANCET LA English DT Letter ID DONATION; PROGRAM C1 [Sun, Qiquan] Sun Yat Sen Univ, Div Renal Transplantat, Affiliated Hosp 3, Guangzhou 510530, Guangdong, Peoples R China. [Gao, Xinpu] China Organ Donat Adm Ctr, Beijing, Peoples R China. [Wang, Haibo] China Organ Transplant Response Syst Res Ctr, Shenzhen, Peoples R China. [Wang, Haibo] Univ Hong Kong, Queen Mary Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Ko, Dicken Shiu-Chung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. [Li, Xian Chang] Houston Methodist Hosp, Texas Med Ctr, Houston, TX USA. RP Sun, QQ (reprint author), Sun Yat Sen Univ, Div Renal Transplantat, Affiliated Hosp 3, Guangzhou 510530, Guangdong, Peoples R China. EM sunqiquan@hotmail.com OI Li, Xian Chang/0000-0002-5981-2762 NR 5 TC 7 Z9 8 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 7 PY 2014 VL 383 IS 9933 BP 1971 EP 1972 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AI4PV UT WOS:000336848200023 PM 24910229 ER PT J AU Ley, SH Hamdy, O Mohan, V Hu, FB AF Ley, Sylvia H. Hamdy, Osama Mohan, Viswanathan Hu, Frank B. TI Prevention and management of type 2 diabetes: dietary components and nutritional strategies SO LANCET LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; IMPAIRED GLUCOSE-TOLERANCE; INSULIN-RESISTANCE ATHEROSCLEROSIS; DOSE-RESPONSE METAANALYSIS; LIFE-STYLE INTERVENTION; CORONARY-HEART-DISEASE; LOOK-AHEAD TRIAL; CARDIOVASCULAR-DISEASE; CLINICAL-TRIAL; RISK-FACTORS AB In the past couple of decades, evidence from prospective observational studies and clinical trials has converged to support the importance of individual nutrients, foods, and dietary patterns in the prevention and management of type 2 diabetes. The quality of dietary fats and carbohydrates consumed is more crucial than is the quantity of these macronutrients. Diets rich in wholegrains, fruits, vegetables, legumes, and nuts; moderate in alcohol consumption; and lower in refined grains, red or processed meats, and sugar-sweetened beverages have been shown to reduce the risk of diabetes and improve glycaemic control and blood lipids in patients with diabetes. With an emphasis on overall diet quality, several dietary patterns such as Mediterranean, low glycaemic index, moderately low carbohydrate, and vegetarian diets can be tailored to personal and cultural food preferences and appropriate calorie needs for weight control and diabetes prevention and management. Although much progress has been made in development and implementation of evidence-based nutrition recommendations in developed countries, concerted worldwide efforts and policies are warranted to alleviate regional disparities. C1 [Ley, Sylvia H.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hamdy, Osama] Joslin Diabet Ctr, Boston, MA 02215 USA. [Mohan, Viswanathan] Dr Mohans Diabet Special Ctr, Madras, Tamil Nadu, India. [Mohan, Viswanathan] Madras Diabet Res Fdn, Madras, Tamil Nadu, India. RP Hu, FB (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM frank.hu@channing.harvard.edu FU NIH [DK58845, U54 CA155626, HL60712, P30DK046200]; CIHR FX FBH is supported by NIH grants DK58845, U54 CA155626, HL60712, and P30DK046200. SHL is supported by a CIHR Fellowship Award. These funding sources had no involvement in the writing of the review. NR 90 TC 109 Z9 112 U1 19 U2 134 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 7 PY 2014 VL 383 IS 9933 BP 1999 EP 2007 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AI4PV UT WOS:000336848200028 PM 24910231 ER PT J AU Bian, JG Yang, K Boone, JM Han, X Sidky, EY Pan, XC AF Bian, Junguo Yang, Kai Boone, John M. Han, Xiao Sidky, Emil Y. Pan, Xiaochuan TI Investigation of iterative image reconstruction in low-dose breast CT SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE computed tomography; optimization-based reconstruction; image quality assessment ID TOTAL-VARIATION MINIMIZATION; FILTERED BACK-PROJECTION; CONE-BEAM CT; X-RAY CT; COMPUTED-TOMOGRAPHY; ABDOMINAL CT; ALGORITHM; QUALITY; FEASIBILITY; DETECTOR AB There is interest in developing computed tomography (CT) dedicated to breast-cancer imaging. Because breast tissues are radiation-sensitive, the total radiation exposure in a breast-CT scan is kept low, often comparable to a typical two-view mammography exam, thus resulting in a challenging low-dose-data-reconstruction problem. In recent years, evidence has been found that suggests that iterative reconstruction may yield images of improved quality from low-dose data. In this work, based upon the constrained image total-variation minimization program and its numerical solver, i.e., the adaptive steepest descent-projection onto the convex set (ASD-POCS), we investigate and evaluate iterative image reconstructions from low-dose breast-CT data of patients, with a focus on identifying and determining key reconstruction parameters, devising surrogate utility metrics for characterizing reconstruction quality, and tailoring the program and ASD-POCS to the specific reconstruction task under consideration. The ASD-POCS reconstructions appear to outperform the corresponding clinical FDK reconstructions, in terms of subjective visualization and surrogate utility metrics. C1 [Bian, Junguo] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Bian, Junguo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yang, Kai; Boone, John M.] Univ Calif Davis, Med Ctr, Dept Radiol, Sacramento, CA 95817 USA. [Han, Xiao; Sidky, Emil Y.; Pan, Xiaochuan] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Pan, Xiaochuan] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. RP Pan, XC (reprint author), Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. EM xpan@uchicago.edu FU National Institutes of Health (NIH) [R01s CA120540, EB000225, EB002138, CA158446] FX The authors would like to thank Dr Ingrid Reiser for helpful discussions. This work was supported in part by the National Institutes of Health (NIH) under grants R01s CA120540, EB000225, EB002138, and CA158446. NR 60 TC 15 Z9 16 U1 2 U2 32 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 7 PY 2014 VL 59 IS 11 BP 2659 EP 2685 DI 10.1088/0031-9155/59/11/2659 PG 27 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AH9JT UT WOS:000336459000008 PM 24786683 ER PT J AU Bennett, DL Hamberg, LM Wang, B Hirsch, JA Gonzalez, RG Hunter, GJ AF Bennett, Debbie L. Hamberg, Leena M. Wang, Bing Hirsch, Joshua A. Gonzalez, R. Gilberto Hunter, George J. TI Diagnostic Yield of Delayed Phase Imaging in CT Angiography of the Head and Neck: A Retrospective Study SO PLOS ONE LA English DT Article ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; INTERNAL CAROTID ARTERIES; ISCHEMIC-STROKE; OCCLUSION; MANAGEMENT; DISEASE AB Purpose: To evaluate how often delayed images, obtained during neurovascular CTA, provide unique information relative to early phase imaging alone. Materials and Methods: Informed consent was waived by the institutional review body for this study. Neurovascular CTAs from January through June 2009 were searched to identify those with delayed phase imaging. Reports were reviewed to identify cases where delayed images provided potentially unique information. The studies with potentially unique information were re-interpreted to determine if the information was indeed unique. Results: 645 CTAs with delayed phase imaging were identified. There were 324 men and 310 women (median age 67 years; range 20-96 years). 59 studies (59/645: 9.1%) had findings on the delayed images. There were 13 cases with hemorrhage, with 4 showing progression on delayed views. Of the remaining 46 cases, 28 had occlusion of a vessel that did not reconstitute on the delayed images, 6 had occlusion of a vessel that did reconstitute on the delayed images, 7 had a string sign which was unchanged on the delayed views and 5 had no abnormal findings. Thus in 10 cases the findings were unique to the delayed images (10/645: 1.55%). Four showed active bleeding, three showed proximal occlusion with distal internal carotid filling from ophthalmic collaterals, two showed pial vessels filling distal to proximal MCA occlusion, and one showed retrograde vertebral artery filling due to subclavian steal. 95% confidence limits of the expected incidence of unique information from the delayed phase images are 0.6% - 2.5%. Conclusion: Obtaining delayed phase imaging for neurovascular CTA should be an active decision and not the default protocol. This avoids imaging with little, if any value. If delayed images had not been obtained in our cohort, no detriment in patient management would have occurred. C1 [Bennett, Debbie L.; Hirsch, Joshua A.; Gonzalez, R. Gilberto; Hunter, George J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hamberg, Leena M.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Wang, Bing] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Hunter, GJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM gjhunter@partners.org NR 26 TC 1 Z9 1 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 JUN 6 PY 2014 VL 9 IS 6 AR e99020 DI 10.1371/journal.pone.0099020 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP1YS UT WOS:000341869000092 PM 24905932 ER PT J AU Volkman, JE Luger, TM Harvey, KLL Hogan, TP Shimada, SL Amante, D McInnes, DK Feng, H Houston, TK AF Volkman, Julie E. Luger, Tana M. Harvey, Kimberly L. L. Hogan, Timothy P. Shimada, Stephanie L. Amante, Daniel McInnes, D. Keith Feng, Hua Houston, Thomas K. TI The National Cancer Institute's Health Information National Trends Survey [HINTS]: a national cross-sectional analysis of talking to your doctor and other healthcare providers for health information SO BMC FAMILY PRACTICE LA English DT Article DE Health information needs; Sources for health information; Doctor-patient communication; National cross-sectional survey ID DECISION-MAKING; INTERNET; SEEKING; COMMUNICATION; LITERACY; PROFILE; TRUST; WEB AB Background: The need to understand preferred sources of health information remains important to providing patient-centered care. The Internet remains a popular resource for health information, but more traditional sources may still be valid for patients during a recent health need. This study sought to understand the characteristics of patients that turn to their doctor or healthcare provider first for a recent health or medical information need. Methods: Using the national cross-sectional survey, Health Information National Trend Study [HINTS], characteristics of those who sought a doctor or healthcare provider for a recent health information need were compared to other sources. Weighted survey responses from Cycle 1 and Cycle 2 of the HINTS survey were used for multivariable logistic regression. Results: A total 5,307 patient responses were analyzed. Overall, those who seek a doctor or healthcare provider first for a health need are female, 46-64 years, White non-Hispanic, educated, in good health and users of the Internet. Yet, adjusted logistic regressions showed that those who sought a doctor or healthcare provider first during a recent health information need compared to other sources were most likely to be 65+ years, in poor health, less educated and have health insurance. Conclusions: Patients who seek their doctor or healthcare provider first for health information rather than other sources of information represent a unique population. Doctors or healthcare providers remain an important resource for these patients during recent needs, despite the wide use of the Internet as a source of health information. C1 [Volkman, Julie E.; Luger, Tana M.; Harvey, Kimberly L. L.; Hogan, Timothy P.; Shimada, Stephanie L.; McInnes, D. Keith; Feng, Hua; Houston, Thomas K.] US Dept Vet Affairs, eHlth Qual Enhancement Res Initiat, Bedford, MA 01730 USA. [Volkman, Julie E.; Harvey, Kimberly L. L.; Hogan, Timothy P.; Shimada, Stephanie L.; Amante, Daniel; Feng, Hua; Houston, Thomas K.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Shimada, Stephanie L.; McInnes, D. Keith] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02118 USA. RP Volkman, JE (reprint author), US Dept Vet Affairs, eHlth Qual Enhancement Res Initiat, 200 Springs Rd, Bedford, MA 01730 USA. EM julie.volkman@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX This material is the result of work supported with resources and the use of facilities at the U.S. Department of Veterans Affairs, eHealth Quality Enhancement Research Initiative (QUERI) EHQ 10-190 at the Bedford, MA Veterans Affairs Medical Center. Drs. Volkman, Luger, Hogan, Shimada, McInnes, Feng, Houston, and Ms. Harvey, and Mr. Amante's efforts were supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. A subset of these analyses was presented at the Society of Behavioral Medicine Annual Meeting, March 2013. NR 32 TC 3 Z9 3 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2296 J9 BMC FAM PRACT JI BMC Fam. Pract. PD JUN 6 PY 2014 VL 15 AR 111 DI 10.1186/1471-2296-15-111 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AK3ID UT WOS:000338315900001 PM 24906558 ER PT J AU Garcia-Garcia, HM Jang, IK Serruys, PW Kovacic, JC Narula, J Fayad, ZA AF Garcia-Garcia, Hector M. Jang, Ik-Kyung Serruys, Patrick W. Kovacic, Jason C. Narula, Jagat Fayad, Zahi A. TI Imaging Plaques to Predict and Better Manage Patients With Acute Coronary Events SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; cardiac imaging techniques; coronary artery disease; interventional ultrasonography; therapeutics ID OPTICAL COHERENCE TOMOGRAPHY; RANDOMIZED CONTROLLED-TRIAL; ACUTE MYOCARDIAL-INFARCTION; POSITRON-EMISSION-TOMOGRAPHY; MULTIDETECTOR COMPUTED-TOMOGRAPHY; PHOSPHOLIPASE A(2) INHIBITOR; INFRARED SPECTROSCOPY SYSTEM; THIN-CAP FIBROATHEROMA; INTRAVASCULAR ULTRASOUND; STATIN THERAPY AB Culprit lesions of patients, who have had an acute coronary syndrome commonly, are ruptured coronary plaques with superimposed thrombus. The precursor of such lesions is an inflamed thin-capped fibroatheroma. These plaques can be imaged by means of invasive techniques, such as intravascular ultrasound (and derived techniques), optical coherence tomography, and near-infrared spectroscopy. Often these patients exhibit similar (multiple) plaques beyond the culprit lesion. These remote plaques can be assessed noninvasively by computed tomographic angiography and MRI and also using invasive imaging. The detection of these remote plaques is not only feasible but also in natural history studies have been associated with clinical coronary events. Different systemic pharmacological treatments have been studied (mostly statins) with modest success and, therefore, newer approaches are being tested. Local treatment for such lesions is in its infancy and larger, prospective, and randomized trials are needed. This review will describe the pathological and imaging findings in culprit lesions of patients with acute coronary syndrome and the assessment of remote plaques. In addition, the pharmacological and local treatment options will be reviewed. C1 [Garcia-Garcia, Hector M.; Serruys, Patrick W.] Erasmus Univ, Thoraxctr, Med Ctr, Dept Cardiol, NL-3000 DR Rotterdam, Netherlands. [Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Kovacic, Jason C.; Narula, Jagat; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Dept Cardiol, Zena & Michael Wiener Cardiovasc Inst, New York, NY 10029 USA. [Kovacic, Jason C.; Narula, Jagat; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Dept Cardiol, Cardiovasc Res Ctr, New York, NY 10029 USA. [Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, Dept Radiol, New York, NY 10029 USA. RP Fayad, ZA (reprint author), Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, One Gustave L Levy Pl,POB 1030, New York, NY 10029 USA. EM zahi.fayad@mssm.edu FU National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) [R01 HL071021, R01 HL078667]; NIH/National Institute of Biomedical Imaging and Bioengineering [R01 EB009638]; NIH/NHLBI Program of Excellence in Nanotechnology Award [HHSN268201000045C]; NIH/National Center for Advancing Translational Sciences Clinical and Translational Science Awards [UL1TR000067]; National Institutes of Health [K08HL111330]; Leducq Foundation (Transatlantic Network of Excellence Award); AstraZeneca FX Z.A. Fayad acknowledges the support by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01 HL071021, R01 HL078667; NIH/National Institute of Biomedical Imaging and Bioengineering R01 EB009638; NIH/NHLBI Program of Excellence in Nanotechnology Award, Contract #HHSN268201000045C; and NIH/National Center for Advancing Translational Sciences Clinical and Translational Science Awards UL1TR000067 (Imaging Core). J. Kovacic acknowledges research support from National Institutes of Health (K08HL111330), The Leducq Foundation (Transatlantic Network of Excellence Award), and AstraZeneca NR 89 TC 13 Z9 13 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 6 PY 2014 VL 114 IS 12 BP 1904 EP 1917 DI 10.1161/CIRCRESAHA.114.302745 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AJ5FE UT WOS:000337707200006 PM 24902974 ER PT J AU He, HH Kise, Y Izadifar, A Urwyler, O Ayaz, D Parthasarthy, A Yan, B Erfurth, ML Dascenco, D Schmucker, D AF He, Haihuai Kise, Yoshiaki Izadifar, Azadeh Urwyler, Olivier Ayaz, Derya Parthasarthy, Akhila Yan, Bing Erfurth, Maria-Luise Dascenco, Dan Schmucker, Dietmar TI Cell-intrinsic requirement of Dscam1 isoform diversity for axon collateral formation SO SCIENCE LA English DT Article ID DENDRITIC SELF-AVOIDANCE; MOLECULAR DIVERSITY; DROSOPHILA-DSCAM; RECOGNITION; PROTOCADHERINS; ORGANIZATION; SPECIFICITY; ADHESION; GUIDANCE AB The isoform diversity of the Drosophila Dscam1 receptor is important for neuronal self-recognition and self-avoidance. A canonical model suggests that homophilic binding of identical Dscam1 receptor isoforms on sister dendrites ensures self-avoidance even when only a single isoform is expressed. We detected a cell-intrinsic function of Dscam1 that requires the coexpression of multiple isoforms. Manipulation of the Dscam1 isoform pool in single neurons caused severe disruption of collateral formation of mechanosensory axons. Changes in isoform abundance led to dominant dosage-sensitive inhibition of branching. We propose that the ratio of matching to nonmatching isoforms within a cell influences the Dscam1-mediated signaling strength, which in turn controls axon growth and growth cone sprouting. Cell-intrinsic use of surface receptor diversity may be of general importance in regulating axonal branching during brain wiring. C1 [He, Haihuai; Kise, Yoshiaki; Izadifar, Azadeh; Urwyler, Olivier; Ayaz, Derya; Yan, Bing; Erfurth, Maria-Luise; Dascenco, Dan; Schmucker, Dietmar] Vlaams Inst Biotechnol VIB Vesalius Res Ctr, Neuronal Wiring Lab, B-3000 Louvain, Belgium. [He, Haihuai; Kise, Yoshiaki; Izadifar, Azadeh; Urwyler, Olivier; Ayaz, Derya; Yan, Bing; Erfurth, Maria-Luise; Dascenco, Dan; Schmucker, Dietmar] Univ Louvain, Sch Med, Dept Oncol, B-3000 Louvain, Belgium. [He, Haihuai; Parthasarthy, Akhila] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Erfurth, Maria-Luise] Univ Kiel, Inst Biochem, D-24118 Kiel, Germany. RP Schmucker, D (reprint author), Vlaams Inst Biotechnol VIB Vesalius Res Ctr, Neuronal Wiring Lab, B-3000 Louvain, Belgium. EM schmucker@vib-kuleuven.be FU NIH [2RO1NS046747-05A1]; Fonds Wetenschappelijk Onderzoek (FWO) [G059611N, G078913N, G077013N]; BELSPO IUAP VII-20 "WIBRAIN project"; VIB; JSPS postdoctoral fellowship; Human Frontier Science Program long-term fellowship; FWO Ph.D. fellowship; Swiss National Science Foundation postdoctoral fellowship; Boehringer Ingelheim Fonds Ph.D. fellowship FX Supported by NIH grant 2RO1NS046747-05A1 (D. S.); Fonds Wetenschappelijk Onderzoek (FWO) grants G059611N, G078913N, and G077013N (D. S.); BELSPO IUAP VII-20 "WIBRAIN project" (D. S.); VIB funding; a JSPS postdoctoral fellowship and a Human Frontier Science Program long-term fellowship (Y.K.); an FWO Ph.D. fellowship (D. D.); a Swiss National Science Foundation postdoctoral fellowship (O.U.); and a Boehringer Ingelheim Fonds Ph.D. fellowship (M.-L. E.). We thank members of the lab and especially B. Hassan (VIB, Center for the Biology of Disease) for critical reading of the manuscript, discussions, and insightful comments. NR 20 TC 17 Z9 17 U1 2 U2 13 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 6 PY 2014 VL 344 IS 6188 BP 1182 EP 1186 DI 10.1126/science.1251852 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI3UU UT WOS:000336791200053 PM 24831526 ER PT J AU Cheah, CY Burbury, K Apperley, JF Huguet, F Pitini, V Gardembas, M Ross, DM Forrest, D Genet, P Rousselot, P Patton, N Smith, G Dunbar, CE Ito, S Aguiar, RCT Odenike, O Gimelfarb, A Cross, NCP Seymour, JF AF Cheah, Chan Y. Burbury, Kate Apperley, Jane F. Huguet, Francoise Pitini, Vincenzo Gardembas, Martine Ross, David M. Forrest, Donna Genet, Philippe Rousselot, Philippe Patton, Nigel Smith, Graeme Dunbar, Cynthia E. Ito, Sawa Aguiar, Ricardo C. T. Odenike, Olatoyosi Gimelfarb, Alla Cross, Nicholas C. P. Seymour, John F. TI Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib SO BLOOD LA English DT Article ID FACTOR RECEPTOR-BETA; CHRONIC MYELOMONOCYTIC LEUKEMIA; MYELOPROLIFERATIVE DISORDERS; MESYLATE; DISEASE; REARRANGEMENT; EOSINOPHILIA; EFFICACY; THERAPY; TEL AB Myeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n 5 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements. C1 [Cheah, Chan Y.; Burbury, Kate; Seymour, John F.] Peter MacCallum Canc Ctr, Dept Haematol, East Melbourne, Vic 8006, Australia. [Cheah, Chan Y.; Burbury, Kate; Seymour, John F.] Univ Melbourne, Parkville, Vic 3052, Australia. [Apperley, Jane F.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Haematol, London, England. [Huguet, Francoise] Ctr Hosp Univ, Dept Haematol, Toulouse, France. [Pitini, Vincenzo] Oncol Med & Trapianto Midollo Osseo, Messina, Italy. [Gardembas, Martine] Ctr Hosp Univ, Dept Haematol, Angers, France. [Ross, David M.] South Australia Pathol, Haematol, Adelaide, SA, Australia. [Ross, David M.] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Ross, David M.] Flinders Univ S Australia, Sch Med, Adelaide, SA 5001, Australia. [Forrest, Donna] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Genet, Philippe] Hop Victor Dupouy, Dept Haematol, Argenteuil, France. [Rousselot, Philippe] Hop Versailles, Dept Haematol, Le Chesnay, France. [Rousselot, Philippe] Univ Versailles St Quentin, Le Chesnay, France. [Patton, Nigel] Auckland City Hosp, Dept Haematol, Auckland, New Zealand. [Smith, Graeme] St James Univ Hosp, Dept Haematol, Leeds, W Yorkshire, England. [Dunbar, Cynthia E.; Ito, Sawa] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Aguiar, Ricardo C. T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Aguiar, Ricardo C. T.] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. [Odenike, Olatoyosi] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Gimelfarb, Alla] Northshore Univ Hlth Syst, Chicago, IL USA. [Cross, Nicholas C. P.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. RP Seymour, JF (reprint author), Peter MacCallum Canc Ctr, Dept Haematol, East Melbourne, Vic 8006, Australia. EM john.seymour@petermac.org RI Cross, Nicholas/B-4817-2009; OI Cross, Nicholas/0000-0001-5481-2555; Ross, David/0000-0001-7171-2935; Cheah, Chan Yoon/0000-0001-7988-1565 FU Victorian Cancer Agency [CTCB11_18]; Haematology Society of Australia and New Zealand FX The authors thank Dr N. Carvalho and Dr E. Velloso (Sao Paulo, Brazil) for clinical updates and Professor Francois Xavier Mahon for providing molecular analysis for French patients. This work was funded in part by the Victorian Cancer Agency (grant CTCB11_18) and the Haematology Society of Australia and New Zealand (New Investigator Scholarship). NR 25 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 5 PY 2014 VL 123 IS 23 BP 3574 EP 3577 DI 10.1182/blood-2014-02-555607 PG 4 WC Hematology SC Hematology GA AQ2LF UT WOS:000342616900016 PM 24687085 ER PT J AU Armand, P Kim, HT Logan, BR Wang, ZW Alyea, EP Kalaycio, ME Maziarz, RT Antin, JH Soiffer, RJ Weisdorf, DJ Rizzo, JD Horowitz, MM Saber, W AF Armand, Philippe Kim, Haesook T. Logan, Brent R. Wang, Zhiwei Alyea, Edwin P. Kalaycio, Matt E. Maziarz, Richard T. Antin, Joseph H. Soiffer, Robert J. Weisdorf, Daniel J. Rizzo, J. Douglas Horowitz, Mary M. Saber, Wael TI Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERNATIONAL-BLOOD; MARROW; CYTOGENETICS; MORTALITY; SCORE AB Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13 131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. TheDRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories. C1 [Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Soiffer, Robert J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Armand, Philippe; Kim, Haesook T.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Logan, Brent R.; Wang, Zhiwei; Rizzo, J. Douglas; Horowitz, Mary M.; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Logan, Brent R.] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Kalaycio, Matt E.] Cleveland Clin, Dept Hematol Oncol & Blood Disorders, Cleveland, OH 44106 USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Knight Canc Inst, Ctr Hematol Malignancies, Portland, OR 97201 USA. [Weisdorf, Daniel J.] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. RP Armand, P (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM parmand@partners.org FU American Society of Clinical Oncology Career Development Award; National Institute of Allergy and Infectious Diseases (NIAID) [U19 AI 29530]; National Heart, Lung and Blood Institute (NHLBI) [PO1 HL 070149]; Public Health Service from the National Cancer Institute (NCI) [U24-CA76518]; NHLBI; NIAID; NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration/Department of Health and Human Services [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos, Inc.; Amgen, Inc.; Angioblast FX This work was supported by an American Society of Clinical Oncology Career Development Award (P.A.), by grant U19 AI 29530 from the National Institute of Allergy and Infectious Diseases (NIAID), and grant PO1 HL 070149 from the National Heart, Lung and Blood Institute (NHLBI). The Center for International Blood and Marrow Transplant Research is supported by Public Health Service grant/cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the NHLBI, and the NIAID, by grant/cooperative agreement 5U01HL069294 from NHLBI and NCI, by contract HHSH234200637015C with Health Resources and Services Administration/Department of Health and Human Services), by grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research, and by grants from Allos, Inc.; Amgen, Inc.; Angioblast; an anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; Therakos, Inc.; and Wellpoint, Inc. NR 17 TC 72 Z9 72 U1 0 U2 4 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 5 PY 2014 VL 123 IS 23 BP 3664 EP 3671 DI 10.1182/blood-2014-01-552984 PG 8 WC Hematology SC Hematology GA AQ2LF UT WOS:000342616900027 PM 24744269 ER PT J AU Kiskinis, E Sandoe, J Williams, LA Boulting, GL Moccia, R Wainger, BJ Han, S Peng, T Thams, S Mikkilineni, S Mellin, C Merkle, FT Davis-Dusenbery, BN Ziller, M Oakley, D Ichida, J Di Costanzo, S Atwater, N Maeder, ML Goodwin, MJ Nemesh, J Handsaker, RE Paull, D Noggle, S McCarroll, SA Joung, JK Woolf, CJ Brown, RH Eggan, K AF Kiskinis, Evangelos Sandoe, Jackson Williams, Luis A. Boulting, Gabriella L. Moccia, Rob Wainger, Brian J. Han, Steve Peng, Theodore Thams, Sebastian Mikkilineni, Shravani Mellin, Cassidy Merkle, Florian T. Davis-Dusenbery, Brandi N. Ziller, Michael Oakley, Derek Ichida, Justin Di Costanzo, Stefania Atwater, Nick Maeder, Morgan L. Goodwin, Mathew J. Nemesh, James Handsaker, Robert E. Paull, Daniel Noggle, Scott McCarroll, Steven A. Joung, J. Keith Woolf, Clifford J. Brown, Robert H. Eggan, Kevin TI Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1 SO CELL STEM CELL LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CU,ZN SUPEROXIDE-DISMUTASE; UNFOLDED PROTEIN RESPONSE; PLURIPOTENT STEM-CELLS; HEXANUCLEOTIDE REPEAT; ER STRESS; C9ORF72; EXPANSION; GENOME; VULNERABILITY AB Althoughmany distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS. C1 [Kiskinis, Evangelos; Sandoe, Jackson; Williams, Luis A.; Boulting, Gabriella L.; Moccia, Rob; Han, Steve; Peng, Theodore; Mikkilineni, Shravani; Merkle, Florian T.; Davis-Dusenbery, Brandi N.; Ichida, Justin; Di Costanzo, Stefania; Atwater, Nick; Eggan, Kevin] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Kiskinis, Evangelos; Sandoe, Jackson; Williams, Luis A.; Boulting, Gabriella L.; Moccia, Rob; Han, Steve; Peng, Theodore; Mikkilineni, Shravani; Merkle, Florian T.; Davis-Dusenbery, Brandi N.; Ziller, Michael; Ichida, Justin; Di Costanzo, Stefania; Atwater, Nick; Eggan, Kevin] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Kiskinis, Evangelos; Sandoe, Jackson; Williams, Luis A.; Moccia, Rob; Han, Steve; Peng, Theodore; Mikkilineni, Shravani; Merkle, Florian T.; Davis-Dusenbery, Brandi N.; Atwater, Nick; Nemesh, James; Handsaker, Robert E.; McCarroll, Steven A.; Eggan, Kevin] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02138 USA. [Wainger, Brian J.; Mellin, Cassidy; Woolf, Clifford J.] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Wainger, Brian J.; Mellin, Cassidy; Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Wainger, Brian J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. [Thams, Sebastian; Oakley, Derek] Columbia Univ, Project ALS Jenifer Estess Lab Stem Cell Res, Dept Pathol, Ctr Motor Neuron Biol & Dis MNC, New York, NY 10027 USA. [Thams, Sebastian; Oakley, Derek] Columbia Univ, Project ALS Jenifer Estess Lab Stem Cell Res, Dept Neurol, Ctr Motor Neuron Biol & Dis MNC, New York, NY 10027 USA. [Thams, Sebastian; Oakley, Derek] Columbia Univ, Project ALS Jenifer Estess Lab Stem Cell Res, Dept Neurosci, Ctr Motor Neuron Biol & Dis MNC, New York, NY 10027 USA. [Thams, Sebastian; Oakley, Derek] CSCI, New York, NY 10027 USA. [Maeder, Morgan L.; Goodwin, Mathew J.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Maeder, Morgan L.; Goodwin, Mathew J.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Nemesh, James; Handsaker, Robert E.; McCarroll, Steven A.; Brown, Robert H.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. [Nemesh, James; Handsaker, Robert E.; McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Paull, Daniel; Noggle, Scott] New York Stem Cell Fdn, Res Inst, New York, NY 10023 USA. RP Eggan, K (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM eggan@mcb.harvard.edu OI Merkle, Florian/0000-0002-8513-2998 FU ALS Therapy Alliance, Project ALS, P2ALS; Angel Fund; Pierre L. de Bourgknecht ALS Research Foundation; Al-Athel ALS Research Foundation; ALS Family Charitable Foundation; NIH/NINDS [1R01NS050557]; NIH/NINDS (NINDS ARRA Award) [RC2-NS070-342]; Target ALS, Project A.L.S., P2ALS; NINDS GO grant [5RC2NS069395-02]; NINDS R24 [1U24NS078736-01]; HHMI; NIH Director's Pioneer Award DP1 [OD006862] FX We thank H. Mitsumoto and D. McKenna-Yasek for performing skin biopsies; K. Koszka for maintaining mice; all members of the Eggan Lab; and C. Henderson and M. W. Amoroso for helpful comments on the manuscript. R. H. B. acknowledges generous support from the ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the NIH/NINDS (1R01NS050557 and NINDS ARRA Award RC2-NS070-342). This work was funded by Target ALS, Project A.L.S., P2ALS, NINDS GO grant (5RC2NS069395-02), NINDS R24 (1U24NS078736-01), the HHMI, and the NIH Director's Pioneer Award DP1 (OD006862). E. K. is a Charles A. King Trust Postdoctoral fellow, and K. E. is an HHMI early career scientist. J.K.J. has financial interests in Editas Medicine and Transposagen Biopharmaceuticals. J.K.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 42 TC 96 Z9 101 U1 6 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUN 5 PY 2014 VL 14 IS 6 BP 781 EP 795 DI 10.1016/j.stem.2014.03.004 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AO3QK UT WOS:000341248500015 PM 24704492 ER PT J AU Rao, RR Long, JZ White, JP Svensson, KJ Lou, J Lokurkar, I Jedrychowski, MP Ruas, JL Wrann, CD Lo, JC Camera, DM Lachey, J Gygi, S Seehra, J Hawley, JA Spiegelman, BM AF Rao, Rajesh R. Long, Jonathan Z. White, James P. Svensson, Katrin J. Lou, Jesse Lokurkar, Isha Jedrychowski, Mark P. Ruas, Jorge L. Wrann, Christiane D. Lo, James C. Camera, Donny M. Lachey, Jenn Gygi, Steven Seehra, Jasbir Hawley, John A. Spiegelman, Bruce M. TI Meteorin-like Is a Hormone that Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis SO CELL LA English DT Article ID SKELETAL-MUSCLE; ADAPTIVE THERMOGENESIS; INSULIN-RESISTANCE; WHITE FAT; EXERCISE; PGC-1-ALPHA; MACROPHAGES; COACTIVATOR; ACTIVATION; OBESITY AB Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-alpha (PGC1-alpha 4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases. C1 [Rao, Rajesh R.; Long, Jonathan Z.; White, James P.; Svensson, Katrin J.; Lou, Jesse; Lokurkar, Isha; Wrann, Christiane D.; Lo, James C.; Spiegelman, Bruce M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Rao, Rajesh R.; Long, Jonathan Z.; White, James P.; Svensson, Katrin J.; Lou, Jesse; Lokurkar, Isha; Jedrychowski, Mark P.; Wrann, Christiane D.; Lo, James C.; Gygi, Steven; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ruas, Jorge L.] Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden. [Camera, Donny M.; Hawley, John A.] Australian Catholic Univ, Dept Exercise Sci, Exercise & Nutr Res Grp, Fitzroy, Vic 3065, Australia. [Hawley, John A.] Liverpool John Moores Univ, Res Inst Sport & Exercise Sci, Liverpool L3 2AJ, Merseyside, England. [Lachey, Jenn; Seehra, Jasbir] Ember Therapeut Inc, Watertown, MA 02472 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu OI Svensson, Katrin J/0000-0001-5376-5128; Ruas, Jorge/0000-0002-1110-2606 FU National Institutes of Health [DK061562]; JPB foundation; Irvington Institute Fellowship Program of the Cancer Research Institute; American Diabetics Association/Canadian Diabetics Association (ADA/CDA) joint postdoctoral fellowship; Swedish Research Council FX We thank members of the Spiegelman laboratory for useful discussions and suggestions on the manuscript. This work was funded by National Institutes of Health grant (DK061562) to B. M. S. and a grant from the JPB foundation. R. R. R. is supported by Irvington Institute Fellowship Program of the Cancer Research Institute. J.Z.L. is supported by the American Diabetics Association/Canadian Diabetics Association (ADA/CDA) joint postdoctoral fellowship. K.J.S. was supported by a Swedish Research Council postdoctoral fellowship. B. M. S. is a consultant and shareholder in Ember Therapeutics. NR 32 TC 140 Z9 148 U1 4 U2 39 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 5 PY 2014 VL 157 IS 6 BP 1279 EP 1291 DI 10.1016/j.cell.2014.03.065 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN8UV UT WOS:000340881400007 PM 24906147 ER PT J AU Dimitrova, N Zamudio, JR Jong, RM Soukup, D Resnick, R Sarma, K Ward, AJ Raj, A Lee, JT Sharp, PA Jacks, T AF Dimitrova, Nadya Zamudio, Jesse R. Jong, Robyn M. Soukup, Dylan Resnick, Rebecca Sarma, Kavitha Ward, Amanda J. Raj, Arjun Lee, Jeannie T. Sharp, Phillip A. Jacks, Tyler TI LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint SO MOLECULAR CELL LA English DT Article ID REPRESSIVE COMPLEX 2; LONG NONCODING RNAS; P53; DIFFERENTIATION; TRANSCRIPTION; RESTORATION; PROGRESSION; SENESCENCE; PATHWAY; ERNAS AB The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression. C1 [Dimitrova, Nadya; Zamudio, Jesse R.; Jong, Robyn M.; Soukup, Dylan; Resnick, Rebecca; Sharp, Phillip A.; Jacks, Tyler] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Dimitrova, Nadya; Zamudio, Jesse R.; Jong, Robyn M.; Soukup, Dylan; Resnick, Rebecca; Sharp, Phillip A.; Jacks, Tyler] MIT, Dept Biol, Cambridge, MA 02142 USA. [Sarma, Kavitha; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Ward, Amanda J.] Isis Pharmaceut Inc, Carlsbad, CA 92010 USA. [Raj, Arjun] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Jacks, T (reprint author), MIT, Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02142 USA. EM tjacks@mit.edu OI Ward, Amanda/0000-0002-7000-2453; Raj, Arjun/0000-0002-2915-6960 FU NIH; Howard Hughes Medical Institute; Ludwig Center for Molecular Oncology at MIT; Damon Runyon Fellowship Award FX We thank John Rinn, Vasilena Gocheva, and Thales Papagiannakopoulos for critical review of the manuscript. We are extremely grateful to Dirk Hockemeyer (UC Berkeley) for technical assistance and reagents related to the reprogramming experiment and to Jerry Ruth (Biosearch Technologies) for generously providing RNA FISH reagents. We are grateful to Aurora Burds O'Connor from the Rippel Mouse ES Cell and Transgenics Facility of the Swanson Biotechnology Center. This work was supported by NIH (T.J.), the Howard Hughes Medical Institute, and the Ludwig Center for Molecular Oncology at MIT. N.D. was supported by a Damon Runyon Fellowship Award. T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar at MIT. 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 39 TC 84 Z9 87 U1 3 U2 24 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 5 PY 2014 VL 54 IS 5 BP 777 EP 790 DI 10.1016/j.molcel.2014.04.025 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5JG UT WOS:000340626100008 PM 24857549 ER PT J AU Jarvik, GP Amendola, LM Berg, JS Brothers, K Clayton, EW Chung, W Evans, BJ Evans, JP Fullerton, SM Gallego, CJ Garrison, NA Gray, SW Holm, IA Kullo, IJ Lehmann, LS McCarty, C Prows, CA Rehm, HL Sharp, RR Salama, J Sanderson, S Van Driest, SL Williams, MS Wolf, SM Wolf, WA Burke, W AF Jarvik, Gail P. Amendola, Laura M. Berg, Jonathan S. Brothers, Kyle Clayton, Ellen W. Chung, Wendy Evans, Barbara J. Evans, James P. Fullerton, Stephanie M. Gallego, Carlos J. Garrison, Nanibaa' A. Gray, Stacy W. Holm, Ingrid A. Kullo, Iftikhar J. Lehmann, Lisa Soleymani McCarty, Cathy Prows, Cynthia A. Rehm, Heidi L. Sharp, Richard R. Salama, Joseph Sanderson, Saskia Van Driest, Sara L. Williams, Marc S. Wolf, Susan M. Wolf, Wendy A. Burke, Wylie CA eMERGE Act-ROR Comm CERC Comm CSER Act-ROR Working Grp TI Return of Genomic Results to Research Participants: The Floor, the Ceiling, and the Choices In Between SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MANAGING INCIDENTAL FINDINGS; ACMG RECOMMENDATIONS; CLINICAL GENOMICS; PATIENT AUTONOMY; WORKING GROUP; CHILDREN; EXOME; BREAST; CANCER; ISSUES AB As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles. C1 [Jarvik, Gail P.; Amendola, Laura M.; Gallego, Carlos J.; Salama, Joseph] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Berg, Jonathan S.; Evans, James P.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Brothers, Kyle] Hudson Alpha Inst Biotechnol, Huntsville, AL 35806 USA. [Brothers, Kyle] Univ Louisville, Dept Pediat, Louisville, KY 40292 USA. [Clayton, Ellen W.; Garrison, Nanibaa' A.; Van Driest, Sara L.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37204 USA. [Clayton, Ellen W.; Garrison, Nanibaa' A.; Van Driest, Sara L.] Vanderbilt Univ, Med Ctr, Ctr Biomed Eth & Soc, Nashville, TN 37204 USA. [Chung, Wendy] Columbia Univ, New York, NY 10032 USA. [Evans, Barbara J.] Univ Houston, Ctr Law, Houston, TX 77204 USA. [Fullerton, Stephanie M.; Burke, Wylie] Univ Washington, Dept Bioeth & Humanities, Seattle, WA 98195 USA. [Gray, Stacy W.; Lehmann, Lisa Soleymani; Rehm, Heidi L.] Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Gray, Stacy W.; Lehmann, Lisa Soleymani; Rehm, Heidi L.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Gray, Stacy W.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Holm, Ingrid A.; Wolf, Wendy A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Holm, Ingrid A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Holm, Ingrid A.; Wolf, Wendy A.] Boston Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. [Holm, Ingrid A.; Wolf, Wendy A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [McCarty, Cathy] Essentia Inst Rural Hlth, Duluth, MN 55805 USA. [Prows, Cynthia A.] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Prows, Cynthia A.] Cincinnati Childrens Hosp Med Ctr, Div Patient Serv, Cincinnati, OH 45229 USA. [Sharp, Richard R.] Mayo Clin, Biomed Eth Program, Rochester, MN 55905 USA. [Sanderson, Saskia] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA 17822 USA. [Wolf, Susan M.] Univ Minnesota, Sch Med, Law Sch, Minneapolis, MN 55455 USA. [Wolf, Susan M.] Univ Minnesota, Consortium Law & Values Hlth Environm & Life Sci, Minneapolis, MN 55455 USA. RP Jarvik, GP (reprint author), Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. EM pair@u.washington.edu RI Jarvik, Gail/N-6476-2014; Burke, William/C-1203-2012; OI Jarvik, Gail/0000-0002-6710-8708; Clayton, Ellen/0000-0002-0308-4110; Pan, Vivian/0000-0002-1666-9273 FU NIH [U01HG006507, U01 HG006487, U01 HG007307, U01HG007307, U01HG006500, U01 G006492]; Electronic Medical Records and Genomics (eMERGE) Network [U01HG006375, U01HG006378, U01HG04603, U01HG006828, U01HG006379, U01HG006382]; eMERGE Return of Results awards [R21HG00612, R01 HG006615, R01 HG004500, 1R01CA154517]; Robert Wood Johnson Foundation Investigator Award [69763] FX This work was supported by NIH Clinical Sequencing Exploratory Research (CSER) awards U01HG006507, U01 HG006487, U01 HG007307, U01HG007307, U01HG006500, and U01 G006492; Electronic Medical Records and Genomics (eMERGE) Network awards U01HG006375, U01HG006378, U01HG04603, U01HG006828, U01HG006379, and U01HG006382; eMERGE Return of Results awards R21HG00612, R01 HG006615, R01 HG004500, and 1R01CA154517; and Robert Wood Johnson Foundation Investigator Award 69763. All views expressed are those of the authors and do not necessarily reflect the views of the funding agencies, the CSER Consortium, or the eMERGE Network. L.A.H., J.M., C.H., K.S., N.L., S.S., and C.C. are members of the NIH CSER staff team, responsible for scientific program management of the CSER program. NR 40 TC 84 Z9 84 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 5 PY 2014 VL 94 IS 6 BP 818 EP 826 DI 10.1016/j.ajhg.2014.04.009 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AJ0HK UT WOS:000337331200003 PM 24814192 ER PT J AU Kapoor, A Sekar, RB Hansen, NF Fox-Talbot, K Morley, M Pihur, V Chatterjee, S Brandimarto, J Moravec, CS Pulit, SL Pfeufer, A Mullikin, J Ross, M Green, ED Bentley, D Newton-Cheh, C Boerwinkle, E Tomaselli, GF Cappola, TP Arking, DE Halushka, MK Chakravarti, A AF Kapoor, Ashish Sekar, Rajesh B. Hansen, Nancy F. Fox-Talbot, Karen Morley, Michael Pihur, Vasyl Chatterjee, Sumantra Brandimarto, Jeffrey Moravec, Christine S. Pulit, Sara L. Pfeufer, Arne Mullikin, Jim Ross, Mark Green, Eric D. Bentley, David Newton-Cheh, Christopher Boerwinkle, Eric Tomaselli, Gordon F. Cappola, Thomas P. Arking, Dan E. Halushka, Marc K. Chakravarti, Aravinda CA QT Interval-Int GWAS Consortium TI An Enhancer Polymorphism at the Cardiomyocyte Intercalated Disc Protein NOS1AP Locus Is a Major Regulator of the QT Interval SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NITRIC-OXIDE SYNTHASE; SUDDEN CARDIAC DEATH; SIMPLE SEQUENCE REPEATS; HUMAN GENOME; COMMON VARIANTS; GENETIC-VARIATION; HUMAN-CELLS; REPOLARIZATION; CHROMATIN; DURATION AB QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders. C1 [Kapoor, Ashish; Pihur, Vasyl; Chatterjee, Sumantra; Arking, Dan E.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Sekar, Rajesh B.; Tomaselli, Gordon F.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21205 USA. [Fox-Talbot, Karen; Halushka, Marc K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Hansen, Nancy F.; Mullikin, Jim; Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Morley, Michael; Brandimarto, Jeffrey; Cappola, Thomas P.] Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Moravec, Christine S.] Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44195 USA. [Pulit, Sara L.] Univ Med Ctr Utrecht, NL-3584 CX Utrecht, Netherlands. [Pfeufer, Arne] Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol, D-85764 Neuherberg, Germany. [Pfeufer, Arne] Isar Med Zentrum, D-80331 Munich, Germany. [Ross, Mark; Bentley, David] Illumina United Kingdom, Saffron Walden CB10 1XL, Essex, England. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. RP Chakravarti, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. EM aravinda@jhmi.edu RI Pfeufer, Arne/B-6634-2013; OI Halushka, Marc/0000-0002-7112-7389 FU NIH [RO1HL086694, RO1HL105993]; Donald W. Reynolds Foundation FX We are grateful to William C. Claycomb (Louisiana State University, New Orleans) for providing HL1 cells, Norman Barker (Johns Hopkins University, Baltimore) for help with imaging, and Akhilesh Pandey and Andrew S. McCallion (Johns Hopkins University, Baltimore) for critical discussions. We also thank Ashley O'Connor and Maria X. Sosa (Johns Hopkins University, Baltimore) for technical assistance, Paula Kokko-Gonzales, Louise Fraser, Niall Gormley, and Terena James (Illumina) for sequencing, and Ankit Rakha (Johns Hopkins University Baltimore), Keira Cheetham, and Lisa Murray (Illumina) for computational support. This work was supported by NIH grants RO1HL086694 and RO1HL105993 and funds from the Donald W. Reynolds Foundation. A.C. is on the Scientific Advisory Board of Biogen Idec and this potential competing interest is managed by the policies of the Johns Hopkins University, School of Medicine. M.R. and D.B. are employees of Illumina, Inc., a public company that develops and markets systems for genetic analysis. NR 67 TC 24 Z9 24 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 5 PY 2014 VL 94 IS 6 BP 854 EP 869 DI 10.1016/j.ajhg.2014.05.001 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AJ0HK UT WOS:000337331200006 PM 24857694 ER PT J AU Blumenthal, I Ragavendran, A Erdin, S Klei, L Sugathan, A Guide, JR Manavalan, P Zhou, JQ Wheeler, VC Levin, JZ Ernst, C Roeder, K Devlin, B Gusella, JF Talkowski, ME AF Blumenthal, Ian Ragavendran, Ashok Erdin, Serkan Klei, Lambertus Sugathan, Aarathi Guide, Jolene R. Manavalan, Poornima Zhou, Julian Q. Wheeler, Vanessa C. Levin, Joshua Z. Ernst, Carl Roeder, Kathryn Devlin, Bernie Gusella, James F. Talkowski, Michael E. TI Transcriptional Consequences of 16p11.2 Deletion and Duplication in Mouse Cortex and Multiplex Autism Families SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DE-NOVO MUTATIONS; DIFFERENTIAL EXPRESSION ANALYSIS; LONG-RANGE INTERACTIONS; COPY-NUMBER VARIATIONS; SPECTRUM DISORDERS; INTELLECTUAL DISABILITY; MICRODELETION SYNDROME; ENRICHMENT ANALYSIS; FUNCTIONAL IMPACT; R PACKAGE AB Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis. C1 [Blumenthal, Ian; Ragavendran, Ashok; Erdin, Serkan; Sugathan, Aarathi; Guide, Jolene R.; Manavalan, Poornima; Wheeler, Vanessa C.; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Blumenthal, Ian; Ragavendran, Ashok; Erdin, Serkan; Sugathan, Aarathi; Guide, Jolene R.; Manavalan, Poornima; Wheeler, Vanessa C.; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Klei, Lambertus; Devlin, Bernie] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15213 USA. [Levin, Joshua Z.; Gusella, James F.; Talkowski, Michael E.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02141 USA. [Ernst, Carl] McGill Univ, Dept Psychiat, Douglas Hosp, Res Inst, Verdun, PQ H4H 1R3, Canada. [Zhou, Julian Q.; Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02141 USA. [Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02141 USA. [Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02141 USA. [Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02141 USA. [Gusella, James F.; Talkowski, Michael E.] Harvard Univ, Sch Med, Boston, MA 02141 USA. RP Talkowski, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. EM talkowski@chgr.mgh.harvard.edu RI Erdin, Serkan/B-4988-2008; OI Erdin, Serkan/0000-0001-6587-2625; Zhou, Quan/0000-0001-9602-2092 FU National Institute of Mental Health [MH095867, R37 MH057881, 1U24MH081810]; Simons Foundation for Autism Research; Nancy Lurie Marks Family Foundation; Brain and Behavorial Research Foundation (NARSAD); Autism Genetic Resource Exchange (AGRE) and Autism Speaks FX We thank A. Mills for development of the mouse models and AGRE for providing biological materials. These studies were supported by the National Institute of Mental Health (MH095867 to M.E.T., R37 MH057881 to B.D. and K.R.), the Simons Foundation for Autism Research (M.E.T., J.F.G.), the Nancy Lurie Marks Family Foundation (M.E.T., J.F.G.), and the Brain and Behavorial Research Foundation (NARSAD; M.E.T.). We also acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Autism Speaks (to J.F.G.). We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). NR 70 TC 24 Z9 24 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 5 PY 2014 VL 94 IS 6 BP 870 EP 883 DI 10.1016/j.ajhg.2014.05.004 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AJ0HK UT WOS:000337331200007 PM 24906019 ER PT J AU Ogino, S Lochhead, P Giovannucci, E Meyerhardt, JA Fuchs, CS Chan, AT AF Ogino, S. Lochhead, P. Giovannucci, E. Meyerhardt, J. A. Fuchs, C. S. Chan, A. T. TI Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology SO ONCOGENE LA English DT Review DE molecular pathologic epidemiology; systems biology; systems pathology; network medicine; unique tumor principle; translational epidemiology ID ISLAND METHYLATOR PHENOTYPE; RECEPTOR INHIBITOR CETUXIMAB; III COLON-CANCER; BODY-MASS INDEX; KRAS-MUTATION; MICROSATELLITE INSTABILITY; PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; POOR SURVIVAL; TASK-FORCE AB Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the 'Provocative Questions' in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the 'colorectal continuum' paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as 'epidemiology of molecular heterogeneity of disease'. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine clinical practices. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biological sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care. C1 [Ogino, S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ogino, S.; Meyerhardt, J. A.; Fuchs, C. S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Ogino, S.; Giovannucci, E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lochhead, P.] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Giovannucci, E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, E.; Fuchs, C. S.; Chan, A. T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Chan, A. T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Ogino, S (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU USA National Institute of Health (NIH) [R01 CA151993, R01 CA137178, P50 CA127003, R01 CA124908, P01 CA87969, UM1 CA167552] FX This work was supported by grants from the USA National Institute of Health (NIH) (R01 CA151993 (to SO), R01 CA137178 (to ATC), P50 CA127003 (to CSF), R01 CA124908 (to CSF), P01 CA87969 (to SEH) and UM1 CA167552 to WCW). ATC is a Damon Runyon Clinical Investigator. NR 171 TC 39 Z9 40 U1 4 U2 44 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 5 PY 2014 VL 33 IS 23 BP 2949 EP 2955 DI 10.1038/onc.2013.244 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AI9EL UT WOS:000337232200001 PM 23792451 ER PT J AU Manthiram, K Blood, EA Kuppuswamy, V Martins, Y Narayan, A Burmeister, K Parvathy, K Hassan, A AF Manthiram, Kalpana Blood, Emily A. Kuppuswamy, Vasanthan Martins, Yolanda Narayan, Athi Burmeister, Kelly Parvathy, K. Hassan, Areej TI Predictors of optional immunization uptake in an urban south Indian population SO VACCINE LA English DT Article DE Immunization coverage; Optional immunizations; Parental attitudes ID CHILDHOOD IMMUNIZATION; ROTAVIRUS VACCINATION; DEVELOPING-COUNTRIES; COST-EFFECTIVENESS; CHILDREN; VACCINES; MORTALITY; REASONS; ATTITUDES; ISTANBUL AB Background: In Tamil Nadu, India, bacille Calmette-Guerin, diphtheria-tetanus-pertussis, oral poliomyelitis, hepatitis B, and measles vaccines are part of the routine immunization schedule and are available free from government health centers. All other vaccines are optional and available in the private sector at a cost to families. This study assesses immunization rates of routine and optional vaccines and examines parental attitudes toward vaccines in Pallavapuram, Tamil Nadu. Methods: The cluster sampling method was used to estimate immunization coverage. Seven children 18 to 36 months old were selected from 30 clusters for a total sample of 210 children. Demographics and vaccination data were collected from interviews and immunization records. Predictors of vaccination status were identified with logistic regression models. In addition, 21 parents participated in semi-structured interviews regarding their attitudes toward vaccination. Interviews were analyzed qualitatively for themes. Results: Eighty one percent of children were fully immunized with routine vaccines. However, only 21% received all "major" optional vaccines, defined as 3 doses of Haemophilus influenzae type b vaccine, one dose of measles, mumps, rubella vaccine, and one dose of varicella zoster virus vaccine. Birth in a private hospital (OR 5.6, 95% CI 1.3 to 22.9, P < 0.01), higher income (P = 0.03), and maternal completion of high school (OR 6.4, 95% CI 1.5 to 27.6, P < 0.01) were significant predictors of receiving all major optional vaccines. Elucidated themes from interviews included (1) strong parental support for immunizations, (2) low concern for side effects, and (3) low uptake of optional vaccines due to high cost and lack of awareness. Conclusions: Coverage of optional vaccines is low despite positive attitudes toward immunizations. Efforts to reduce cost and increase awareness of these vaccines particularly among low-income families or to include these vaccines in the routine schedule may increase uptake and reduce morbidity and mortality from vaccine-preventable diseases. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Manthiram, Kalpana] Vanderbilt Univ, Med Ctr, Div Pediat Infect Dis, Nashville, TN 37203 USA. [Blood, Emily A.; Hassan, Areej] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Adolescent Med, Boston, MA USA. [Blood, Emily A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Clin Res Ctr, Boston, MA USA. [Kuppuswamy, Vasanthan] Med Univ S Carolina, Charleston, SC 29425 USA. [Martins, Yolanda; Burmeister, Kelly] Dana Farber Canc Inst, Ctr Populat Sci, Boston, MA 02115 USA. [Narayan, Athi] Emory Johns Creek Hosp, Dept Neonatal, Johns Creek, GA USA. [Parvathy, K.] Pallavaram Childrens Med Ctr, Pallavaram, Tamil Nadu, India. RP Manthiram, K (reprint author), Vanderbilt Univ, Med Ctr, Div Pediat Infect Dis, Nashville, TN 37203 USA. EM Kalpana.manthiram@vanderbilt.edu OI Martins, Yolanda/0000-0002-3983-3531 FU Leadership Education in Adolescent Health training grant from the Maternal and Child Health Bureau at the Health Resources and Services Administration [T71MC00009]; Schiesman Traveling Fellowship from Boston Children's Hospital FX The authors would like to thank the Pallavapuram community for participating in this study. Funding was provided from the Leadership Education in Adolescent Health training grant #T71MC00009 from the Maternal and Child Health Bureau at the Health Resources and Services Administration and the Schiesman Traveling Fellowship from Boston Children's Hospital. Dr. S. Swarnalakshmi, PhD, Ms. Geetha, and Dr. Suniti Solomon, MD, at YRG-CARE kindly reviewed the ethical aspects of the project in India. Mr. and Mrs. Kuppuswamy, Ms. Mary, Ms. Anjali, Ms. Dhanam, Ms. Pilomina, Mr. Vignesh, Mr. Rajendran Venkattareddy, Mr. Ravikumar, Ms. Uma Ganapathi, Mr. Shankar Kumar, Mr. Kolandavel Ramasamy, and Ms. Rajeswari Manthiram were graciously helpful in data collection and translation. Drs. Kathryn Edwards, MD, Elizabeth Woods, MD, Heather Corliss, PhD, Atsuko Koyama, MD, and Kathryn Brigham, MD provided helpful input on study design and/or manuscript review. NR 45 TC 3 Z9 3 U1 0 U2 4 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 5 PY 2014 VL 32 IS 27 BP 3417 EP 3423 DI 10.1016/j.vaccine.2014.04.012 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AI8WT UT WOS:000337208400012 PM 24736005 ER PT J AU Godinho, SA Picone, R Burute, M Dagher, R Su, Y Leung, CT Polyak, K Brugge, JS Thery, M Pellman, D AF Godinho, Susana A. Picone, Remigio Burute, Mithila Dagher, Regina Su, Ying Leung, Cheuk T. Polyak, Kornelia Brugge, Joan S. Thery, Manuel Pellman, David TI Oncogene-like induction of cellular invasion from centrosome amplification SO NATURE LA English DT Article ID HUMAN BREAST-CANCER; CENTRIOLE DUPLICATION; CHROMOSOMAL INSTABILITY; SPINDLE CHECKPOINT; JUNCTION FORMATION; CELLS; EXPRESSION; ROLES; RAC; TUMORIGENESIS AB Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear(1). Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost(2). Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours(3), raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumour progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behaviour is similar to that induced by overexpression of the breast cancer oncogene ERBB2 (ref.4) and indeed enhances invasiveness triggered by ERBB2. Our data indicate that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. C1 [Godinho, Susana A.; Picone, Remigio; Dagher, Regina; Pellman, David] Childrens Hosp, Howard Hughes Med Inst, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Godinho, Susana A.; Picone, Remigio; Dagher, Regina; Pellman, David] Childrens Hosp, Boston, MA 02115 USA. [Godinho, Susana A.; Picone, Remigio; Dagher, Regina; Leung, Cheuk T.; Brugge, Joan S.; Pellman, David] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Burute, Mithila; Thery, Manuel] UMR5168 CEA UJF INRA CNRS, Inst Rech Technol & Sci Vivant, Grenoble, France. [Burute, Mithila; Thery, Manuel] U1160 INSERM AP HP Univ Paris Diderot, Inst Univ Hematol, Hop St Louis, F-75010 Paris, France. [Burute, Mithila] CYTOO SA, F-38054 Grenoble, France. [Su, Ying; Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Godinho, SA (reprint author), Childrens Hosp, Howard Hughes Med Inst, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM s.godinho@qmul.ac.uk; david_pellman@dfci.harvard.edu FU FCT [HMSP-CT/SAU-ICT/0075/2009]; ERC [310472]; ISI program of BPIFrance; NIH [GM083299-1] FX We are grateful to S. Jhaveri-Schneider, S. Muthuswamy, M. Bettencourt-Dias, R. Basto, D. Calado, N. Ganem, A. Spektor, M. Kwon and B. Atkins for comments or discussion of the manuscript; the Nikon Imaging Center at Harvard Medical School; J. Waters, J. Rosenberg and H. Elliott from the Image and Data Analysis Core at Harvard Medical School for their help with FRET microscopy and analysis; L. Cameron of the Confocal and Light Microcopy Facility at Dana-Farber Cancer Institute; H. Li of SNP analysis; A. Bui for help establishing the 3D cultures; Q. Tseng for establishing MCF 10A doublets on micropatterns; and C. Sproat and J. Marshall for help with the organotypic cultures. Reagents were kindly provided by L. Pelletier, J. Locarek, M. Matsuda, A. Hall and J. Marshall. S. A. G. is supported by an FCT grant HMSP-CT/SAU-ICT/0075/2009. M. T. is supported by the ERC grant 310472 and the ISI program of BPIFrance. D.P. is an HHMI investigator and is supported by an NIH grant GM083299-1. NR 46 TC 74 Z9 75 U1 2 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 5 PY 2014 VL 510 IS 7503 BP 167 EP + DI 10.1038/nature13277 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI3NR UT WOS:000336768900050 PM 24739973 ER PT J AU Truwit, JD Bernard, GR Steingrub, J Matthay, MA Liu, KD Albertson, TE Brower, RG Shanholtz, C Rock, P Douglas, IS Deboisblanc, BP Hough, CL Hite, RD Thompson, BT AF Truwit, Jonathon D. Bernard, Gordon R. Steingrub, Jay Matthay, Michael A. Liu, Kathleen D. Albertson, Timothy E. Brower, Roy G. Shanholtz, Carl Rock, Peter Douglas, Ivor S. deBoisblanc, Bennett P. Hough, Catherine L. Hite, R. Duncan Thompson, B. Taylor CA Natl Heart Lung Blood Inst ARDS TI Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE LUNG INJURY; RANDOMIZED CLINICAL-TRIAL; STATIN THERAPY; SEPTIC SHOCK; MORTALITY; ATORVASTATIN; BACTEREMIA; INFECTION; PHARMACOKINETICS; INFLAMMATION AB BACKGROUND In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. METHODS We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14. RESULTS The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P = 0.21) or in mean (+/-SD) ventilator-free days (15.1+/-10.8 with rosuvastatin and 15.1+/-11.0 with placebo, P = 0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1+/-5.3 vs. 11.0+/-4.7, P = 0.01) and fewer days free of hepatic failure to day 14 (10.8+/-5.0 vs. 11.8+/-4.3, P = 0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. Conclusions Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.) C1 [Truwit, Jonathon D.] Froedtert & Med Coll Wisconsin, Milwaukee, WI USA. [Bernard, Gordon R.] Vanderbilt Univ, Nashville, TN 37235 USA. [Steingrub, Jay] Baystate Med Ctr, Springfield, MA USA. [Steingrub, Jay] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Matthay, Michael A.; Liu, Kathleen D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Albertson, Timothy E.] Univ Calif Davis, Sacramento, CA 95817 USA. [Brower, Roy G.] Johns Hopkins Univ, Baltimore, MD USA. [Shanholtz, Carl; Rock, Peter] Univ Maryland, Baltimore, MD 21201 USA. [Douglas, Ivor S.] Denver Hlth Med Ctr, Denver, CO USA. [Douglas, Ivor S.] Univ Colorado, Denver, CO 80202 USA. [deBoisblanc, Bennett P.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Hough, Catherine L.] Univ Washington, Seattle, WA 98195 USA. [Hite, R. Duncan] Cleveland Clin, Cleveland, OH 44106 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thompson, B. Taylor] Harvard Univ, Sch Med, Boston, MA USA. RP Truwit, JD (reprint author), Med Coll Wisconsin, Ctr Clin Canc, Suite C4000,9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM jtruwit@mcw.edu OI Shanholtz, Carl/0000-0003-3938-178X FU National Heart, Lung, and Blood Institute; AstraZeneca FX Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121. NR 46 TC 92 Z9 95 U1 1 U2 19 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 5 PY 2014 VL 370 IS 23 BP 2191 EP 2200 DI 10.1056/NEJMoa1401520 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AI3AF UT WOS:000336729900007 ER PT J AU Criner, GJ Connett, JE Aaron, SD Albert, RK Bailey, WC Casaburi, R Cooper, JAD Curtis, JL Dransfield, MT Han, MK Make, B Marchetti, N Martinez, FJ Niewoehner, DE Scanlon, PD Sciurba, FC Scharf, SM Sin, DD Voelker, H Washko, GR Woodruff, PG Lazarus, SC AF Criner, G. J. Connett, J. E. Aaron, S. D. Albert, R. K. Bailey, W. C. Casaburi, R. Cooper, J. A. D., Jr. Curtis, J. L. Dransfield, M. T. Han, M. K. Make, B. Marchetti, N. Martinez, F. J. Niewoehner, D. E. Scanlon, P. D. Sciurba, F. C. Scharf, S. M. Sin, D. D. Voelker, H. Washko, G. R. Woodruff, P. G. Lazarus, S. C. CA COPD Clinical Res Network Canadian Inst Hlth Res TI Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; MRC/BHF HEART PROTECTION; PLACEBO-CONTROLLED TRIAL; QUALITY-OF-LIFE; STATIN USE; RANDOMIZED-TRIAL; LUNG-FUNCTION; MORTALITY; INHIBITORS; POPULATION AB BACKGROUND Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (+/-SD) age of 62.2+/-8.4 years, an FEV1 that was 41.6+/-17.7% of the predicted value, and a smoking history of 50.6+/-27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36+/-1.61 exacerbations and 1.39+/-1.73 exacerbations, respectively (P = 0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P = 0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P = 0.89). CONCLUSIONS Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.) C1 [Criner, G. J.; Marchetti, N.] Temple Univ, Sch Med, Dept Pulm & Crit Care Med, Philadelphia, PA 19140 USA. [Connett, J. E.] Univ Minnesota, Sch Publ Hlth, Dept Biostat, Minneapolis, MN USA. [Connett, J. E.] Univ Minnesota, Data Coordinating Ctr, Minneapolis, MN USA. [Niewoehner, D. E.] Univ Minnesota, Dept Pulm Allergy Crit Care & Sleep Med, Minneapolis, MN USA. [Scanlon, P. D.] Mayo Clin, Dept Pulm & Crit Care Med, Rochester, MN USA. [Aaron, S. D.] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Sin, D. D.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Sin, D. D.] Univ British Columbia, Inst Heart & Lung Hlth, James Hogg Res Ctr, Vancouver, BC, Canada. [Albert, R. K.] Denver Hlth Med Ctr, Dept Med, Denver, CO USA. [Make, B.] Natl Jewish Hlth, Div Pulm Crit Care & Sleep Med, Denver, CO USA. [Bailey, W. C.; Dransfield, M. T.] Univ Alabama Birmingham, Dept Pulm Allergy & Crit Care Med, Birmingham, AL 35205 USA. [Cooper, J. A. D., Jr.] Univ Alabama Birmingham, Pulm Sect, Birmingham, AL USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Casaburi, R.] Harbor UCLA Res & Educ Inst, Los Angeles, CA USA. [Curtis, J. L.] Vet Affairs Med Ctr, Dept Pulm Med, Ann Arbor, MI USA. [Curtis, J. L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Han, M. K.; Martinez, F. J.] Univ Michigan Hlth Syst, Dept Pulm & Crit Care Med, Ann Arbor, MI USA. [Sciurba, F. C.] Univ Pittsburgh, Med Ctr, Dept Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Scharf, S. M.] Univ Maryland, Dept Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Washko, G. R.] Brigham & Womens Hosp, Dept Pulm & Crit Care Med, Boston, MA 02115 USA. [Woodruff, P. G.; Lazarus, S. C.] Univ Calif San Francisco, Dept Pulm & Crit Care Med, San Francisco, CA 94143 USA. RP Criner, GJ (reprint author), Temple Univ, Sch Med, Temple Lung Ctr, 745 Parkinson Pavil,3401 N Broad St, Philadelphia, PA 19140 USA. EM gerard.criner@tuhs.temple.edu OI Curtis, Jeffrey/0000-0001-5191-4847; Aaron, Shawn/0000-0002-4762-3542 FU National Heart, Lung, and Blood Institute; Canadian Institutes of Health Research FX Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671. NR 44 TC 90 Z9 95 U1 3 U2 23 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 5 PY 2014 VL 370 IS 23 BP 2201 EP 2210 DI 10.1056/NEJMoa1403086 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AI3AF UT WOS:000336729900008 PM 24836125 ER PT J AU Silberman, DM Ross, K Sande, PH Kubota, S Ramaswamy, S Apte, RS Mostoslavsky, R AF Silberman, Dafne M. Ross, Kenneth Sande, Pablo H. Kubota, Shunsuke Ramaswamy, Sridhar Apte, Rajendra S. Mostoslavsky, Raul TI SIRT6 Is Required for Normal Retinal Function SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE; HUMAN EYE; ACUTE HYPOGLYCEMIA; EXPRESSION; LONGEVITY AB The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod and cone photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin. C1 [Silberman, Dafne M.; Sande, Pablo H.] CEFyBO CONICET UBA, Lab Retinal Neurochem & Expt Ophthalmol, Dept Human Biochem, Sch Med, Buenos Aires, DF, Argentina. [Silberman, Dafne M.; Ross, Kenneth; Ramaswamy, Sridhar; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Kubota, Shunsuke; Apte, Rajendra S.] Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA. [Kubota, Shunsuke; Apte, Rajendra S.] Washington Univ, St Louis, MO USA. RP Silberman, DM (reprint author), CEFyBO CONICET UBA, Lab Retinal Neurochem & Expt Ophthalmol, Dept Human Biochem, Sch Med, Buenos Aires, DF, Argentina. EM dsilberman@fmed.uba.ar FU CONICET [PIP 0030]; National Institutes of Health [GM093072-01]; NIH [R01EY019287, P30EY02687]; Carl Marshall and Mildred Almen Reeves Foundation Inc.; Lacy Foundation; Research to Prevent Blindness Inc. Unrestrict University FX This work was supported in part by PIP 0030 CONICET (D.M.S.), National Institutes of Health grant GM093072-01 (R.M.), NIH grant R01EY019287, NIH Vision Core Grant P30EY02687, the Carl Marshall and Mildred Almen Reeves Foundation Inc. Award, the Lacy Foundation research Award, and a Research to Prevent Blindness Inc. Unrestrict University (R.S.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 9 Z9 9 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2014 VL 9 IS 6 AR e98831 DI 10.1371/journal.pone.0098831 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK4YO UT WOS:000338430700084 PM 24896097 ER PT J AU Zumbrennen-Bullough, KB Becker, L Garrett, L Holter, SM Calzada-Wack, J Mossbrugger, I Quintanilla-Fend, L Racz, I Rathkolb, B Klopstock, T Wurst, W Zimmer, A Wolf, E Fuchs, H Gailus-Durner, V de Angelis, MH Romney, SJ Leibold, EA AF Zumbrennen-Bullough, Kimberly B. Becker, Lore Garrett, Lillian Hoelter, Sabine M. Calzada-Wack, Julia Mossbrugger, Ilona Quintanilla-Fend, Leticia Racz, Ildiko Rathkolb, Birgit Klopstock, Thomas Wurst, Wolfgang Zimmer, Andreas Wolf, Eckhard Fuchs, Helmut Gailus-Durner, Valerie de Angelis, Martin Hrabe Romney, Steven J. Leibold, Elizabeth A. TI Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments SO PLOS ONE LA English DT Article ID ELEMENT-BINDING-PROTEIN; REGULATORY PROTEIN-2; NEURODEGENERATIVE DISEASE; TARGETED DELETION; MESSENGER-RNAS; KNOCKOUT MICE; HOMEOSTASIS; MOUSE; GENE; TRANSFERRIN AB Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2(-/-) mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2(-/-) mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments. C1 [Zumbrennen-Bullough, Kimberly B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Program Membrane Biol,Ctr Syst Biol, Program Anemia Signaling Res,Div Nephrol, Boston, MA USA. [Becker, Lore; Garrett, Lillian; Hoelter, Sabine M.; Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia; Racz, Ildiko; Rathkolb, Birgit; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabe] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, German Mouse Clin, Neuherberg, Germany. [Becker, Lore; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabe] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany. [Garrett, Lillian; Hoelter, Sabine M.; Wurst, Wolfgang] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Dev Genet, Neuherberg, Germany. [Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Pathol, Neuherberg, Germany. [Racz, Ildiko; Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, Life & Brain Ctr, Bonn, Germany. [Rathkolb, Birgit; Wolf, Eckhard] Univ Munich, Inst Mol Anim Breeding & Biotechnol, Gene Ctr, Munich, Germany. [Klopstock, Thomas] Klinikum Ludwig Maximilians Univ, Friedrich Baur Inst, Dept Neurol, Munich, Germany. [de Angelis, Martin Hrabe] Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Chair Expt Genet, Freising Weihenstephan, Germany. [de Angelis, Martin Hrabe] German Ctr Diabet Res, Neuherberg, Germany. [Wurst, Wolfgang] Tech Univ Munich, Chair Dev Genet, Freising Weihenstephan, Germany. [Wurst, Wolfgang] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Klopstock, Thomas; Wurst, Wolfgang] Deutsch Zentrum Neurodegenerat Erkrankungen, Munich, Germany. [Klopstock, Thomas; Wurst, Wolfgang] Munich Cluster Syst Neurol, Munich, Germany. [Romney, Steven J.; Leibold, Elizabeth A.] Univ Utah, Dept Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA. RP Leibold, EA (reprint author), Univ Utah, Dept Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA. EM betty.leibold@genetics.utah.edu RI Becker, Lore/E-3717-2010; Gailus-Durner, Valerie/M-7337-2014; Fuchs, Helmut/M-7347-2014; Zimmer, Andreas/B-8357-2009; Racz, Ildiko/C-3074-2009; Hrabe de Angelis, Martin/F-5531-2012; Holter, Sabine/N-5868-2014; OI Wolf, Eckhard/0000-0002-0430-9510; Fuchs, Helmut/0000-0002-5143-2677; Racz, Ildiko/0000-0002-1549-3616; Hrabe de Angelis, Martin/0000-0002-7898-2353; Holter, Sabine/0000-0003-4878-5241; Becker, Lore/0000-0002-6890-4984; Calzada, Julia/0000-0003-0816-9305 FU NIH [R01GM45201, T32DK007115]; German Federal Ministry of Education and Research [01KX1012]; German Center for Vertigo and Balance Disorders [01EO 0901]; Helmholtz Alliance HelMA-Helmholtz Alliance for Mental Health in an Ageing Society, through the Initiative and Network Fund of the Helmholtz Association; Helmholtz Portfolio Theme 'Metabolic Dysfunction and disease'; DFG [WU 164/5-1]; Seventh Framework Programme of the European Commission (FP7) [HEALTH-F2-2011]; [277984] FX This work was supported by the NIH grant R01GM45201 to EAL and the NIH Hematology training grant T32DK007115 to KZB. German Mouse Clinic researchers (SMH, WW, BR, EW, LG, LB, IM, JCW, LQF, IR and AZ) were supported by the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012); the German Center for Vertigo and Balance Disorders (grant 01EO 0901); by the Helmholtz Alliance HelMA-Helmholtz Alliance for Mental Health in an Ageing Society, through the Initiative and Network Fund of the Helmholtz Association; by the Helmholtz Portfolio Theme 'Metabolic Dysfunction and disease', by the DFG grant 'DJ-1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson's Disease'(WU 164/5-1). TK was supported by the Seventh Framework Programme of the European Commission (FP7/2007-2013, HEALTH-F2-2011), grant agreement no. 277984 to TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 6 Z9 7 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2014 VL 9 IS 6 AR e98072 DI 10.1371/journal.pone.0098072 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK4YO UT WOS:000338430700024 PM 24896637 ER PT J AU Cho, J Bass, AJ Lawrence, MS Cibulskis, K Cho, A Lee, SN Yamauchi, M Wagle, N Pochanard, P Kim, N Park, AKJ Won, J Hur, HS Greulich, H Ogino, S Sougnez, C Voet, D Tabernero, J Jimenez, J Baselga, J Gabriel, SB Lander, ES Getz, G Eck, MJ Park, WY Meyerson, M AF Cho, Jeonghee Bass, Adam J. Lawrence, Michael S. Cibulskis, Kristian Cho, Ahye Lee, Shi-Nai Yamauchi, Mai Wagle, Nikhil Pochanard, Panisa Kim, Nayoung Park, Angela K. J. Won, Jonghwa Hur, Hyung-Suk Greulich, Heidi Ogino, Shuji Sougnez, Carrie Voet, Douglas Tabernero, Josep Jimenez, Jose Baselga, Jose Gabriel, Stacey B. Lander, Eric S. Getz, Gad Eck, Michael J. Park, Woong-Yang Meyerson, Matthew TI Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab SO MOLECULAR CANCER LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; ADVANCED COLORECTAL-CANCER; PROTEIN-KINASE; HUMAN BREAST; MUTATIONS; GEFITINIB; GENE; ADENOCARCINOMAS; AMPLIFICATION AB Background: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. Findings: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. Conclusion: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy. C1 [Cho, Jeonghee; Bass, Adam J.; Yamauchi, Mai; Wagle, Nikhil; Pochanard, Panisa; Greulich, Heidi; Ogino, Shuji; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cho, Jeonghee; Bass, Adam J.; Wagle, Nikhil; Pochanard, Panisa; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Cho, Jeonghee; Cho, Ahye; Kim, Nayoung; Park, Angela K. J.; Park, Woong-Yang] Samsung Med Ctr, Samsung Genome Inst, Seoul 135967, South Korea. [Cho, Jeonghee; Cho, Ahye; Kim, Nayoung; Park, Angela K. J.; Park, Woong-Yang] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Seoul 135967, South Korea. [Bass, Adam J.; Lawrence, Michael S.; Cibulskis, Kristian; Greulich, Heidi; Sougnez, Carrie; Voet, Douglas; Gabriel, Stacey B.; Lander, Eric S.; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Lee, Shi-Nai; Won, Jonghwa; Hur, Hyung-Suk] Mogam Biotechnol Res Inst, Oncol Team, Yongin 446799, South Korea. [Greulich, Heidi] Harvard Univ, Brigham & Womens Hosp, Dept Med, Sch Med, Boston, MA 02115 USA. [Tabernero, Josep] Univ Autonoma Barcelona, Vall Hebron Univ Hosp, Mol Pathol Lab, Barcelona, Spain. [Jimenez, Jose] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Baselga, Jose] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Eck, Michael J.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cho, J (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM jeong.cho@skku.edu; matthew_meyerson@dfci.harvard.edu FU NCI [R01 CA116020]; Samsung Medical Center [SGI-13-15] FX We would like to thank all Meyerson lab members for thoughtful discussion. These works were in part supported by NCI R01 CA116020 (MM and MJE) and Samsung Medical Center intramural grant SGI-13-15 (JC). NR 36 TC 5 Z9 5 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUN 4 PY 2014 VL 13 AR 141 DI 10.1186/1476-4598-13-141 PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AK2OS UT WOS:000338259500002 PM 24894453 ER PT J AU Eryilmaz, H De Ville, DV Schwartz, S Vuilleumier, P AF Eryilmaz, Hamdi De Ville, Dimitri Van Schwartz, Sophie Vuilleumier, Patrik TI Lasting Impact of Regret and Gratification on Resting Brain Activity and Its Relation to Depressive Traits SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cingulate; counterfactual emotions; fMRI; resting state; rumination; ventral striatum ID CINGULATE CORTEX; COUNTERFACTUAL THINKING; RUMINATION; EMOTION; BEHAVIOR; CHOICE; SELF; CONNECTIVITY; EXPERIENCE; CAPACITY AB Obtaining lower gains than rejected alternatives during decision making evokes feelings of regret, whereas higher gains elicit gratification. Although decision-related emotions produce lingering effects on mental state, neuroscience research has generally focused on transient brain responses to positive or negative events, but ignored more sustained consequences of emotional episodes on subsequent brain states. We investigated how spontaneous brain activity and functional connectivity at rest are modulated by postdecision regret and gratification in 18 healthy human subjects using a gambling task in fMRI. Differences between obtained and unobtained outcomes were manipulated parametrically to evoke different levels of regret or gratification. We investigated how individual personality traits related to depression and rumination affected these responses. Medial and ventral prefrontal areas differentially responded to favorable and unfavorable outcomes during the gambling period. More critically, during subsequent rest, rostral anterior and posterior cingulate cortex, ventral striatum, and insula showed parametric response to the gratification level of preceding outcomes. Functional coupling of posterior cingulate with striatum and amygdala was also enhanced during rest after high gratification. Regret produced distinct changes in connectivity of subgenual cingulate with orbitofrontal cortex and thalamus. Interestingly, individual differences in depressive traits and ruminations correlated with activity of the striatum after gratification and orbitofrontal cortex after regret, respectively. By revealing lingering effects of decision-related emotions on key nodes of resting state networks, our findings illuminate how such emotions may influence self-reflective processing and subsequent behavioral adjustment, but also highlight the malleability of resting networks in emotional contexts. C1 [Eryilmaz, Hamdi; Schwartz, Sophie; Vuilleumier, Patrik] Univ Geneva, Univ Med Sch Geneva, Dept Neurosci, Lab Neurol & Imaging Cognit, CH-1205 Geneva, Switzerland. [Eryilmaz, Hamdi; De Ville, Dimitri Van; Schwartz, Sophie; Vuilleumier, Patrik] Univ Geneva, Geneva Neurosci Ctr, CH-1205 Geneva, Switzerland. [De Ville, Dimitri Van] Ecole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland. [De Ville, Dimitri Van] Univ Geneva, Dept Radiol & Med Informat, CH-1205 Geneva, Switzerland. [Schwartz, Sophie; Vuilleumier, Patrik] Univ Geneva, Swiss Ctr Affect Sci, CH-1211 Geneva, Switzerland. RP Eryilmaz, H (reprint author), Massachusetts Gen Hosp, Martinos Imaging Ctr, Dept Psychiat, CNY 149,13th St, Boston, MA 02129 USA. EM hamdi.eryilmaz@gmail.com OI Van De Ville, Dimitri/0000-0002-2879-3861 FU National Center of Competence in Research (NCCR) Affective Sciences - Swiss National Science Foundation [51NF40-104897]; Swiss National Science Foundation [320030-135653, PP00P2-146318]; Academic Society of Geneva (Foremane Fund) FX This work was supported by the National Center of Competence in Research (NCCR) Affective Sciences financed by the Swiss National Science Foundation (Grant 51NF40-104897) and hosted by the University of Geneva, the Swiss National Science Foundation (Individual Project Grants 320030-135653 to S. S. and PP00P2-146318 to D. V. D. V.), and the Academic Society of Geneva (Foremane Fund to P. V.). We thank David Sander and Klaus Scherer for helpful discussions about the study design and interpretations. NR 42 TC 9 Z9 9 U1 1 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 4 PY 2014 VL 34 IS 23 BP 7825 EP 7835 DI 10.1523/JNEUROSCI.0065-14.2014 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AJ4GH UT WOS:000337630700011 PM 24899706 ER PT J AU Mulder, WJM Jaffer, FA Fayad, ZA Nahrendorf, M AF Mulder, Willem J. M. Jaffer, Farouc A. Fayad, Zahi A. Nahrendorf, Matthias TI Imaging and Nanomedicine in Inflammatory Atherosclerosis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; ULTRASMALL SUPERPARAMAGNETIC PARTICLES; TARGETED FUMAGILLIN NANOPARTICLES; CAROTID PLAQUE INFLAMMATION; RAY COMPUTED-TOMOGRAPHY; CONTRAST-ENHANCED MRI; IRON-OXIDE; IN-VIVO; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION AB Bioengineering provides unique opportunities to better understand and manage atherosclerotic disease. The field is entering a new era that merges the latest biological insights into inflammatory disease processes with targeted imaging and nanomedicine. Preclinical cardiovascular molecular imaging allows the in vivo study of targeted nanotherapeutics specifically directed toward immune system components that drive atherosclerotic plaque development and complication. The first multicenter trials highlight the potential contribution of multimodality imaging to more efficient drug development. This review describes how the integration of engineering, nanotechnology, and cardiovascular immunology may yield precision diagnostics and efficient therapeutics for atherosclerosis and its ischemic complications. C1 [Mulder, Willem J. M.; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Dept Radiol, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Mulder, Willem J. M.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jaffer, Farouc A.; Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Mulder, WJM (reprint author), Icahn Sch Med Mt Sinai, Dept Radiol, Translat & Mol Imaging Inst, One Gustave L Levy Pl, New York, NY 10029 USA. EM willem.mulder@mssm.edu FU National Institutes of Health National Heart, Lung, and Blood Institute, as a Program of Excellence in Nanotechnology (PEN) Award [HHSN268201000045C, HHSN268201000044C]; NIH [NIBIB R01 EB009638, NHLBI R01 HL071021, NHLBI R01HL114477, R01 NHLBI HL108229, NHLBI R01HL096576, NCI R01 CA155432]; AHA [13GRNT17060040]; NWO ZonMW Vidi [91713324] FX This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute, as a Program of Excellence in Nanotechnology (PEN) Award, Contracts HHSN268201000045C (Z.A.F.) and HHSN268201000044C; the NIH grants NIBIB R01 EB009638 and NHLBI R01 HL071021 (Z.A.F.), NHLBI R01HL114477 and R01 NHLBI HL108229 (F.A.J.), NHLBI R01HL096576 (M.N.), NCI R01 CA155432 (W.J.M.M.), as well as AHA #13GRNT17060040 (F.A.J.); and NWO ZonMW Vidi 91713324 (W.J.M.M.). NR 99 TC 37 Z9 37 U1 3 U2 56 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUN 4 PY 2014 VL 6 IS 239 AR 239sr1 DI 10.1126/scitranslmed.3005101 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AI8PY UT WOS:000337184200006 PM 24898749 ER PT J AU Mortensen, EM Halm, EA Pugh, MJ Copeland, LA Metersky, M Fine, MJ Johnson, CS Alvarez, CA Frei, CR Good, C Restrepo, MI Downs, JR Anzueto, A AF Mortensen, Eric M. Halm, Ethan A. Pugh, Mary Jo Copeland, Laurel A. Metersky, Mark Fine, Michael J. Johnson, Christopher S. Alvarez, Carlos A. Frei, Christopher R. Good, Chester Restrepo, Marcos I. Downs, John R. Anzueto, Antonio TI Association of Azithromycin With Mortality and Cardiovascular Events Among Older Patients Hospitalized With Pneumonia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; BACTEREMIC PNEUMOCOCCAL PNEUMONIA; EMPIRIC ANTIBIOTIC-THERAPY; DIFFUSE PANBRONCHIOLITIS; ELDERLY-PATIENTS; MACROLIDE ANTIBIOTICS; ANTIMICROBIAL THERAPY; SECONDARY PREVENTION; VETERANS-AFFAIRS; BETA-LACTAM AB IMPORTANCE Although clinical practice guidelines recommend combination therapy with macrolides, including azithromycin, as first-line therapy for patients hospitalized with pneumonia, recent research suggests that azithromycin may be associated with increased cardiovascular events. OBJECTIVE To examine the association of azithromycin use with all-cause mortality and cardiovascular events for patients hospitalized with pneumonia. DESIGN Retrospective cohort study comparing older patients hospitalized with pneumonia from fiscal years 2002 through 2012 prescribed azithromycin therapy and patients receiving other guideline-concordant antibiotic therapy. SETTING This study was conducted using national Department of Veterans Affairs administrative data of patients hospitalized at any Veterans Administration acute care hospital. PARTICIPANTS Patients were included if they were aged 65 years or older, were hospitalized with pneumonia, and received antibiotic therapy concordant with national clinical practice guidelines. MAIN OUTCOMES AND MEASURES Outcomes included 30- and 90-day all-cause mortality and 90-day cardiac arrhythmias, heart failure, myocardial infarction, and any cardiac event. Propensity score matching was used to control for the possible effects of known confounders with conditional logistic regression. RESULTS Of 73 690 patients from 118 hospitals identified, propensity-matched groups were composed of 31 863 patients exposed to azithromycin and 31 863 matched patients who were not exposed. There were no significant differences in potential confounders between groups after matching. Ninety-day mortality was significantly lower in those who received azithromycin (exposed, 17.4%, vs unexposed, 22.3%; odds ratio [On 0.73; 95% CI, 0.70-0.76). However, we found significantly increased odds of myocardial infarction (5.1% vs 4.4%; OR, 1.17; 95% CI,1.08-1.25) but not any cardiac event (43.0% vs 42.7%; OR, 1.01; 95% CI, 0.98-1.05), cardiac arrhythmias (25.8% vs 26.0%; OR, 0.99; 95% CI, 0.95-1.02), or heart failure (26.3% vs 26.2%; OR, 1.01; 95% CI, 0.97-1.04). CONCLUSIONS AND RELEVANCE Among older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarction. These findings are consistent with a net benefit associated with azithromycin use. Copyright 2014 American Medical Association. All rights reserved. C1 [Mortensen, Eric M.; Johnson, Christopher S.; Alvarez, Carlos A.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Mortensen, Eric M.; Halm, Ethan A.; Johnson, Christopher S.; Alvarez, Carlos A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Alvarez, Carlos A.] Texas Tech Univ, Hlth Sci Ctr, Dallas, TX USA. [Pugh, Mary Jo; Restrepo, Marcos I.; Downs, John R.; Anzueto, Antonio] South Texas Vet Hlth Care Syst, VERDICT Res Program, San Antonio, TX USA. [Pugh, Mary Jo; Frei, Christopher R.; Restrepo, Marcos I.; Downs, John R.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fine, Michael J.; Good, Chester] Univ Pittsburgh, VA Ctr Hlth Equ Res & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Copeland, Laurel A.] Cent Texas Vet Hlth Care Syst Jointly Scott & Whi, Ctr Appl Hlth Res, Temple, TX USA. [Metersky, Mark] Univ Connecticut, Med Ctr, Farmington, CT USA. [Frei, Christopher R.] Univ Texas Austin, Austin, TX 78712 USA. RP Mortensen, EM (reprint author), Dallas VA Med Ctr, Gen Internal Med Sect, 4500 S Lancaster,Ste 111E, Dallas, TX 75216 USA. EM eric.mortensen@utsouthwestern.edu RI Restrepo, Marcos/H-4442-2014; OI Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU National Institute of Nursing Research [R01NR010828]; National Heart, Lung, and Blood Institute [K23HL096054] FX This study was supported by a grant from the National Institute of Nursing Research (R01NR010828), and Dr Restrepo was supported by the National Heart, Lung, and Blood Institute (K23HL096054). This material is the result of work supported with resources and the use of facilities at the VA North Texas Health Care System. NR 45 TC 43 Z9 46 U1 3 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 4 PY 2014 VL 311 IS 21 BP 2199 EP 2208 DI 10.1001/jama.2014.4304 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AI2DU UT WOS:000336668400021 PM 24893087 ER PT J AU Dowdy, DW Andrews, JR Dodd, PJ Gilman, RH AF Dowdy, David W. Andrews, Jason R. Dodd, Peter J. Gilman, Robert H. TI A User-Friendly, Open-Source Tool to Project Impact and Cost of Diagnostic Tests for Tuberculosis SO ELIFE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DRUG-RESISTANT TUBERCULOSIS; HIGH HIV PREVALENCE; MYCOBACTERIUM-TUBERCULOSIS; UNDIAGNOSED TUBERCULOSIS; PULMONARY TUBERCULOSIS; TREATMENT OUTCOMES; POTENTIAL IMPACT; SMEAR MICROSCOPY; METAANALYSIS AB Background: Most existing models of infectious diseases, including tuberculosis (TB), do not allow end-users to customize results to local conditions. Methods: We created a dynamic transmission model to project TB incidence, TB mortality, multidrug-resistant (MDR) TB prevalence, and incremental costs over five years after scale-up of nine alternative diagnostic strategies including combinations of sputum smear microscopy, Xpert MTB/RIF, microcolony-based culture, and same-day diagnosis. We developed a corresponding web-based interface that allows users to specify local costs and epidemiology. Full model code -including the ability to change any input parameter -is also included. Results: The impact of improved diagnostic testing was greater for mortality and MDR-TB prevalence than TB incidence, and was maximized in high-incidence, low-HIV settings. More costly interventions generally had greater impact. In settings with little capacity for up-front investment, same-day microscopy had greatest impact on TB incidence and became cost-saving within five years if feasible to deliver at $ 10/test. In settings where more initial investment was possible, population-level scale-up of either Xpert MTB/RIF or microcolony-based culture offered substantially greater benefits, often averting ten times more TB cases than narrowly-targeted diagnostic strategies at minimal incremental long-term cost. Where containing MDR-TB is the overriding concern, Xpert for smear-positives has reasonable impact on MDR-TB incidence, but at substantial price and little impact on overall TB incidence and mortality. Conclusions: This novel, user-friendly modeling framework improves decision-makers' ability to evaluate the impact of TB diagnostic strategies, accounting for local conditions. C1 [Dowdy, David W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Dowdy, David W.] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. [Andrews, Jason R.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Dodd, Peter J.] Univ Sheffield, Sch Hlth & Related Res, Sheffield S1 4DA, S Yorkshire, England. [Gilman, Robert H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. RP Dowdy, DW (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Suite E6531, Baltimore, MD 21205 USA. OI Dodd, Pete/0000-0001-5825-9347 NR 55 TC 4 Z9 4 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 4 PY 2014 VL 3 AR e02565 DI 10.7554/eLife.02565 PG 55 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AI4LQ UT WOS:000336837300004 ER PT J AU Merrill, E Corlosquet, S Ciccarese, P Clark, T Das, S AF Merrill, Emily Corlosquet, Stephane Ciccarese, Paolo Clark, Tim Das, Sudeshna TI Semantic Web repositories for genomics data using the eXframe platform SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article ID GENE-EXPRESSION; MGED ONTOLOGY; MICROARRAY; BIOINFORMATICS; INTEGRATION; STANDARDS; FRAMEWORK; RESOURCE; SYSTEMS AB Background: With the advent of inexpensive assay technologies, there has been an unprecedented growth in genomics data as well as the number of databases in which it is stored. In these databases, sample annotation using ontologies and controlled vocabularies is becoming more common. However, the annotation is rarely available as Linked Data, in a machine-readable format, or for standardized queries using SPARQL. This makes large-scale reuse, or integration with other knowledge bases very difficult. Methods: To address this challenge, we have developed the second generation of our eXframe platform, a reusable framework for creating online repositories of genomics experiments. This second generation model now publishes Semantic Web data. To accomplish this, we created an experiment model that covers provenance, citations, external links, assays, biomaterials used in the experiment, and the data collected during the process. The elements of our model are mapped to classes and properties from various established biomedical ontologies. Resource Description Framework (RDF) data is automatically produced using these mappings and indexed in an RDF store with a built-in Sparql Protocol and RDF Query Language (SPARQL) endpoint. Conclusions: Using the open-source eXframe software, institutions and laboratories can create Semantic Web repositories of their experiments, integrate it with heterogeneous resources and make it interoperable with the vast Semantic Web of biomedical knowledge. C1 [Merrill, Emily; Corlosquet, Stephane; Ciccarese, Paolo; Clark, Tim; Das, Sudeshna] Massachusetts Gen Hosp, Cambridge, MA 02139 USA. [Ciccarese, Paolo; Clark, Tim; Das, Sudeshna] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Clark, Tim] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. RP Merrill, E (reprint author), Massachusetts Gen Hosp, Partners Res Bldg,65 Landsdowne St, Cambridge, MA 02139 USA. EM mmerrill@partners.org; scorlosquet@gmail.com; sdas5@partners.org OI Clark, Timothy/0000-0003-4060-7360 FU Harvard Stem Cell Institute FX We would like to acknowledge the Harvard Stem Cell Institute for funding and support. We would like to thank Dr. Winston Hide and Dr. Shannan Ho Sui for their feedback and guidance on ontology mappings. NR 31 TC 2 Z9 2 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD JUN 3 PY 2014 VL 5 SU 1 AR S3 DI 10.1186/2041-1480-5-S1-S3 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AU6BO UT WOS:000345687700004 PM 25093072 ER PT J AU Pereira, JB Svenningsson, P Weintraub, D Bronnick, K Lebedev, A Westman, E Aarsland, D AF Pereira, Joana B. Svenningsson, Per Weintraub, Daniel Bronnick, Kolbjorn Lebedev, Alexander Westman, Eric Aarsland, Dag TI Initial cognitive decline is associated with cortical thinning in early Parkinson disease SO NEUROLOGY LA English DT Article ID SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; SOCIETY TASK-FORCE; ALZHEIMERS-DISEASE; BRAIN ATROPHY; IMPAIRMENT; DEMENTIA; PROGRESSION; BIOMARKERS; INCIDENT AB Objectives: Our aim was to assess cortical thickness in a large multicenter cohort of drug-naive patients with early Parkinson disease (PD), with and without mild cognitive impairment (MCI), and explore the cognitive correlates of regional cortical thinning. Methods: One hundred twenty-three newly diagnosed patients with PD and 56 healthy controls with 3-tesla structural MRI scans and complete neuropsychological assessment from the Parkinson's Progression Markers Initiative were included. Modified Movement Disorders Society Task Force level II criteria were applied to diagnose MCI in PD. FreeSurfer image processing and analysis software was used to measure cortical thickness across groups and the association with cognitive domains and tests. Results: In patients with MCI, atrophy was found in temporal, parietal, frontal, and occipital areas compared with controls. Specific regional thinning in the right inferior temporal cortex was also found in cognitively normal patients. Memory, executive, and visuospatial performance was associated with temporoparietal and superior frontal thinning, suggesting a relationship between cognitive impairment and both anterior and posterior cortical atrophy in the whole patient sample. Conclusions: These findings confirm that MCI is associated with widespread cortical atrophy. In addition, they suggest that regional cortical thinning is already present at the time of diagnosis in patients with early, untreated PD who do not meet the criteria for MCI. Together, the results indicate that cortical thinning can serve as a marker for initial cognitive decline in early PD. C1 [Pereira, Joana B.; Westman, Eric] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Aarsland, Dag] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimers Dis Res, Stockholm, Sweden. [Svenningsson, Per] Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, Stockholm, Sweden. [Svenningsson, Per] Karolinska Univ Hosp, Stockholm, Sweden. [Weintraub, Daniel] Univ Penn, Philadelphia VA Med Ctr, Perelman Sch Med, Dept Psychiat & Neurol, Philadelphia, PA 19104 USA. [Bronnick, Kolbjorn] Stavanger Univ Hosp, Norwegian Ctr Movement Disorders, Stavanger, Norway. [Lebedev, Alexander; Aarsland, Dag] Stavanger Univ Hosp, Ctr Age Related Med, Dept Psychiat, Stavanger, Norway. RP Pereira, JB (reprint author), Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. EM joana.pereira@ki.se RI Westman, Eric/H-5771-2011; OI Pereira, Joana/0000-0002-4604-2711; Lebedev, Alexander/0000-0002-0319-2357; Westman, Eric/0000-0002-3115-2977; Aarsland, Dag/0000-0001-6314-216X FU Michael J. Fox Foundation for Parkinson's Research; Abbott; Avid Radiopharmaceuticals; Biogen Idec; Bristol-Myers Squibb; Covance; Elan; GE Healthcare; Genentech; GSK-GlaxoSmithKline; Lilly; Merck; MSD-Meso Scale Discovery; Pfizer; Roche; UCB; Marie Curie fellowship for postdoctoral researchers [FP7-PEOPLE-2012-IEF-328758] FX Parkinson's Progression Markers Initiative, a public-private partnership, is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbott, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Elan, GE Healthcare, Genentech, GSK-GlaxoSmithKline, Lilly, Merck, MSD-Meso Scale Discovery, Pfizer, Roche, and UCB (www.ppmi-info.org/fundingpartners). J.B.P. was funded by a Marie Curie fellowship for postdoctoral researchers (grant no FP7-PEOPLE-2012-IEF-328758). NR 39 TC 26 Z9 28 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 3 PY 2014 VL 82 IS 22 BP 2017 EP 2025 DI 10.1212/WNL.0000000000000483 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AQ5BQ UT WOS:000342818100017 PM 24808018 ER PT J AU Bhattacharyya, S Berkowitz, AL Jha, RM AF Bhattacharyya, Shamik Berkowitz, Aaron L. Jha, Ruchira M. TI Clinical Reasoning: A 24-year-old woman with progressive headache and somnolence SO NEUROLOGY LA English DT Editorial Material ID CEREBRAL VENOUS THROMBOSIS; MOLECULAR-WEIGHT HEPARIN; SINUS THROMBOSIS; TRIAL C1 [Bhattacharyya, Shamik; Berkowitz, Aaron L.; Jha, Ruchira M.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Bhattacharyya, Shamik; Berkowitz, Aaron L.; Jha, Ruchira M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bhattacharyya, Shamik; Berkowitz, Aaron L.; Jha, Ruchira M.] Harvard Univ, Sch Med, Boston, MA USA. RP Bhattacharyya, S (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM sbhattacharyya3@partners.org NR 10 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 3 PY 2014 VL 82 IS 22 BP E188 EP E193 DI 10.1212/WNL.0000000000000469 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AQ5BQ UT WOS:000342818100001 PM 24891545 ER PT J AU Martin, CR Zaman, MM Gilkey, C Salguero, MV Hasturk, H Kantarci, A Van Dyke, TE Freedman, SD AF Martin, Camilia R. Zaman, Munir M. Gilkey, Calvin Salguero, Maria V. Hasturk, Hatice Kantarci, Alpdogan Van Dyke, Thomas E. Freedman, Steven D. TI Resolvin D1 and Lipoxin A(4) Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; BIRTH-WEIGHT INFANTS; BRONCHOPULMONARY DYSPLASIA; PRETERM INFANTS; TGF-BETA; LIPID MEDIATORS; COUNT METHOD; MOUSE LUNG; MICE; INTRAUTERINE AB Background: The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A(4) would prevent lung injury in a murine model of BPD. Objective: To determine the effect of Resolvin D1 and/or Lipoxin A(4) on hyperoxia-induced lung injury. Methods: C57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A(4), or Hyperoxia + Resolvin D1/Lipoxin A(4). Resolvin D1 and/or Lipoxin A(4) (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGF beta(1) and TGF beta(2). Result: The increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A(4); while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A(4). Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPAR gamma (4.8 fold). Treatment with Lipoxin A(4) also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGF beta(2) (2.1 fold) and Smad3 (1.58 fold). Conclusion: The histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants. C1 [Martin, Camilia R.] Beth Israel Deaconess Med Ctr, Dept Neonatol, Boston, MA 02215 USA. [Martin, Camilia R.; Freedman, Steven D.] Beth Israel Deaconess Med Ctr, Div Translat Res, Boston, MA 02215 USA. [Zaman, Munir M.; Gilkey, Calvin; Salguero, Maria V.; Freedman, Steven D.] Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA 02215 USA. [Hasturk, Hatice; Kantarci, Alpdogan; Van Dyke, Thomas E.] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA USA. RP Martin, CR (reprint author), Beth Israel Deaconess Med Ctr, Dept Neonatol, Boston, MA 02215 USA. EM cmartin1@bidmc.harvard.edu FU Program for Faculty Development and Diversity; Harvard Catalyst; Harvard Clinical and Translational Science Center; National Center for Research Resources [UL1 RR 025758]; Harvard University; Charles H. Hood Foundation; National Institute of Dental and Craniofacial Research [s R01 DE15566, R01 DE19938, R21 DE20906, K23 DE18917] FX The work of CRM was supported by the Program for Faculty Development and Diversity supported by Harvard Catalyst, and the Harvard Clinical and Translational Science Center, from the National Center for Research Resources (award #UL1 RR 025758 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, the National Center for Research Resources or the National Institutes of Health. This study was also funded by the Charles H. Hood Foundation (CRM; www.hria.org/tmfservices/tmfgrants/hood.html), generous philanthropic donors to the Infant Health Research Program at Beth Israel Deaconess Medical Center, and the National Institute of Dental and Craniofacial Research (Award #s R01 DE15566, R01 DE19938, R21 DE20906, and K23 DE18917. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 11 Z9 11 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2014 VL 9 IS 6 AR e98773 DI 10.1371/journal.pone.0098773 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI5ML UT WOS:000336911400090 PM 24892762 ER PT J AU Lalonde, J Saia, G Gill, G AF Lalonde, Jasmin Saia, Gregory Gill, Grace TI Store-Operated Calcium Entry Promotes the Degradation of the Transcription Factor Sp4 in Resting Neurons SO SCIENCE SIGNALING LA English DT Article ID CAPACITATIVE CA2+ ENTRY; GENOME-WIDE ANALYSIS; INTRACELLULAR CALCIUM; NEURODEGENERATIVE DISORDERS; PSYCHIATRIC-DISORDERS; ENDOPLASMIC-RETICULUM; HIPPOCAMPAL-NEURONS; BIPOLAR DISORDER; CRAC CHANNELS; RECEPTOR AB Calcium (Ca2+) signaling activated in response to membrane depolarization regulates neuronal maturation, connectivity, and plasticity. Store-operated Ca2+ entry (SOCE) occurs in response to depletion of Ca2+ from endoplasmic reticulum (ER), mediates refilling of this Ca2+ store, and supports Ca2+ signaling in non-excitable cells. We report that maximal activation of SOCE occurred in cerebellar granule neurons cultured under resting conditions and that this Ca2+ influx promoted the degradation of transcription factor Sp4, a regulator of neuronal morphogenesis and function. Lowering the concentration of extracellular potassium, a condition that reduces neuronal excitability, stimulated depletion of intracellular Ca2+ stores, resulted in the relocalization of the ER Ca2+ sensor STIM1 into punctate clusters consistent with multimerization and accumulation at junctions between the ER and plasma membrane, and induced a Ca2+ influx with characteristics of SOCE. Compounds that block SOCE prevented the ubiquitylation and degradation of Sp4 in neurons exposed to a low concentration of extracellular potassium. Knockdown of STIM1 blocked degradation of Sp4, whereas expression of constitutively active STIM1 decreased Sp4 abundance under depolarizing conditions. Our findings indicated that, in neurons, SOCE is induced by hyperpolarization, and suggested that this Ca2+ influx pathway is a distinct mechanism for regulating neuronal gene expression. C1 [Lalonde, Jasmin; Saia, Gregory; Gill, Grace] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. [Saia, Gregory] Tufts Univ, Sch Med, Sackler Sch Grad Biomed Sci, Cell Mol & Dev Biol Program, Boston, MA 02111 USA. RP Lalonde, J (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Richard B Simches Res Ctr, 185 Cambridge St, Boston, MA 02114 USA. EM lalonde@chgr.mgh.harvard.edu; grace.gill@tufts.edu OI Lalonde, Jasmin/0000-0002-6797-1894 FU NIH [HD043364]; Postdoctoral Fellowship from the Canadian Institutes of Health Research; Synapse Neurobiology Training Program from the National Institute of Neurological Disorders and Stroke [T32 NS061764]; [P30 NS047243] FX This work was supported in part by a grant from the NIH to G.G. (HD043364). J.L. was supported by a Postdoctoral Fellowship from the Canadian Institutes of Health Research, and G.S. was supported by the Synapse Neurobiology Training Program grant T32 NS061764 from the National Institute of Neurological Disorders and Stroke. The Tufts Imaging Facility is supported by grant P30 NS047243. NR 72 TC 18 Z9 18 U1 0 U2 5 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 3 PY 2014 VL 7 IS 328 DI 10.1126/scisignal.2005242 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AI8OK UT WOS:000337178500001 PM 24894994 ER PT J AU Tian, JW Ren, XF Vergallo, R Xing, L Yu, H Jia, HB Soeda, T McNulty, I Hu, SN Lee, H Yu, B Jang, IK AF Tian, Jinwei Ren, Xuefeng Vergallo, Rocco Xing, Lei Yu, Huai Jia, Haibo Soeda, Tsunenari McNulty, Iris Hu, Sining Lee, Hang Yu, Bo Jang, Ik-Kyung TI Distinct Morphological Features of Ruptured Culprit Plaque for Acute Coronary Events Compared to Those With Silent Rupture and Thin-Cap Fibroatheroma A Combined Optical Coherence Tomography and Intravascular Ultrasound Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndrome(s); lumen narrowing; plaque rupture; plaque vulnerability; thin-cap fibroatheroma ID ACUTE MYOCARDIAL-INFARCTION; ARTERY-DISEASE; ATHEROSCLEROSIS; PROGRESSION; LESIONS; ACQUISITION; DISRUPTION; ANGIOSCOPY; THROMBOSIS; SEVERITY AB Objectives The study sought to identify specific morphological characteristics of ruptured culprit plaques (RCP) responsible for acute events, and compare them with ruptured nonculprit plaques (RNCP) and nonruptured thin-cap fibroatheroma (TCFA) in patients presenting with acute coronary syndromes (ACS). Background Nonruptured TCFA and multiple ruptured plaques are detected in the same patients with ACS. It remains unknown whether certain morphological characteristics determine rupture of TCFA and subsequently result in ACS. Methods We analyzed 126 plaques (RCP 49, RNCP 19, TCFA 58) from 82 ACS patients using optical coherence tomography (OCT) and intravascular ultrasound (IVUS). Fibrous cap thickness was determined by OCT. Plaque burden and lumen area were measured with IVUS. Results Fibrous cap was thinner in RCP (43 +/- 11 mu m) and RNCP (41 +/- 10 mu m) than in TCFA (56 +/- 9 mu m, p < 0.001 and p < 0.001, respectively). Plaque burden was greater in RCP (82 +/- 7.2%), compared with RNCP (64 +/- 7.2%, p < 0.001) and TCFA (62 +/- 12.5%, p < 0.001). Lumen area was smaller in RCP (2.1 +/- 0.9 mm(2)), compared with RNCP (4.6 +/- 2.3 mm(2), p 0.001) and TCFA (5.1 +/- 2.7 mm(2), p < 0.001). The fibrous cap thickness < 52 mm had good performance in discriminating ruptured plaque from TCFA (area under the curve [AUC] 0.857, p < 0.001), and plaque burden >76% and lumen area < 2.6 mm(2) had good performance in discriminating RCP from RNCP and TCFA (AUC 0.923, p < 0.001 and AUC 0.881, p < 0.001, respectively). Conclusions Fibrous cap thickness is a critical morphological discriminator between ruptured plaques and nonruptured TCFA, while plaque burden and lumen area appear to be important morphological features of RCP. These findings suggest that plaque rupture is determined by fibrous cap thickness, and a combination of large plaque burden and luminal narrowing result in ACS. (C) 2014 by the American College of Cardiology Foundation C1 [Tian, Jinwei; Ren, Xuefeng; Xing, Lei; Yu, Huai; Jia, Haibo; Hu, Sining; Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. [Tian, Jinwei; Ren, Xuefeng; Xing, Lei; Yu, Huai; Jia, Haibo; Hu, Sining; Yu, Bo] Chinese Minist Educ, Key Lab Myocardial Ischemia, Harbin, Peoples R China. [Tian, Jinwei; Vergallo, Rocco; Jia, Haibo; Soeda, Tsunenari; McNulty, Iris; Hu, Sining; Yu, Bo; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. RP Yu, B (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin, Peoples R China. EM yubodr@163.com FU National Natural Science Foundation of China [81300201, 30871064]; China Post-Doctoral Science Foundation [2013M531074]; Heilongjiang Post-Doctoral Science Foundation [LBH-Z12180]; LightLab Imaging/St. Jude Medical FX Dr. Tian has received grants from the National Natural Science Foundation of China (81300201), China Post-Doctoral Science Foundation (2013M531074), and Heilongjiang Post-Doctoral Science Foundation (LBH-Z12180). Dr. Yu has received a grant from the National Natural Science Foundation of China (30871064). Dr. Jang has received research grants and consulting fees from LightLab Imaging/St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 31 TC 43 Z9 45 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 3 PY 2014 VL 63 IS 21 BP 2209 EP 2216 DI 10.1016/j.jacc.2014.01.061 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI0UC UT WOS:000336564500004 PM 24632266 ER PT J AU Franzosa, EA Morgan, XC Segata, N Waldron, L Reyes, J Earl, AM Giannoukos, G Boylan, MR Ciulla, D Gevers, D Izard, J Garrett, WS Chan, AT Huttenhower, C AF Franzosa, Eric A. Morgan, Xochitl C. Segata, Nicola Waldron, Levi Reyes, Joshua Earl, Ashlee M. Giannoukos, Georgia Boylan, Matthew R. Ciulla, Dawn Gevers, Dirk Izard, Jacques Garrett, Wendy S. Chan, Andrew T. Huttenhower, Curtis TI Relating the metatranscriptome and metagenome of the human gut SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN MICROBIOME; GENE-EXPRESSION; ENVIRONMENTS; COMMUNITIES; BACTERIA; SAMPLES; TWINS AB Although the composition of the human microbiome is now well-studied, the microbiota's >8 million genes and their regulation remain largely uncharacterized. This knowledge gap is in part because of the difficulty of acquiring large numbers of samples amenable to functional studies of the microbiota. We conducted what is, to our knowledge, one of the first human microbiome studies in a well-phenotyped prospective cohort incorporating taxonomic, metagenomic, and metatranscriptomic profiling at multiple body sites using self-collected samples. Stool and saliva were provided by eight healthy subjects, with the former preserved by three different methods (freezing, ethanol, and RNAlater) to validate self-collection. Within-subject microbial species, gene, and transcript abundances were highly concordant across sampling methods, with only a small fraction of transcripts (< 5%) displaying between-method variation. Next, we investigated relationships between the oral and gut microbial communities, identifying a subset of abundant oral microbes that routinely survive transit to the gut, but with minimal transcriptional activity there. Finally, systematic comparison of the gut metagenome and metatranscriptome revealed that a substantial fraction (41%) of microbial transcripts were not differentially regulated relative to their genomic abundances. Of the remainder, consistently underexpressed pathways included sporulation and amino acid biosynthesis, whereas up-regulated pathways included ribosome biogenesis and methanogenesis. Across subjects, metatranscriptional profiles were significantly more individualized than DNA-level functional profiles, but less variable than microbial composition, indicative of subject-specific whole-community regulation. The results thus detail relationships between community genomic potential and gene expression in the gut, and establish the feasibility of metatranscriptomic investigations in subject-collected and shipped samples. C1 [Franzosa, Eric A.; Morgan, Xochitl C.; Segata, Nicola; Waldron, Levi; Reyes, Joshua; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Franzosa, Eric A.; Morgan, Xochitl C.; Earl, Ashlee M.; Giannoukos, Georgia; Ciulla, Dawn; Gevers, Dirk; Garrett, Wendy S.; Huttenhower, Curtis] Broad Inst, Cambridge, MA 02142 USA. [Boylan, Matthew R.; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Izard, Jacques] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. [Izard, Jacques] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. RP Huttenhower, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM chuttenh@hsph.harvard.edu OI Izard, Jacques/0000-0002-5904-5436; Earl, Ashlee/0000-0001-7857-9145; Morgan, Xochitl/0000-0002-6264-6961; Segata, Nicola/0000-0002-1583-5794; Waldron, Levi/0000-0003-2725-0694 FU National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases [HHSN272200900018C]; NIH [R01 CA137178, P30 DK043351, P50 CA127003, R01 HG005969]; American Gastroenterological Association Gut Microbiome Pilot Research award; Danone Research [PLF-5972-GD]; National Science Foundation [DBI-1053486]; Army Research Office [W911NF-11-1-0473]; Center for the Study of Inflammatory Bowel Disease Pilot Study grant; Eric Larson and Barbara Wu Trust; [CA166150] FX We thank the participants in the Health Professionals Follow-up Study who graciously participated in this research; Elizabeth Frost-Hawes, Jill Arnold, and Siobhan Saint-Surin at the Harvard School of Public Health, who assisted with recruitment for this study; and James Bocchichio, Doyle Ward, Kimberly Kanki, Scott Mahan, and Erin Euler at the Broad Institute for their assistance in project logistics, sample handling, and nucleic acid extractions. This work was supported by National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases Contract HHSN272200900018C (to the Broad Institute); Grant CA166150 (to J.I.); Grants NIH R01 CA137178, P30 DK043351, and P50 CA127003, and an American Gastroenterological Association Gut Microbiome Pilot Research award (to A. T. C.); Danone Research PLF-5972-GD (to W. S. G.); NIH Grant R01 HG005969, National Science Foundation Grant DBI-1053486, Army Research Office Grant W911NF-11-1-0473, and a Center for the Study of Inflammatory Bowel Disease Pilot Study grant (to C. H.); and in part by the generous support of the Eric Larson and Barbara Wu Trust. A.T.C. is a Damon Runyon Clinical Investigator. NR 39 TC 92 Z9 93 U1 9 U2 145 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 3 PY 2014 VL 111 IS 22 BP E2329 EP E2338 DI 10.1073/pnas.1319284111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI2KY UT WOS:000336687900014 PM 24843156 ER PT J AU Liew, CW Assmann, A Templin, AT Raum, JC Lipson, KL Rajan, S Qiang, GF Hu, J Kawamori, D Lindberg, I Philipson, LH Sonenberg, N Goldfine, AB Stoffers, DA Mirmira, RG Urano, F Kulkarni, RN AF Liew, Chong Wee Assmann, Anke Templin, Andrew T. Raum, Jeffrey C. Lipson, Kathryn L. Rajan, Sindhu Qiang, Guifen Hu, Jiang Kawamori, Dan Lindberg, Iris Philipson, Louis H. Sonenberg, Nahum Goldfine, Allison B. Stoffers, Doris A. Mirmira, Raghavendra G. Urano, Fumihiko Kulkarni, Rohit N. TI Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic beta cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ER stress; prohormone; bIRKO; GWAS ID DISPROPORTIONATELY ELEVATED PROINSULIN; DEPENDENT DIABETES-MELLITUS; ELEMENT-BINDING PROTEIN-1C; ENDOPLASMIC-RETICULUM; SUBTILISIN FAMILY; PLASMA-INSULIN; MICE; RESISTANCE; GLUCOSE; STRESS AB Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of beta-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying beta-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in beta cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulinresistant states. C1 [Liew, Chong Wee; Assmann, Anke; Hu, Jiang; Kawamori, Dan; Goldfine, Allison B.; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02215 USA. [Liew, Chong Wee; Assmann, Anke; Hu, Jiang; Kawamori, Dan; Goldfine, Allison B.; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Liew, Chong Wee; Qiang, Guifen] Univ Illinois, Dept Physiol & Biophys, Chicago, IL 60612 USA. [Templin, Andrew T.; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Raum, Jeffrey C.; Stoffers, Doris A.] Univ Penn, Perelman Sch Med, Dept Med Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Raum, Jeffrey C.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Lipson, Kathryn L.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Rajan, Sindhu; Philipson, Louis H.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Lindberg, Iris] Univ Maryland, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada. [Urano, Fumihiko] Washington Univ, Sch Med, Dept Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA. RP Liew, CW (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02215 USA. EM cwliew@uic.edu; rohit.kulkarni@joslin.harvard.edu FU National Institutes of Health (NIH) [RO1 DK67536]; Juvenile Diabetes Research Foundation [17-2011-644]; NIH [K99 DK090210, R00 DK090210, RO1 DK 049703, DA05084, RO1 DK 048494, P01 DK049210, R01 DK068157, 1RL9EB008539-01, KO1 DK075706-01A1]; American Diabetes Association [1-06-CD-07]; Diabetes Research Center Advanced Microscopy and Proteomics Cores (NIH) [DK 5P30 DK36836]; Joslin Specialized Assay Core; University of Chicago Diabetes Research and Training Center [P60 DK020595]; Juvenile Diabetes Research Foundation FX We thank L. Fricker, PhD (Albert Einstein College of Medicine); D. F. Steiner, MD (The University of Chicago); C. R. Kahn, MD, and S. Bonner-Weir, PhD (Joslin Diabetes Center); and E. Nillni, PhD (Brown University) for discussions. We thank E. Morgan and K. Parlee for excellent assistance with preparation of the manuscript; E. Feener, PhD, for assistance with MS analyses; C. Cahill for assistance with EM; H. Welters, PhD (Joslin Diabetes Center) and C. J. Rhodes, PhD, and P. Moore (The University of Chicago Kovler Diabetes Center) for assistance with HPLC analyses; B. Hambro and R. Martinez (Joslin Diabetes Center) for assistance with the mouse colony; and S. Liu, PhD, and C. Hinault, PhD (Joslin Diabetes Center) for technical assistance. This work was supported by National Institutes of Health (NIH) Grant RO1 DK67536 and Juvenile Diabetes Research Foundation Grant 17-2011-644 (to R.N.K.), NIH Grants K99 DK090210 and R00 DK090210 (to C. W. L.), NIH Grants RO1 DK 049703 and DA05084 (to I. L.), NIH Grant RO1 DK 048494 (to L. H. P.), NIH Grants P01 DK049210 and R01 DK068157 (to D. A. S.), American Diabetes Association Grant 1-06-CD-07 (to A. B. G.), the Diabetes Research Center Advanced Microscopy and Proteomics Cores (NIH Grant DK 5P30 DK36836), and the Joslin Specialized Assay Core. C. W. L. was supported by NIH Interdisciplinary Training Grant 1RL9EB008539-01 (System-based Consortium for Organ Design & Engineering) and NIH Pathway to Independence Award K99 DK090210. S. R. was supported by NIH Career Award KO1 DK075706-01A1, and L. P. H. was supported by The University of Chicago Diabetes Research and Training Center Grant P60 DK020595 and the Juvenile Diabetes Research Foundation. NR 66 TC 9 Z9 10 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 3 PY 2014 VL 111 IS 22 BP E2319 EP E2328 DI 10.1073/pnas.1323066111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI2KY UT WOS:000336687900013 PM 24843127 ER PT J AU Naik, AD McCullough, LB AF Naik, Aanand D. McCullough, Laurence B. TI Health Intuitions Inform Patient-Centered Care SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID MANAGEMENT C1 [Naik, Aanand D.] Michael E DeBakey VA Med Ctr, Houston Ctr Innovat Qual Effectiveness & Safety I, Houston, TX 77030 USA. [Naik, Aanand D.; McCullough, Laurence B.] Baylor Coll Med, Houston, TX 77030 USA. RP Naik, AD (reprint author), Michael E DeBakey VA Med Ctr 152, Houston Ctr Innovat Qual Effectiveness & Safety, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM anaik@bcm.edu FU Houston Center for Innovations in Quality, Effectiveness and Safety [CIN 13-413] FX This work was supported in part by the Houston Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413). NR 7 TC 5 Z9 5 U1 0 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUN 3 PY 2014 VL 14 IS 6 BP 1 EP 3 DI 10.1080/15265161.2014.915650 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AH1EK UT WOS:000335862400001 PM 24809597 ER PT J AU Baek, JH Kang, ES Fava, M Mischoulon, D Nierenberg, AA Yu, BH Lee, D Jeon, HJ AF Baek, Ji Hyun Kang, Eun-Suk Fava, Maurizio Mischoulon, David Nierenberg, Andrew A. Yu, Bum-Hee Lee, Dongsoo Jeon, Hong Jin TI Serum lipids, recent suicide attempt and recent suicide status in patients with major depressive disorder SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE LDL; Lipid; Major depressive disorder; Suicide; Triglycerides; VLDL ID CORONARY-HEART-DISEASE; TRIGLYCERIDE LEVELS; CHOLESTEROL LEVELS; RISK-FACTORS; PLASMA; MOOD; ASSOCIATION; VALIDATION; INPATIENTS; BEHAVIOR AB Objective: Major depressive disorder (MDD) is associated with suicide. Although several studies have reported its association with low serum lipid, few studies have investigated relationships between current suicidality and lipid profiles, comparing with other blood measures in MDD patients. Methods: The study population consisted of 555 subjects with MDD who were >= 18 years old, evaluated by the Mini International Neuropsychiatric Interview (MINI) with the suicidality module. At the evaluation visit, we measured serum lipid profiles including total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL), and blood measures such as fasting glucose, total protein, albumin, blood urea nitrogen, creatinine, thyroid hormones, red and white blood cells, platelet count, hemoglobin, and hematocrit. Results: Recent attempters who had attempted suicide within the past month showed significantly lower TG and higher HDL levels than lifetime and never attempters, using Tukey's post-hoc analysis. Recent attempters exhibited lower TG and higher HDL than those with recent suicide ideation and wish to self-harm and those without previous attempt. Linear regression analysis revealed that TG was negatively associated with current suicidality scores (beta = -0.187, p = 0.039), whereas VLDL was positively associated with the recent suicide status (beta = 0.198, p = 0.032) after controlling for age and sex. There were no significant differences between the groups in terms of other serum lipid profiles and blood measures. Conclusions: Low serum TG, high HDL and VLDL levels are associated with recent suicide attempt or recent suicide status in patients with MDD. (C) 2014 Elsevier Inc. All rights reserved. C1 [Baek, Ji Hyun; Yu, Bum-Hee; Lee, Dongsoo; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul 135710, South Korea. [Jeon, Hong Jin] SAIHST, Seoul, South Korea. [Fava, Maurizio; Mischoulon, David; Nierenberg, Andrew A.; Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Kang, Eun-Suk] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med, Seoul, South Korea. [Baek, Ji Hyun; Nierenberg, Andrew A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bipolar Clin, Boston, MA USA. [Baek, Ji Hyun; Nierenberg, Andrew A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Res Program, Boston, MA USA. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, 50 Irwon Dong, Seoul 135710, South Korea. EM jeonhj@skku.edu FU National Research Foundation of Korea (NRF); Samsung Biomedical Research Institute Grant (SBRI) FX Funding for this study was provided by the National Research Foundation of Korea (NRF) and Samsung Biomedical Research Institute Grant (SBRI). They 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 33 TC 14 Z9 14 U1 3 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUN 3 PY 2014 VL 51 BP 113 EP 118 DI 10.1016/j.pnpbp.2014.01.018 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AD4YL UT WOS:000333257800017 PM 24495778 ER PT J AU Wen, XH Dizhoor, AM Makino, CL AF Wen, Xiao-Hong Dizhoor, Alexander M. Makino, Clint L. TI Membrane guanylyl cyclase complexes shape the photoresponses of retinal rods and cones SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Review DE guanylate cyclase; guanylyl cyclase activating protein; Ca2+ feedback; Ca2+-binding protein; photo-transduction; rod and cone photoreceptors; knockout mouse; neuronal calcium sensors ID MONKEY MACACA-FASCICULARIS; ACTIVATING PROTEINS GCAPS; PHOTORECEPTOR OUTER SEGMENTS; SPECTRAL SENSITIVITY; KNOCKOUT MICE; MOLECULAR-CLONING; TIGER SALAMANDER; LIGHT RESPONSE; DARK NOISE; IN-VIVO AB In vertebrate rods and cones, photon capture by rhodopsin leads to the destruction of cyclic GMP (cGMP) and the subsequent closure of cyclic nucleotide gated ion channels in the outer segment plasma membrane. Replenishment of cGMP and reopening of the channels limit the growth of the photon response and are requisite for its recovery. In different vertebrate retinas, there may be as many as four types of membrane guanylyl cyclases (GCs) for cGMP synthesis. Ten neuronal Ca2+ sensor proteins could potentially modulate their activities. The mouse is proving to be an effective model for characterizing the roles of individual components because its relative simplicity can be reduced further by genetic engineering. There are two types of GC activating proteins (GCAPs) and two types of GCs in mouse rods, whereas cones express one type of GCAP and one type of GC. Mutant mouse rods and cones bereft of both GCAPs have large, long lasting photon responses. Thus, GCAPs normally mediate negative feedback tied to the light-induced decline in intracellular Ca2+ that accelerates GC activity to curtail the growth and duration of the photon response. Rods from other mutant mice that express a single GCAP type reveal how the two GCAPs normally work together as a team. Because of its lower Ca2+ affinity, GCAP1 is the first responder that senses the initial decrease in Ca2+ following photon absorption and acts to limit response amplitude. GCAP2, with a higher Ca2+ affinity, is recruited later during the course of the photon response as Ca2+ levels continue to decline further. The main role of GCAP2 is to provide for a timely response recovery and it is particularly important after exposure to very bright light. The multiplicity of GC isozymes and GCAP homologs in the retinas of other vertebrates confers greater flexibility in shaping the photon responses in order to tune visual sensitivity, dynamic range and frequency response. C1 [Wen, Xiao-Hong; Makino, Clint L.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Wen, Xiao-Hong; Makino, Clint L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Dizhoor, Alexander M.] Salus Univ, Dept Basic Sci Res, Elkins Pk, PA USA. [Dizhoor, Alexander M.] Salus Univ, Penn Coll Optometry, Elkins Pk, PA USA. RP Wen, XH (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. EM wenx@meei.harvard.edu OI Makino, Clint/0000-0002-6005-9069 FU Howe Laboratory Endowment of the Massachusetts Eye and Ear Infirmary, Research to Prevent Blindness, National Eye Institute [EY014104, EY011522] FX This work was supported by the Howe Laboratory Endowment of the Massachusetts Eye and Ear Infirmary, Research to Prevent Blindness, National Eye Institute EY014104, EY011522. Alexander M. Dizhoor is the Martin and Florence Hatter Chair Professor of Pharmacology. The authors bear sole responsibility for the contents herein. The views expressed do not necessarily convey those of the National Eye Institute. NR 77 TC 15 Z9 15 U1 1 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD JUN 2 PY 2014 VL 7 AR 45 DI 10.3389/fnmol.2014.00045 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AZ2KA UT WOS:000348061400001 PM 24917784 ER PT J AU Adler, D Schmidt, CM Al-Haddad, M Barthel, JS Ljung, BM Merchant, NB Romagnuolo, J Shaaban, AM Simeone, D Pitman, MB Layfield, LJ AF Adler, Douglas Schmidt, C. Max Al-Haddad, Mohammad Barthel, James S. Ljung, Britt-Marie Merchant, Nipun B. Romagnuolo, Joseph Shaaban, Akram M. Simeone, Diane Pitman, Martha Bishop Layfield, Lester J. TI Clinical evaluation, imaging studies, indications for cytologic study and preprocedural requirements for duct brushing studies and pancreatic fine-needle aspiration: The Papanicolaou Society of Cytopathology Guidelines SO CYTOJOURNAL LA English DT Article DE Bile duct; cytology; fine-needle aspiration; guidelines; indications; pancreas; primary sclerosing cholangitis ID PHASE HELICAL CT; INTERNATIONAL CONSENSUS GUIDELINES; PRIMARY SCLEROSING CHOLANGITIS; PAPILLARY MUCINOUS NEOPLASMS; EUS-GUIDED FNA; COMPUTED-TOMOGRAPHY; INFORMED-CONSENT; ENDOSCOPIC ULTRASONOGRAPHY; SPIRAL CT; MR CHOLANGIOPANCREATOGRAPHY AB The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreaticobiliary cytology including indications for endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) biopsy, techniques for EUS-FNA, terminology and nomenclature to be used for pancreaticobiliary disease, ancillary testing and postbiopsy management. All documents are based on expertise of the authors, literature review, discussions of the draft document at national and international meetings and synthesis of online comments of the draft document. This document selectively presents the results of these discussions. This document summarizes recommendations for the clinical and imaging work-up of pancreatic and biliary tract lesions along with indications for cytologic study of these lesions. Prebrushing and FNA requirements are also discussed. C1 [Adler, Douglas] Univ Utah, Sch Med, Dept Internal Med, Div Gastroenterol, Indianapolis, IN USA. [Schmidt, C. Max] Indiana Univ Sch Med, Dept Surg & Biochem Mol Biol, Indianapolis, IN 46202 USA. [Al-Haddad, Mohammad] Indiana Univ, Dept Med, Div Gastroenterol, Indianapolis, IN USA. [Barthel, James S.] Florida Digest Hlth Specialists, Bradenton, FL USA. [Ljung, Britt-Marie] Univ Calif San Francisco, Dept Pathol & Lab Med, San Francisco, CA 94143 USA. [Merchant, Nipun B.] Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. [Romagnuolo, Joseph] Med Univ S Carolina, Dept Med, Div Gastroenterol, Charleston, SC 29425 USA. [Shaaban, Akram M.] Univ Utah, Sch Med, Dept Radiol, Salt Lake City, UT USA. [Simeone, Diane] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Pitman, Martha Bishop] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Layfield, Lester J.] Univ Missouri, Dept Pathol & Anat Sci, Columbia, MO 65211 USA. RP Layfield, LJ (reprint author), Univ Missouri, Dept Pathol & Anat Sci, Columbia, MO 65211 USA. EM douglas.Adler@hsc.utah.edu; maxschmi@iupui.edu; malhaddad@iupui.edu; docbarthel@yahoo.com; britt-marie.ljung@ucsf.edu; nipun.merchant@vanderbilt.edu; romagnuo@musc.edu; akram.shaaban@hsc.utah.edu; simeone@umich.edu; mpitman@partners.org; layfieldl@health.missouri.edu NR 68 TC 1 Z9 1 U1 0 U2 4 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0974-5963 EI 1742-6413 J9 CYTOJOURNAL JI CytoJournal PD JUN 2 PY 2014 VL 11 AR 1 DI 10.4103/1742-6413.133326 PG 8 WC Pathology SC Pathology GA AO3QV UT WOS:000341249800001 PM 25191515 ER EF